Physiol Rev 88: 1119 –1182, 2008;
doi:10.1152/physrev.00020.2007.
Physiology and Pathophysiology of Potassium Channels
in Gastrointestinal Epithelia
DIRK HEITZMANN AND RICHARD WARTH
Institute of Physiology and Clinic and Policlinic for Internal Medicine II, Regensburg, Germany
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I. Introduction
A. K⫹ channel families, structures, and expression profiles along the gastrointestinal tract
B. 6/7TM-1P channels
C. 4TM-2P channels (K2P)
D. 2TM-1P channels
E. Ways of K⫹ channel regulation
F. Expression of K⫹ channels in gastrointestinal epithelial cells
G. Multifaceted functions of epithelial K⫹ channels
II. K⫹ Channels Acting in Concert With H⫹-K⫹-ATPase in Gastric Parietal Cells
A. Histology of gastric mucosa
B. Composition of gastric juice
C. Cellular mechanisms of HCl secretion by parietal cells
D. Basolateral K⫹ channels of parietal cells
E. Luminal K⫹ channels of parietal cells
F. Bicarbonate secretion of surface cells in gastric mucosa
III. Transport Across the Epithelium of the Small Intestine
A. Mechanisms of Cl⫺ secretion in crypts of small intestine
B. Bicarbonate secretion in small intestinal villus cells
C. Function of K⫹ channels for reabsorption and secretion in small intestine
IV. K⫹ Channel of the Large Intestine
A. Anatomy of the colon
B. Pathways of luminal K⫹ secretion
C. Role of K⫹ channels for Cl⫺ secretion in colonic crypt cells
D. Do K⫹ channels influence cell fate, proliferation, and carcinogenesis?
V. Exocrine Pancreas and Salivary Glands: Paradigms for Exocrine Secretion
A. Enzyme and Cl⫺ secretion in pancreatic acinar cells
B. Role of the K⫹ conductance for bicarbonate secretion in pancreatic ducts
C. Fluid and electrolyte secretion in salivary glands
D. Formation of primary saliva by acinus cells
E. Modification of the primary saliva by duct epithelia
VI. Conclusions and Perspectives
Heitzmann D, Warth R. Physiology and Pathophysiology of Potassium Channels in Gastrointestinal Epithelia.
Physiol Rev 88: 1119 –1182, 2008; doi:10.1152/physrev.00020.2007.—Epithelial cells of the gastrointestinal tract are an
important barrier between the “milieu interne” and the luminal content of the gut. They perform transport of
nutrients, salts, and water, which is essential for the maintenance of body homeostasis. In these epithelia, a variety
of K⫹ channels are expressed, allowing adaptation to different needs. This review provides an overview of the
current literature that has led to a better understanding of the multifaceted function of gastrointestinal K⫹ channels,
thereby shedding light on pathophysiological implications of impaired channel function. For instance, in gastric
mucosa, K⫹ channel function is a prerequisite for acid secretion of parietal cells. In epithelial cells of small intestine,
K⫹ channels provide the driving force for electrogenic transport processes across the plasma membrane, and they
are involved in cell volume regulation. Fine tuning of salt and water transport and of K⫹ homeostasis occurs in
colonic epithelia cells, where K⫹ channels are involved in secretory and reabsorptive processes. Furthermore, there
is growing evidence for changes in epithelial K⫹ channel expression during cell proliferation, differentiation,
apoptosis, and, under pathological conditions, carcinogenesis. In the future, integrative approaches using functional
and postgenomic/proteomic techniques will help us to gain comprehensive insights into the role of K⫹ channels of
the gastrointestinal tract.
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0031-9333/08 $18.00 Copyright © 2008 the American Physiological Society
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I. INTRODUCTION
A. Kⴙ Channel Families, Structures, and
Expression Profiles Along the Gastrointestinal
Tract
B. 6/7TM-1P Channels
Forty different genes of the human genome comprise
the large group of voltage-gated K⫹ channels (200, 201):
Physiol Rev • VOL
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Origin of the channel names: “Shaker”: Drosophila melanogaster
carrying a mutated “shaker” channel gene exhibited shaking behavior
when recovering from diethylether anesthesia (471); “Shab”: Shaker
cognate B; “Shaw” Shaker cognate W; “Shal” Shaker cognate L (61);
“EAG” (ether à go-go gene): flies carrying a mutated “eag” channel gene
exhibited movements during recovery from diethylether anesthesia
which were reminiscent of dancers at the “Whisky-à-Go-Go” night club
(West Hollywood) (276, 673); “ERG”: “ether à go-go related gene” (658);
“ELK”: “ether à go-go like gene” (658); “Slo” (slowpoke): a slow, noninactivating Ca2⫹-dependent K⫹ current orignally descirbed in flies (16,
129).
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The major tasks of the epithelia of the gastrointestinal tract are mass transport of salt, solutes, and water
across epithelial cells which serve as barrier function
between the “milieu interne” and the “milieu externe.” To
perform such mass transport of nutrients, chemical and
electrical gradients are used as driving forces for salt and
solute transport mechanisms. Those gradients are established by the activity of the basolateral Na⫹-K⫹-ATPase
and epithelial K⫹-selective ion channels which hyperpolarize the plasma membrane thereby “charging the battery” for electrically driven transport. This review provides an overview of the molecular and functional diversity of K⫹ channels in epithelia of the gastrointestinal
tract with focus on the physiological role of K⫹ channels.
K⫹ channels form the largest group of ion channels in
the human genome. Unfortunately, the nomenclature of
K⫹ channels is rather confusing and redundant, e.g., for
many K⫹ channels four to six different aliases can be
found in the literature. At present, two “competing” K⫹
channel classifications systems exist, encompassing all
genes of pore-forming K⫹ channel subunits: one is published by the “Human Genome Organization” (HUGO;
http://www.gene.ucl.ac.uk/nomenclature/genefamily/kcn.php), and the other one by the “International Union of
Pharmacology” (IUPHAR; http://www.iuphar-db.org/
iuphar-ic/index.html). For this review, we have decided to
use the nomenclature proposed by HUGO because the
“KCN” names allow quick access to information of transcriptome and gene databases hosted by the “National
Center for Biotechnology Information” (NCBI; http://www.ncbi.nlm.nih.gov/). The “KCN” nomenclature of human
K⫹ channel genes comprises 78 genes with the “P loop”
signature of pore-forming ␣-subunits and 13 genes for
␤-subunits. Based on the similarity in the amino acid
sequence and functional properties, the genes of poreforming subunits can be subdivided into three large families (Fig. 1): 1) channel subunits with six or seven transmembrane domains and one pore loop (6/7TM-1P): voltage-gated and Ca2⫹-activated K⫹ channels; 2) channel
subunits with four transmembrane domains and two pore
loops (4TM-2P): K2P channels; and 3) channel subunits
with two transmembrane domains and one pore loop
(2TM-1P): inwardly rectifying K⫹ channels.
KCNA “Shaker”;1 KCNB “Shab”; KCNC “Shaw”; KCND
“Shal”; KCNH “EAG, ERG, ELK”; and “modifiers” (KCNF,
KCNG, KCNS, KCNV), which do not form functional channels as homomers (Fig. 1). Structurally, they are characterized by six (in the case of “Slo” family by 7) transmembrane domains and one pore-forming loop (6/7TM-1P),
and they assemble into tetramers to build functional channels (376). Voltage-gated K⫹ channels are preferentially
expressed in excitable cells, where they have an essential
role for rapid repolarization of the plasma membrane
during the action potential. Interestingly, expression of
voltage-gated K⫹ channels is not restricted to excitable
cells, but they are also found in nonexcitable cells such as
the epithelia of the gastrointestinal tract. In epithelial
cells of the gastrointestinal tract, they are implicated in a
variety of cellular functions, e.g., electrolyte and substrate
transport, cell volume regulation, cell migration, wound
healing, proliferation, apoptosis, carcinogenesis, and oxygen-sensing (456). Among those epithelial voltage-gated
K⫹ channels, KCNQ1 shows the highest levels of expression. Interestingly, KCNQ1 assembles in epithelia predominantly with ␤-subunits which convert the voltagedependent KCNQ1 into a voltage-independent, constitutively open channel complex (549).
In addition to the group of voltage-gated channels,
the family of 6/7TM-2P channels includes two subfamilies
of Ca2⫹-activated channels, the small- to intermediateconductance K⫹ channels (KCNN1– 4), and the family
“SLO”-type large-conductance channels (KCNMA1,
KCNT1–2, KCNU1). In the pore-forming ␣-subunit KCNMA1 (MaxiK), cytosolic Ca2⫹ activity is directly sensed
by a distinct domain of the tail of the channel protein, the
so-called “Ca2⫹ bowl” (20, 668). The other members of the
“SLO” family, although structurally closely related to KCNMA1, do not show the same mechanism of Ca2⫹ regulation. In contrast to the “Ca2⫹ bowl” of KCNMA1, in KCNN
channels the Ca2⫹ sensor is not located in the ␣-subunit
itself; the Ca2⫹ sensitivity is caused by tight coupling of
the channel protein to calmodulin (calmodulin acts as a
␤-subunit of these channels) which results in functional
channels with a very steep Ca2⫹ dependence (134, 269,
557, 676).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
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C. 4TM-2P Channels (K2P)
K2P channels are characterized by four transmembrane segments and two interspersed P loops between
TM1 and -2 and TM3 and -4, respectively (tandem of two
P-domains). The first members of this channel family have
been identified in Saccharomyces cerevisiae and Caenorhabditis elegans in 1995 (280), followed by the first
mammalian member which was named “TWIK1” for “Tandem of P domains in a Weak Inward rectifying K⫹ channel” in 1996 (340). In the human genome, the family of 4
transmembrane and 2-P domains K⫹ channels (4TM-2P)
encompasses 15 members. Most likely, the channel proteins form dimers to build functional channels (341). They
are believed to contribute to the background K⫹ conductance under resting conditions in many tissues (342). K2P
channels are regulated by a variety of stimuli, e.g., KCNK1
and KCNK6 are activated by protein kinase C and inhibited by internal acidification (74, 341); KCNK2, KCNK4,
and KCNK10 are mechano-sensitive channels and stimuPhysiol Rev • VOL
lated by arachidonic acid (381, 382); KCNK3 and KCNK9
are regulated by hypoxia (probably in an indirect and
system-specific way) (56, 267, 335, 499, 641); and several
members of the K2P channel family show activation upon
external alkalinization (126, 127, 274, 430, 518) (Fig. 1).
K2P channels in the central nervous system can be stimulated by volatile anesthetics like halothane (194, 483,
605), thereby silencing neuronal activity. K2P channels
are supposed to be involved in various physiological and
pathological processes, e.g., renal bicarbonate transport
(661), general anesthesia (227, 483), neuroprotection
(227), depression (228), pain sensation (9), oxygen sensing (56), apoptosis, and carcinogenesis (484). Although
abundant evidence from animal models suggests that K2P
channels have also important functions in humans, so far
no direct link between mutations of K2P channels and
human disease has been established. An overview on this
group of channels is provided by several excellent reviews (26, 235, 343, 482, 484, 690) and is available on the
internet (http://www.ipmc.cnrs.fr/⬃duprat/).
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⫹
FIG. 1. “KCN” K channel families. Phylogenetic tree of human K⫹ channels using the
“KCN” nomenclature of the “Human Genome
Organization.” For simplicity, the letter code for
K⫹ channels (KCN) has been omitted (e.g.,
KCNA1 is depicted as A1). The tree has been
constructed
using
“UPGMA”
(http://
bibiserv.techfak.uni-bielefeld.de/dialign/) based
on DIALIGN fragment weight scores on fulllength protein sequences. In case of splice variants, transcript variant 1 (according to NCBI)
has been used for the alignment.
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DIRK HEITZMANN AND RICHARD WARTH
D. 2TM-1P Channels
E. Ways of Kⴙ Channel Regulation
1. Membrane voltage
The effect of changes of the membrane voltage on the
open probability represents the most important way to
regulate channel activity of “voltage-gated K⫹ channels.”
Recently, the structural basis of voltage-sensing has been
addressed in a large number of studies using a variety of
different techniques, e.g., cysteine scans and X-ray analysis of crystallized channel proteins. In those tetrameric
K⫹ channels, the pore domain is built by transmembrane
Physiol Rev • VOL
2. Phosphorylation
A key feature of cellular signal transduction is the
activation of protein kinases which change the function of
target proteins by phosphorylation. K⫹ channels have
been found to be modified by a variety of protein kinases,
e.g., protein kinase A, protein kinase C, Ca2⫹/calmodulindependent kinases, tyrosine kinases, serum- and glucocorticoid-inducible kinases, and WNK [With-NoK(lysine)] kinases (133, 346, 350, 477).
3. Modification of the channel protein
For several K⫹ channels, covalent ubiquitin conjugation has been described as a way to modify channel
activity by changing its surface expression (please refer to
point 14). Recently, small ubiquitin-related modifier proteins (SUMOs) have also been reported to regulate channel function and biophysical properties of K⫹ channels
(31, 506). However, the significance of sumoylation as a
K⫹ channel-regulating protein modification is still a matter of debate (139).
4. Cytosolic Ca2⫹
Cytosolic Ca2⫹ activity is one of the most important
second messengers, e.g., it couples activation of receptors
or action potentials to specific cellular effector mechanisms such as activation of enzymes, exocytosis of transmitter-containing vesicles, muscle contraction, fluid and
enzyme secretion, gene transcription, changes of ion conductances, etc. The open probability of very many K⫹
channels is directly or indirectly regulated by changes in
cytosolic Ca2⫹ ranging from rather small changes of current amplitude to steep dependence of open probability
on cytosolic Ca2⫹ activity. Among these channels, members of the KCNN subfamily and KCNMA1 exhibit the
most impressive Ca2⫹ dependence (190). Similar to KCNN
channels, members of the KCNQ family apparently interact with calmodulin; however, the Ca2⫹ dependence is
less prominent compared with KCNN channels (166, 174,
568).
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The 15 members of the 2TM-1P family are characterized by only two transmembrane domains: one pore loop
and, as the most prominent biophysical feature, by inward
rectification (306). Like voltage-gated K⫹ channels, functional 2TM-1P channels are believed to be tetramers. Several inward rectifiers have important physiological roles,
and gene mutations have been linked to human diseases.
Renal KCNJ1 channels are crucial for luminal K⫹ recycling in the thick ascending loop of Henle. Mutations of
KCNJ1 (ROMK) can cause the salt-wasting “Bartter syndrome” (OMIM 600359, Ref. 576). Mutations in the gene of
KCNJ2 are related to Andersen’s syndrome, which is characterized by cardiac arrhythmia, periodic paralysis, and
dysmorphic features (OMIM 170390, Refs. 30, 500). KCNJ8
channels are relevant for establishing physiological vascular tonus. KCNJ8 knockout mice show a phenotype
similar to that of vasospastic “Prinzmetal” angina (OMIM
600935, Ref. 419); KCNJ11 associates with the sulfonylurea receptor (SUR) to form the ATP-sensitive K⫹ channel of insulin-producing ␤-cells of the islets of Langerhans: loss of function mutations of KCNJ11 have been
found in patients suffering from hyperinsulinemic hypoglycemia (OMIM 600937, Ref. 617).
The large number of different K⫹ channel genes provides the basis for the precise adjustment of the K⫹
conductance to the cellular needs in various tissues. For
several reasons, however, the diversity of K⫹ channels in
native cells is even much larger than suggested just by the
number of different channel genes: alternative splicing of
mRNA, heteromeric assembly of subunits, and association with proteins not classified as members of the “KCN”
gene family enlarge the variability of native K⫹ channels.
In addition, several regulatory pathways and modifications of channel proteins can lead to dramatic changes of
biophysical properties and membrane localization,
thereby broadening functional diversity. Such multifaceted regulation comprises phosphorylation events (133,
346), ubiquitinylation (180, 225, 608), sumoylation (31,
506), palmitoylation (197, 603), and interaction with lipids
(198, 344, 462).
helices 5 and 6 with the linker between both (pore loop)
lining the conduction pathway. As a typical feature of
voltage-sensitive K⫹ channels, the positively charged
fourth transmembrane domain plays an important role in
voltage-sensing. From the pioneering work of Roderick
MacKinnon, who was the first performing X-ray analysis
of crystallized K⫹ channels (120), we have already excellent information about the structure of the crystallized
channels (262). However, the dynamic structure of the
channel protein in native membranes and the precise
mechanism of channel activation by depolarizing voltages
are still a matter of debate (5, 32, 263, 361, 601).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
5. Internal pH
⫹
6. External pH
In many tissues, K⫹ channels have been found that
are regulated by changes of the extracellular pH. Most of
the channels showing very strong and steep regulation by
external pH belong to the family of 2-P-domain channels:
KCNK2 (TREK1), KCNK3 (TASK1), KCNK4 (TRAAK),
KCNK5 (TASK2), KCNK9 (TASK3), KCNK10 (TREK2),
KCNK16 (TALK1), KCNK17 (TALK2), and KCNK18
(TRESK). They all are characterized by the inhibition by
external acidification and activation by external alkalinization (127, 428, 430, 449, 509). In contrast, KCNE/
KCNQ1 channels exhibit a complex response to changes
of extracellular pH which is dependent on the assembling
␤-subunit, e.g., KCNE2/KCNQ1 is activated by acidic external pH and KCNE3/KCNQ1 is completely pH insensitive (154, 220, 491). Also members of the inward rectifier
family (2TM-1P) are activated by low extracellular pH
(388).
7. Modifiers leading to inward rectification
Inwardly rectifying K⫹ channels exhibit a higher conductance for inward than for outward currents. This fascinating phenomenon can be caused by relief of block by
Mg2⫹ or by polyamines such as spermine and spermidine
at negative membrane voltages (363, 639).
8. Other ions
Interestingly, several K⫹ channels are affected by
cytosolic Na⫹ activity, although those channels do not
conduct Na⫹. This type of regulation has been observed
for KCNK5 (TASK2) (429), Ca2⫹-activated K⫹ channels
(277), and voltage-dependent K⫹ channels (KCNB1)
(364). Moreover, “Slo-2”-type channels have been described to be activated by Na⫹ and by Cl⫺ (487, 691, 692).
composition of the membrane embedding the channel.
Several derivatives of lipids serve as specific regulators
(their action cannot be explained by changes of the fluidity of the membrane) which can have dramatic effects
on basic biophysical properties of the respective K⫹ channels, e.g., phosphatidylinositol-4,5-bisphosphate (PIP2),
ceramide and its derivatives, arachidonic acid and its
derivatives, lysophosphatidylcholine (LPC), and cholesterol (71, 78, 198, 215, 287, 318, 344, 367, 383, 462, 511, 648,
651, 652).
10. Hypoxia
K⫹ channels play an important role for sensing hypoxia in chemoreceptive cells of the carotid bodies or in
the lung. Several different types of K⫹ channels have been
shown to be modulated by hypoxia or hypoxia-induced
signals [e.g., via changes is cytosolic ATP (641), via
NADPH oxidase NOX4 (335), and via AMP-activated protein kinase (675)]: voltage-dependent K⫹ channels, MaxiK
channels, and TASK-like channels (408, 481, 489).
11. G proteins
The best known example of a regulation of K⫹ channel by G proteins is the activation of KACh K⫹ channels
(KCNJ3 and KCNJ5) (606) in the heart by pertussis toxinsensitive heterotrimeric G proteins that mediate the effect
of M2 muscarinic and A1-adenosine receptors (314). Similar regulation mechanisms have been found in a variety
of ion channels (54, 118, 688).
12. Cell swelling/shrinkage
A large variety of K⫹ channels are activated by cell
swelling, e.g., KCNN4 (669), KCNQ1 (191), and KCNK5
(448). Swelling-induced K⫹ channel activation then leads
to loss of K⫹ as an osmolyte (together with Cl⫺ or other
anions) and to regulatory volume decrease (215, 325).
13. Cell metabolism
In several cell types, K⫹ channel activity is coupled to
metabolic state and energy metabolism. In ␤-cells of endocrine pancreas, muscle cells, and glucose-sensing hypothalamic neurons, inward rectifier K⫹ channels are regulated by the ATP-to-ADP ratio (14, 444, 480). In epithelial
cells of renal proximal tubules and small intestine, basolateral K⫹ channel activity is regulated according to the
transport activity (especially the activity of the Na⫹-K⫹ATPase) and the metabolic state (185, 404, 555).
9. Lipids and derivatives
14. Membrane surface targeting/retrieval from the
membrane
Functional properties of a large number of K⫹ channels, perhaps of all channels, are dependent on the lipid
Mechanisms affecting targeting of the channel to the
plasma membrane or retrieval from have been shown to
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A large number of K channels are affected by internal pH changes, ranging from relatively slight changes of
biophysical properties (e.g., current amplitude of some
voltage-dependent channels, Ref. 635) up to dramatic
changes of open probability of some members of the
“inward rectifier” family (KCNJ). A prominent example of
the latter group of channels is the “renal outer medulla K⫹
channel” (ROMK or KCNJ1), whose pH regulation has
been analyzed in detail leading to the identification of
amino acid residues which presumably serve as pH sensors. Those channels are inhibited by cytosolic acidification and are activated by internal alkalinization, respectively (41, 513, 551).
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play a major role for the regulation of the epithelial Na⫹
channel (ENaC) which is removed from the membrane
after ubiquitin conjugation (384, 587). Apparently, K⫹
channel function is also dependent on insertion to and
removal from the surface membrane (366). Specific sorting and targeting to the membrane can be mediated by
signal motives of the pore-forming ␣-subunit, ubiquitylation (71, 225, 260, 349), and assembly with ␤-subunits and
adaptor proteins that modify surface localization of the
channel complex (80, 366, 507, 516, 519, 549, 622).
F. Expression of Kⴙ Channels in Gastrointestinal
Epithelial Cells
G. Multifaceted Functions of Epithelial Kⴙ
Channels
In gastrointestinal epithelia, K⫹ channels are involved in a plethora of different physiological and pathophysiological processes. From a general perspective, the
consequences of K⫹ channel activity encompass the electrical effect on the membrane potential and effects related
to the transport of K⫹ as an ion and osmolyte. Dependent
on the specific cellular context, epithelial K⫹ channels
serve the following tasks (Fig. 2).
Physiol Rev • VOL
In practically all living cells, K⫹ channels play a
pivotal role for generation and stabilization of a hyperpolarized membrane voltage. In epithelia, the hyperpolarized membrane voltage fuels so-called “secondary active”
electrogenic transport systems which transport substrates against a chemical gradient. For example, in renal
proximal tubular cells and enterocytes of small intestine,
specific transport proteins reabsorb glucose, neutral
amino acids, and other solutes together with Na⫹ across
the luminal membrane. The coupling of substrate transport to the influx of Na⫹ (driven by the electrical and
chemical gradient for Na⫹) provides a robust driving
force, which, e.g., allows the Na⫹/glucose cotransporter
of proximal tubular cells to build up a ⬎100-fold gradient
for glucose (42). On the other hand, the Na⫹ influx by
such systems depolarizes the membrane, thereby reducing the driving force of further transport. In this situation,
activation of K⫹ channels repolarizes the membrane and
restores the driving force for ongoing electrogenic transport. It is not surprising that the K⫹ conductance of
transporting epithelia is tightly coupled to transport activity. The coupling of transport activity and K⫹ conductance occurs via several mechanisms, e.g., activation by
depolarization of the membrane (voltage-dependent K⫹
channels); activation by intermediates of energy metabolism (ATP-sensitive K⫹ channels); intracellular signaling
such as pH, Ca2⫹, and other second messenger pathways;
and changes in cell volume and membrane stretch (122,
185, 378, 661).
2. Recycling of K⫹ across the plasma membrane
In epithelial cells K⫹ is accumulated within the cytosol predominantly via three transport proteins, Na⫹-K⫹ATPase, H⫹-K⫹-ATPase, and Na⫹-2Cl⫺-K⫹ cotransporter.
The resulting chemical K⫹ gradient is a prerequisite for
the establishment of the normal membrane voltage via K⫹
channels. On the other hand, those transport proteins
serve also other functions: the Na⫹-K⫹-ATPase is needed
to eliminate Na⫹ from the cytosol and thus absorbs K⫹,
H⫹-K⫹-ATPases are used to secrete H⫹, and Na⫹-2Cl⫺-K⫹
cotransporters serve the uptake of Na⫹ and Cl⫺ into the
cell. Sustained activity of Na⫹-K⫹- and H⫹-K⫹-ATPases
and Na⫹-2Cl⫺-K⫹ cotransporter requires a sufficient concentration of extracellular K⫹ which can become the
rate-limiting factor of transport activity (438, 627). Under
this condition, K⫹ channels can serve as an ideal pathway
for recycling of K⫹ across the membrane. The most evident example for the function of K⫹ channels as K⫹
recycling pathway is the gastric parietal cell, where acid
secretion by the H⫹-K⫹-ATPase is almost completely dependent on parallel export of K⫹ through luminal K⫹
channel (see below) (167).
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Central for the understanding of the functional relevance of K⫹ channels in native tissue is the knowledge of
their molecular nature and expression patterns. However,
a complete and detailed analysis of epithelial K⫹ channel
expression is not yet available. At present, three internet
databases are commonly used to evaluate gene expression: the EST-based “Unigene” database which provides
an “organized view of the transcriptome” (hosted by the
National Center for Biotechnology Information “NCBI”,
http://www.ncbi.nlm.nih.gov/entrez/
query.fcgi?db⫽unigene), and the gene array databases
“Gene Expression Omnibus” (hosted by the NCBI, http://
www.ncbi.nlm.nih.gov/geo/) and “GFN SymAtlas” [hosted
by the Genomics Institute of the Novartis Research Foundation (593), http://symatlas.gnf.org/SymAtlas/]. These databases provide very useful information about tissue-dependent gene expression. Besides technique-immanent
problems, the applicability of those data for epithelial
physiology is yet limited by the fact that the gastrointestinal tissues have been mostly harvested “in toto” for
those analyses including muscle layers, the enteric nervous tissue and other intrinsic cell types. Table 1 provides
an overview of expression and function of K⫹ channels in
the gastrointestinal tract. More comprehensive information from mainly hypothesis-driven experiments is discussed in the respective chapters on K⫹ channels of the
stomach, small intestine, colon, and pancreas (see below).
1. Regulation of membrane voltage and electrical
driving force
1.
Aliases
Stomach
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KCNA3 MK3, HLK3, Human: ⫹⫹ Human: ⫹ EST
HPCN3,
Localization:
KV1.3
gastric
cancer cell
lines.
Function:
regulation
of
proliferation.
P (321)
Intestine
Pancreas Acinus
Pancreas Duct
Voltage-gated channels, Shaker-related subfamily
Pancreas (total)
Mouse: ⫹⫹
Guinea pig:
⫹⫹ Canine:
⫹⫹ Rabbit:
⫹⫹
Localization:
interstitial
cells of Cajal
and colonic
mucosa.
Function:
regulating GI
motility, role
in mucosa is
not clear. P,
IF (209); IP,
IF, BA (193)
Canine: ⫹⫹
Rabbit: ⫹
Localization:
colonic
smooth
muscle cells
and colonic
mucosa.
Function:
regulating GI
motility, role
in mucosa is
not clear. N
(208); IP, IF,
BA (193)
Rabbit: ⫹⫹⫹ Human: ⫹⫹
Localization:
Localization:
basolateral
pancreatic
membrane of islets. IF, IS,
colonic crypt P (682); EST
cells.
Function:
role in
mucosa is
not clear. IP,
IF, BA (193)
Colon
Salivary Glands
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Physiol Rev • VOL
KCNA2 HK4, KV1.2
KCNA1 RBK1, HUK1, Rat: ⫹⫹
MBK1,
Localization:
KV1.1
gastric
epithelial
cell lines
Function:
regulation
of cell
proliferation.
P (674)
HUGO
Symbol
TABLE
OMIM
KCNA3 knockout mice
176263
weighed significantly less
than control littermates.
KCNA3 channels may
participate in pathways that
regulate body weight, and
channel inhibition may
increase basal metabolic
rate (678).
176262
KCNA1 knockout mice
176260
displayed frequent
spontaneous seizures
correlating on the cellular
level with alterations in
hippocampal excitability
and nerve conduction (581).
Episodic ataxia type I (55).
Pathophysiology/Disease
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1125
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
Aliases
Stomach
KCNAB1 AKR6A3,
KCNA1B,
Kv〉3,
Kvb1.3,
Kvb3
KCNA10 Kv1.8
KCNA7 HAK6, KV1.7
Human: ⫹
Mouse: ⫹
EST
KCNA5 HK2, HPCN1, Human: ⫹⫹
KV1.5
Mouse: ⫹
Localization:
gastric
cancer cell
lines.
Function:
regulation
of
proliferation?
P (321)
KCNA6 HBK2, KV1.6
KCNA4 HK1, HPCN2,
KV1.4
HUGO
Symbol
1—Continued
Intestine
Rat: ⫹⫹
Localization:
pancreatic
islets (␤-cell).
Function:
insulin
secretion? P
(374)
Human: ⫹ EST
Pancreas (total)
Pancreas Acinus
Pancreas Duct
Human: ⫹ EST Human: ⫹ EST
Voltage-gated channels, Shaker-related subfamily, ␤ members
Human: ⫹
Canine: ⫹⫹
Localization:
colonic
smooth
muscle cells.
Function:
regulation of
GI motility. N
(466); C
(156); EST
Mouse: ⫹
Rat: ⫹⫹
Localization:
Localization:
colonic
pancreatic
smooth
islets. P (374)
muscles
cells.
Function:
regulating GI
motility? P
(293)
Human: ⫹⫹
Mouse: ⫹⫹
Localization:
pancreatic
islets (␤cells).
Function:
insulin
secretion? IS
(273); IF, IS,
P (682)
Colon
Salivary Glands
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TABLE
Pathophysiology/Disease
601141
602420
176268
176257
176267
176266
OMIM
1126
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
Aliases
KCNC1 KV3.1
KCNB2 Kv2.2
KCNB1 KV2.1
KCNAB3 AKR6A9,
KCNA3B
KCNAB2 AKR6A5,
KCNA2B,
Kv␤2.1,
Kv␤2.2
HUGO
Symbol
Stomach
Pancreas (total)
Pancreas Acinus
Voltage-gated channels, Shab-related subfamily
Human: ⫹ EST
Human: ⫹ EST Human: ⫹ EST
Colon
Human: ⫹⫹
Localization:
pancreatic
islets (␣-cell).
Function:
glucagon
secretion? IF,
IS, P (682);
EST
Voltage-gated channels, Shaw-related subfamily
Human: ⫹⫹
Human: ⫹⫹⫹
Function:
Function:
regulating
regulating
neuronal activity
neuronal
and GI motility?
activity and
P (464)
GI motility?
P (464)
Mouse: ⫹ EST
Intestine
Human: ⫹⫹⫹
Mouse: ⫹
Localization:
pancreatic
islets (␤-cell)
Function:
insulin
secretion? P
(464); IF
(375); IF, IS,
P (682); EST
Human: ⫹⫹ Canine: ⫹⫹
Human: ⫹⫹
Human: ⫹⫹
Localization: Localization:
Canine: ⫹⫹
Localization:
gastric
colonic smooth
Localization:
pancreatic
cancer cell
muscle cells.
colonic
islets (␦lines.
Function:
smooth
cells).
Function:
regulation of GI
muscle cells.
Function:
regulation
motility? N, P
Function:
somatostatin
of
(544)
regulation of
secretion? IF,
proliferation?
GI motility?
IS, P (682)
P (321)
P (156); N, P
(544)
1—Continued
Pancreas Duct
Human: ⫹ EST
Salivary Glands
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TABLE
OMIM
176258
607738
600397
KCNAB2 knockout
601142
mice showed
reduced life spans,
occasional
seizures, and cold
swim-induced
tremors (409).
604111
Pathophysiology/Disease
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1127
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
KV4.1
KV4.2, RK5,
KIAA1044
KCND1
KCND2
KV3.4,
KSHIIIC
KV3.3
KCNC3
KCNC4
KV3.2
Aliases
KCNC2
HUGO
Symbol
1—Continued
Human: ⫹ Mouse:
⫹ EST
Intestine
Mouse: ⫹⫹
Human: ⫹ Mouse:
Localization: ⫹ Localization:
antral
jejunal smooth
smooth
muscle cells.
muscle
Function:
cells.
regulation of GI
Function:
motility? QP, IF
regulation
(11); EST
of GI
motility. P,
QP (10)
Mouse: ⫹⫹
Mouse: ⫹⫹
Localization: Localization:
antral
jejunal smooth
myocytes.
muscle cells.
Function:
Function:
gastric
regulation of GI
motility? P,
motility. QP, IF
IF (10);
(11)
EST
Human: ⫹
EST
Human: ⫹
Stomach
Pancreas (total)
Mouse: ⫹⫹
Localization:
pancreatic
acinar cells.
Function:
electrolyte
secretion?
IS(273)
Pancreas Acinus
Human: ⫹
Human: ⫹⫹
Mouse: ⫹⫹
Mouse: ⫹⫹
Localization:
NB, P (241)
colonic
smooth
muscle cells.
Function:
regulating GI
motility? QP,
IF (11); P
(293); EST
Human: ⫹
Human: ⫺
Mouse: ⫹⫹
Mouse: ⫹ P
Localization:
(698)
colonic
smooth
muscle cells.
Function:
regulating GI
motility. QP,
IF (11); P
(293); EST
Voltage-gated channels, Shal-related subfamily
Human: ⫹⫹
Mouse: ⫹
Localization:
pancreatic
islets (␤-cell).
Function:
insulin
secretion? IF,
IS, P (682)
Human: ⫹ EST Human: ⫹⫹
Localization:
not in
pancreatic
islets. IF, IS,
P (682)
Human: ⫹ EST Human: ⫹⫹
Mouse: ⫹⫹
Localization:
pancreatic
islets (␦cells).
Function:
somatostatin
secretion? IF
(181); IF, IS,
P (682); EST
Colon
Pancreas Duct
Salivary Glands
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TABLE
176256
OMIM
605410
300281
176265
Spinocerebellar
176264
ataxia(667).
Pathophysiology/Disease
1128
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
Aliases
KCNE1L KCNE5
KCNE1 minK, ISK,
JLNS2
KCND3 KV4.3,
KSHIVB
HUGO
Symbol
Stomach
Intestine
Colon
Pancreas (total)
Human: ⫺
Mouse:
⫹/⫺⫹ P
(183, 660);
NB (96);
EST
Pancreas Acinus
Human: ⫹ Mouse: Human: ⫹
⫺ Function:
Mouse: ⫹/⫺
electrolyte and
N (79); P
substrate
(660); NB
transport? N
(96); EST
(79); P (660);
NB (96)
Human: ⫺ Rat: Mouse: ⫹⫹ Rat: ⫹⫹
⫹⫹ N (79); P
Localization: not
(604)
clear, possible
association with
KCNQ1. Function:
electrolyte and
enzyme secretion?
F (284, 302, 663)
Voltage-gated channels, Isk-related family
Mouse: ⫹⫹ Human: ⫹⫹
Human: ⫹
Mouse: ⫹⫹
Localization: Mouse: ⫹⫹
Mouse: ⫹⫹
Localization:
antral
Localization:
Localization:
pancreatic
myocytes.
jejunal smooth
colonic
islets (␣Function:
muscle cells.
smooth
cells).
gastric
Function:
muscle cells.
Function:
motility? P,
regulating GI
Function:
glucagon
IF (10);
motility? P (64);
regulating GI
secretion? P
EST
QP, IF (11); P
motility. QP,
(64); NB, P
(293)
IF (11); P
(241); IF
(293); EST
(181)
1—Continued
Pancreas Duct
Pathophysiology/Disease
605411
OMIM
176261
Human: ⫹ Rat:
KCNE1 knockout
⫹⫹ Localization:
mice show
rat
impaired KCNQ1
submandibular
localization in
gland ducts. IF
pancreatic acinar
(596); EST
cells and altered
zymogen granula.
Loss of Na⫹ and
K⫹ via the
intestinal
epithelium,
hyperaldosteronism,
renal Na⫹ loss (12,
637, 660). Human
KCNE1 mutations
can cause “long QT
syndrome” (632).
Deletion of KCNE1L 300194
has been reported
to cause “AMME
contiguous gene
syndrome” (498).
Salivary Glands
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TABLE
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1129
Physiol Rev • VOL
88 • JULY 2008 •
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Aliases
KCNE4 MiRP3
KCNE3 MiRP2,
HOKPP
KCNE2 MiRP1
HUGO
Symbol
Stomach
Intestine
Colon
Pancreas (total)
Human:
Human: ⫺ Mouse: Human: ⫹
⫹⫹⫹
⫺ N, IS, IF (96);
Mouse: ⫺ N,
Mouse:
P (660)
IS, IF (96); P
⫹⫹⫹
(660)
Localization:
luminal
membrane
of gastric
parietal
cells,
association
with
KCNQ1.
Function:
recycling
pathway
for K⫹,
supporting
HCl
secretion.
P (183); IF
(220); N,
IS, IF (96);
P (660); F
(522); EST
Human: ⫹⫹ Human: ⫹⫹
Human: ⫹⫹⫹ Human: ⫹ EST
Mouse:
Mouse: ⫹⫹
Mouse:
⫹⫹ P
Localization:
⫹⫹⫹
(183, 660);
basolateral
Localization:
IS, N, IF
membrane of
basolateral
(96); EST
crypt base cells,
in colonic
association with
crypt cells,
KCNQ1.
association
Function:
with KCNQ1.
repolarization,
Function:
electrolyte and
repolarization,
substrate
generating
transport? N, IS,
driving force
IF (96); P (660);
for Cl⫺
secretion. N,
IS (549); EST
IS, IF (96); P
(660); IS
(549); EST
Human: ⫹
Mouse: ⫺ NB (96) Human: ⫹
Human: ⫹ EST
Mouse:
Mouse: ⫺
⫹⫹/⫺ NB
NB (96); EST
(96); EST
1—Continued
Pancreas Acinus
Pancreas Duct
Salivary Glands
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TABLE
OMIM
607775
Association of human 604433
KCNE3 mutations
with “hypokalemic
periodic paralysis”
is controversially
discussed (1, 271,
610).
KCNE2 knockout
603796
mice display
impaired gastric
acid secretion and
morphological
changes of the
gastric mucosa
(522). Human
KCNE2 mutations
can cause “long QT
syndrome” (2).
Pathophysiology/Disease
1130
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
KV5.1, kH1,
IK8
Aliases
KCNH1 eag, h-eag,
Kv10.1
KCNG3 KV6.3
KCNG4 Kv6.4, Kv6.3
KCNG2 KCNF2,
KV6.2
KCNG1 KV6.1, kH2,
K13
KCNF1
HUGO
Symbol
1—Continued
Stomach
Pancreas Acinus
Voltage-gated channels, subfamily F
Pancreas (total)
Human: ⫹ EST Human: ⫹ N
(594); EST
Voltage-gated channels, subfamily G
Human: ⫹⫹
Localization:
pancreatic
islets (␣-cell).
Function:
glucagons
secretion? N
(594); P, IS,
IF (682)
Human: ⫹⫹
Localization:
pancreatic
islets (␤-cell).
Function:
insulin
secretion? P,
IS, IF (682)
Colon
Human: ⫹
Human: ⫹⫹
Human: ⫹⫹
Function:
Function:
Mouse: ⫹ P
regulating
regulating
(464); N
intestinal
colonic
(643); EST
neuronal and GI
neuronal and
activity? P (464)
GI activity?
P (464)
Voltage-gated channels, subfamily H (eag-related)
Human: ⫹ P (540)
Human: ⫹⫹
Human: ⫹⫹
Function:
Function:
regulating
regulating
intestinal
colonic
neuronal and GI
neuronal and
activity? P (464)
GI activity?
P (464)
Mouse: ⫹
Intestine
Pancreas Duct
Salivary Glands
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TABLE
Pathophysiology/Disease
603305
606767
607603
605696
603788
603787
OMIM
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1131
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
Aliases
Mouse: ⫹
Rat: ⫺ P
(159)
KCNH8 Kv12.1
KCNJ1
ROMK1,
Kir1.1
Intestine
Colon
Pancreas (total)
Pancreas Acinus
Rat: ⫹⫹ P (295)
Rat: ⫹⫹ Function: Rat: ⫹⫹
Function: K⫹
K⫹ secretion? P
(295)
secretion? P
(295)
Inwardly rectifying channels, subfamily J
Human: ⫹⫹
EST
Human: ⫹
Mouse: ⫹
EST
Human: ⫹
Mouse: ⫹
EST
Human: ⫹⫹ Human: ⫹/⫺⫹
Human: ⫹⫹
Human: ⫹⫹
Rat: ⫹⫹
Mouse: ⫹⫹
Localization:
Localization:
Localization: Localization:
colonic
pancreatic
gastric
jejunal smooth
cancer cell
islets (␤cancer cell
muscles,
lines, colonic
cells).
lines,
interstitial cells
cancer (not
Function:
gastric
of Cajal.
normal
insulin
mucosa,
Function: GI
mucosa).
secretion? P
smooth
motility. P (464);
Function:
(464, 527)
muscle
QP, IF (136); P,
regulation of
cells.
IF (699); EST
proliferation.
Function:
P (464); P,
regulation
W, IF (327)
of
proliferation,
GI motility.
P, W, IF
(458, 569)
Stomach
KCNH3 BEC1, Kv12.2
KCNH4 Kv12.3
KCNH5 H-EAG2,
EagII,
Kv10.2
KCNH6 ERG2,
Rat: ⫹⫹
HERG2,
Localization:
Kv11.2
smooth
muscle
cells.
Function:
GI motility.
P, W, IF
(458)
KCNH7 HERG3,
Human: ⫹
Kv11.3
KCNH2 HERG,
Kv11.1
HUGO
Symbol
1—Continued
Pancreas Duct
OMIM
600359
608260
608169
608168
604527
604528
605716
Mutation of KCNH2
152427
can cause “long QT
syndrome” (89).
Pathophysiology/Disease
Human: ⫹
KCNJ1 mutations
Localization:
cause “antenatal
human
Bartter syndrome
submandibulary
type 2” (576).
gland duct cells.
Function: K⫹
secretion. W, P
(353)
Salivary Glands
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TABLE
1132
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
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www.prv.org
Stomach
Intestine
Colon
Pancreas (total)
CIR, KATP1,
GIRK4,
Kir3.4
GIRK2,
KATP2,
BIR1,
Kir3.2
KCNJ6
IRK1, Kir2.1
Rat: ⫺
Human: ⫹
P (159);
EST
Rat: ⫺
Human: ⫹
P (159);
EST
Mouse: ⫹⫹⫹
Localization:
pancreatic
islets (␣-cell).
Function:
glucagon
secretion? P,
IF (689)
Canine: ⫹
Canine: ⫹
Human: ⫹⫹
Localization:
Localization:
Mouse: ⫹⫹
smooth muscles.
smooth
Localization:
Function: GI
muscles.
pancreatic
motility. QP, IF
Function: GI
islets (␣-cell).
(50)
motility. QP,
Function:
IF (50)
glucagon
secretion? P,
IF (689); EST
Rat: ⫺
Human: ⫹⫹ EST Human: ⫹ EST Human: ⫹ EST
Rabbit:
⫹⫹
Localization:
luminal
membrane
of gastric
parietal
cell.
Function:
involved in
HCl
secretion?
P (159); P,
W, IF (388)
GIRK1, Kir3.1 Rat: ⫺ P
Human: ⫹ Canine: Human: ⫹
(159)
⫹⫹⫹
Canine: ⫹
Localization:
Localization:
smooth muscles.
smooth
Function: GI
muscles.
motility. QP, IF
Function: GI
(50); EST
motility. QP,
IF (50)
HIR, HRK1,
Rat: ⫺ P
HIRK2,
(159)
Kir2.3
Aliases
KCNJ5
KCNJ4
KCNJ3
KCNJ2
HUGO
Symbol
1—Continued
Rat: ⫹ Localization:
basolateral
membrane.
Function:
electrolyte and
enzyme secretion.
P, F (285)
Rat: ⫹⫹⫹
Localization:
basolateral
membrane.
Function:
electrolyte and
enzyme secretion?
P, F (285)
Pancreas Acinus
Pancreas Duct
Pathophysiology/Disease
Bovine parotid
Mutations of KCNJ2
gland Function:
cause “Andersen
probably
cardiodysrhythmic
spontaneous
periodic paralysis”
secretion in
(500).
ruminant parotid
gland. P, IF
(211)
Salivary Glands
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TABLE
600877
600734
600504
601534
600681
OMIM
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1133
Intestine
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
GIRK3, Kir3.3 Rat: ⫺ P
(159)
KCNJ9
Human: ⫹ P (642)
Pancreas (total)
Human: ⫹
Mouse: ⫹⫹
Localization:
pancreatic
islets (␤cells).
Function:
association
with SUR2,
regulation of
insulin
secretion. IS
(600); N
(239); EST
Human: ⫹
Function:
insulin
secretion?
(chromosomal
locus
associated
with diabetes
type II). P
(642)
Human: ⫹ EST Human: ⫹
Mouse: ⫹
Rat: ⫹⫹
Localization:
pancreatic
islets EST. N
(239); EST
Colon
Pancreas Acinus
Pancreas Duct
Salivary Glands
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KCNJ10 Kir4.1, Kir1.2 Rat: ⫹⫹
Localization:
luminal
membrane
of gastric
parietal
cells.
Function:
K⫹
recycling
pathway
required
for H⫹-K⫹ATPase
activity. P,
IF (159)
KCNJ11 BIR, Kir6.2
Rat: ⫺ P
Human: ⫹⫹ EST
(159)
Kir6.1
Human: ⫹
Mouse: ⫹ EST
Mouse: ⫹
Rat: ⫺ P
(159); EST
Stomach
KCNJ8
Aliases
1—Continued
HUGO
Symbol
TABLE
-
600935
OMIM
Mutations of KCNJ11
600937
can cause
“permanent neonatal
diabetes mellitus”
(177) and “hyperinsulinemic
hypoglycemia” (617).
Transgenic KCNJ11
mice (expressing a
dominant-negative
KCNJ11) develop
hypoglycemia with
hyperinsulinemia as
neonates and
hyperglycemia with
hypoinsulinemia and
decreased ␤⫺cell
numbers as adults
(420).
Mutant KCNJ10 mice 602208
suffer from inner
ear degeneration
and deafness (250).
Mutations of KCNJ8
are believed to
cause “Prinzmetal
angina”. KCNJ8
knockout mice
show a
corresponding
phenotype (419).
Pathophysiology/Disease
1134
DIRK HEITZMANN AND RICHARD WARTH
Stomach
Intestine
Colon
Pancreas (total)
Pancreas Acinus
88 • JULY 2008 •
www.prv.org
KCNK1 DPK, TWIK-1 Human: ⫹
Human: ⫹ Mouse: Human: ⫹
Human: ⫹
Mouse:
⫹⫹ P (343,
Mouse: ⫹⫹
Mouse: ⫹⫹ N
⫹⫹ QP
518); QP (413);
P (343, 518);
(340); P (343,
(413); P
DB, P (13); EST
DB, P (13);
518); QP
(518); EST
EST
(413); DB, P
(13); EST
Human: ⫹⫹
Localization:
ductal cells.
IS (354)
Pancreas Duct
Human: ⫹ Mouse:
⫹⫹⫹ EST
Salivary Glands
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Physiol Rev • VOL
K2P channels, subfamily K
KCNJ12 Kir2.2,
Rat: ⫺ P
Kir2.2v
(159)
Human: ⫹
KCNJ13 Kir7.1, Kir1.4 Human: ⫹⫹ Human: ⫹⫹⫹
Human: ⫹ N
Rat: ⫹⫹
Function:
Rat: ⫹⫹
Localization:
(105, 438)
Localization:
electrolyte
Localization: basolateral
basolateral
transport? N
gastric
membrane of
membrane of
(105, 438,
mucosa. P
intestinal cells.
acinar cells.
479)
(159); N
Function:
Function:
(105, 438,
possible role in
electrolyte
479)
electrolyte
secretion P, F
transport? N
(285)
(479); P (304);
N, W, IF (438);
EST
KCNJ14 Kir2.4, IRK4 Human: ⫹
Human: ⫹ EST
Human: ⫹ EST
Rat: ⫺ P
(159); EST
KCNJ15 Kir4.2, Kir1.3 Human: ⫹
Human: ⫹⫹ N
Mouse:
(573); EST
⫹⫹ Rat:
⫹⫹
Localization:
gastric
mucosa P
(159); IS
(616); EST
KCNJ16 Kir5.1
Human: ⫹
Human: ⫺ Mouse: Human: ⫺ N
Human: ⫹⫹⫹ N Human: ⫹⫹
Rat: ⫺ P
⫹ N (354); EST
(354)
(354); EST
Localization:
(159); EST
acinar and
centroacinar cells
(no islets). IS
(354)
Aliases
1—Continued
HUGO
Symbol
TABLE
KCNK1 knockout
display impaired
renal phosphate
handling and a
reduced K⫹
conductance in
cortical collecting
ducts (421, 445).
Pathophysiology/Disease
601745
605722
602106
603953
603208
602323
OMIM
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1135
Physiol Rev • VOL
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Aliases
KCNK4 TRAAK
KCNK3 TASK,
TASK-1
KCNK2 TREK-1
HUGO
Symbol
Human: ⫺
QP (413)
Human: ⫺ P
(343, 345)
Colon
Human: ⫹ QP
(413); EST
Human: ⫹⫹⫹
Mouse: ⫹ N
(127); EST
Human: ⫹
Mouse: ⫹⫹
QP (413); N,
QP (412); P
(343, 345);
EST
Pancreas (total)
Human: ⫹/⫺ P Human: ⫺ QP
(344); EST
(413)
Human: ⫹ Mouse: Human: ⫹ N
⫹ N (127, 282)
(127)
Human: ⫹⫹
Mouse: ⫹⫹ QP
(413); N, QP
(412); P (343,
345); EST
Human: ⫹⫹
Mouse:
⫹⫹ QP
(413); N,
QP (412);
EST
Mouse: ⫹ N
(282)
Intestine
Stomach
1—Continued
Pancreas Acinus
Pancreas Duct
Human: ⫹ Mouse:
⫹ EST
Salivary Glands
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TABLE
OMIM
603219
KCNK2 knockout
mice are healthy
and fertile, and
show no
morphological
defects. However,
knockout animals
are more sensitive
to ischemia and
epilepsy.
Additionally,
neuroprotection by
polyunsaturated
fatty acids is
diminished. KCNK2
knockout mice are
also resistant to
anesthesia by
volatile anesthetics
(227) and
depression (228).
603220
KCNK3 knockout
display discrete
changes of
neuronal K⫹
conductance and
sensitivity toward
the sedative
dexmedetomidine.
They have slight
changes in
nociception but no
obvious
neurological
phenotype (8, 351,
417). Female mice
display
hypertension,
hyperaldosteronism,
and adrenocortical
mislocalization of
the aldosterone
synthase (219).
605720
Pathophysiology/Disease
1136
DIRK HEITZMANN AND RICHARD WARTH
Pancreas (total)
88 • JULY 2008 •
www.prv.org
Mouse: ⫹
Rat: ⫹⫹ P
(508); EST
Human: ⫹/⫺ Human: ⫺ N, P
N, P (283)
(283); P (15)
KCNK13 THIK-1
KCNK15 dJ781B1.1,
KT3.3,
KIAA0237,
TASK5,
TASK-5
KCNK16 TALK-1,
TALK1
KCNK12 THIK-2
Human: ⫹
Human: ⫹ Rat: ⫺
Mouse: ⫹
P (345); QP
Rat: ⫺ QP
(413); N, P (17)
(413); N, P
(17); EST
Rat: ⫹ P
Human: ⫹⫹ N, P
(508)
(176)
Human: ⫹⫹⫹ N Human: ⫹⫹ IS (126)
(176, 207);
EST
Human: ⫹/⫺
Human: ⫹⫹⫹
N, P (283); P
N, P (283); P
(15); EST
(15)
Human: ⫹⫹ N,
P (176)
Human: ⫹ Rat:
⫺ P (345); N,
P (17)
Human: ⫹⫹
Rat: ⫹⫹⫹
Localization:
mucosa. P
(288); IF, W
(300)
Human: ⫹ QP
(413)
Human: ⫹⫹
Localization:
predominant
staining of IF
in islets. P
(413) ;IF
(300)
Human: ⫹⫹⫹
Rat: ⫹⫹⫹ P
(345); QP
(413) N, P
(17)
Human: ⫹⫹⫹
N, P (176);
EST
Human: ⫹⫹⫹
Mouse: ⫺ QP
(413); N (74);
P (534); EST
Human: ⫹
Localization:
acinar cells. X-gal
(126); QP (413)
Pancreas Acinus
Pancreas Duct
Human: ⫹ Mouse:
⫹ EST
Human: ⫹ EST
Salivary Glands
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Physiol Rev • VOL
KCNK10 TREK-2,
TREK2
KCNK9 TASK3,
TASK-3
KCNK7
Human: ⫹⫹
Mouse: ⫹⫹
N (74); P
(534); EST
Human: ⫹⫹ Human: ⫹⫹
Mouse:
Mouse: ⫹ QP
⫹⫹⫹ QP
(413); N (74); P
(413); P
(534)
(534); EST
Human: ⫹
Human: ⫹ QP
QP (413)
(413)
Human: ⫹⫹ Human: ⫹ Rat: ⫺
Rat: ⫹⫹ P
P (288, 413)
(288, 413);
IF, W (300)
Colon
KCNK6 TWIK-2
Intestine
Human: ⫹
Human: ⫹ Mouse: Human: ⫹
Human: ⫹⫹
Mouse: ⫹
⫹⫹ QP (413);
Mouse: ⫹ N,
Mouse: ⫹/⫺
QP (413);
N, P (518); EST
P (518); EST
Localization:
N, P (518);
exocrine
EST
pancreas and
islets. N, P
(518); EST
Stomach
KCNK5 TASK-2
Aliases
1—Continued
HUGO
Symbol
TABLE
OMIM
607369
607368
607367
607366
605873
605874
603940
KCNK5 knockout
603493
mice exhibit
metabolic acidosis
caused by renal
loss of bicarbonate
ions due to
impaired proximal
tubular transport
(22, 661).
603939
Pathophysiology/Disease
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1137
Physiol Rev • VOL
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Pancreas (total)
Pancreas Acinus
Pancreas Duct
Human: ⫹⫹
Human: ⫹
Human: ⫹ Mouse: Human: ⫹⫹
Mouse: ⫹
Rabbit:
⫹ DB (28); F
Mouse: ⫹⫹
Rat: ⫹⫹ DB
⫹⫹ DB
(662); EST
Rat: ⫹⫹
(28); P (217);
(28); N, P
Rabbit: ⫹⫹
EST
(426); EST
Localization:
Luminal
membrane of
surface (and
to less
extent crypt)
cells.
Function: K⫹
secretion.
DB (28); F
(662); IF, F
(400, 536);
BA (192);
EST
Salivary Glands
Pathophysiology/Disease
?
607370
OMIM
Human: ⫹⫹ Mouse: Rat: ⫹⫹
Human ⫹⫹⫹
KCNMA1 knockout
600150
⫹⫹ (only in adult
Localization:
Mouse: ⫹⫹ Rat:
mice show
animals) Rat: ⫹⫹
basolateral
⫹⫹ Localization:
moderate vascular
Pig: ⫹⫹⫹ Guinea
membrane of
acinar cells.
dysfunction and
pig: ⫹⫹⫹
ductal cells
Function: saliva
neurological
Localization:
Function:
secretion and
deficits (541). They
basolateral
driving force
ionic
display
membrane of
for
composition,
predisposition for
acinar cells.
secretion. F
resting
generalized
Function: driving
(187); P
membrane
epilepsy and
⫺
force for Cl
(217)
voltage,
paroxysmal
secretion. F (254,
regulatory
dyskinesia (121).
255, 396, 495, 599);
volume decrease
Knockout mice
F, P (463); P (217)
after cell
have no defect in
swelling. P, N
colonic Cl⫺
(437, 441, 523);
secretion, but
W (441); EST
impaired colonic
K⫹ secretion (400,
542). Parotid gland
fluid secretion is
only slightly
affected by the
KCNMA1
knockout. In
KCNMA1/KCNN4
double knockouts,
stimulated saliva
secretion is
reduced (523). In
human ulcerative
colitis, KCNMA1
expression is
broadened along
the crypt axis and
may contribute to
increased fecal K⫹
loss (536).
Large conductance calcium-activated channels, subfamily M, ␣ member
Human: ⫹ EST Human: ⫹⫹⫹ N Human: ⫹⫹
(176); P (93);
Localization:
EST
acinar cells.
Function:
background
channel, role in
inflammation? IS
(126)
Human: ⫹⫹⫹
Rat: ⫹⫹⫹ P
(275)
Colon
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KCNMA1 Kca1.1, Slo1
Rat: ⫹ N (275)
KCNK18 TRESK-2,
TRESK2,
TRESK,
TRIK
Intestine
Human: ⫹⫹ P
(93)
Stomach
KCNK17 TALK-2,
TALK2,
TASK4,
TASK-4
Aliases
1—Continued
HUGO
Symbol
TABLE
1138
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
Aliases
Colon
Pancreas (total)
Pancreas Acinus
Pancreas Duct
Human: ⫹⫹
DB (28); N
(51); EST
Human: ⫹⫹
DB (28); N
(51); EST
Human: ⫹/⫺
DB (28); N
(51); EST
Human: ⫺ Rat:
⫺ P (217); N
(51)
Human: ⫹⫹
Mouse: ⫹
Rat: ⫺
Localization:
pancreatic
duct cells?
Function:
association
with
KCNMA1. P
(217, 633); N
(51); EST
Human: ⫹⫹⫹
Rat: ⫺
Localization:
pancreatic
␤-cells. N (51,
455); P (366);
P, IS (633)
Human: ⫹ EST Mouse: ⫹⫹ Rat:
⫹
Localization:
islets, not in
duct cells. P
(217, 607)
Intermediate/small conductance calcium-activated channel, subfamily N
Human: ⫹⫹ DB
(28); N (51)
Human: ⫹ N (51)
Human: ⫹⫹
Mouse: ⫹
DB (28); EST
Localization:
pancreatic
duct cells?
Function:
association
with
KCNMA1. P
(217)
Large conductance calcium-activated channels, subfamily M, ␤ members
Human: ⫹⫹ DB
(28); EST
Intestine
Human: ⫹ N Human: ⫹⫹ N
(51)
(51)
Human: ⫹⫹
DB (28)
Human: ⫹
Mouse:
⫹⫹ N
(51); EST
Human: ⫹⫹
Mouse:
⫹⫹ DB
(28); EST
Stomach
KCNN1 hSK1, Kca2.1 Human: ⫹
EST
KCNMB3LKCNMB3L1
KCNMB4
KCNMB3
KCNMB2
KCNMB1 hslo-␤
HUGO
Symbol
1—Continued
OMIM
605223
602982
Human ⫹ EST
605222
KCNMB1 deletion in 603951
mice leads to a
decrease in Ca2⫹
sensitivity of BK
channels, a
reduction in
functional coupling
of Ca2⫹ sparks to
BK channel
activation, and
increases in
arterial tone and
blood pressure
(52). Mice have a
relative resistance
against diastolic
hypertension (140).
605214
Pathophysiology/Disease
Mouse ⫹ P, N
(441)
Mouse ⫹ P, N
(441)
Salivary Glands
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TABLE
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1139
Physiol Rev • VOL
88 • JULY 2008 •
Aliases
KCNN3 SK3, SKCA3,
Kca2.3
KCNN2 SK2, Kca2.2
HUGO
Symbol
Stomach
Human: ⫹
EST
1—Continued
Colon
Human: ⫹ Rat:
Human: ⫹ Rat:
⫹⫹ Guinea
⫹⫹ Guinea pig:
pig: ⫹⫹
⫹⫹
Localization:
Localization:
interstitial cells
interstitial
of Cajal.
cells of
Function: GI
Cajal.
motility? P, IF
Function: GI
(160); IF, EM
motility? IF,
(291); EST
EM (291); P,
IF (160);
EST
Guinea pig: ⫹⫹
Localization:
smooth muscle
cells. Function:
GI motility. IF
(291)
Intestine
Mouse: ⫹⫹ Rat:
⫹⫹⫹
Localization:
islets (␤cells), not in
duct cells.
Function:
insulin
secretion? P
(217); P, IF
(607); EST
Human: ⫹
Mouse: ⫹⫹
Rat: ⫹⫹
Localization:
islets (␤cells), not in
duct cells.
Function:
insulin
secretion? P
(217); P, IF
(607); EST
Pancreas (total)
Pancreas Acinus
Pancreas Duct
Salivary Glands
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TABLE
605879
OMIM
602983
KCNN3
overexpression in
mice induced
abnormal
respiratory
responses to
hypoxia and
compromised
parturition,
presumably by
effects on uterine
contraction (44).
Increased
hippocampal
expression of
KCNN3 channels in
aged mice may
represent a
mechanism that
contributes to agedependent decline
in learning and
memory and
synaptic plasticity
(37). The level of
KCNN3 channel
expression in
endothelial cells
may be a
fundamental
determinant of
vascular tone and
blood pressure
(612).
Pathophysiology/Disease
1140
DIRK HEITZMANN AND RICHARD WARTH
www.prv.org
Physiol Rev • VOL
88 • JULY 2008 •
www.prv.org
Aliases
KCNQ1 KCNA8,
KVLQT1,
Kv7.1,
JLNS1
KCNN4 SK4, Kca4,
IK, Ca1,
Kca3.1
HUGO
Symbol
Stomach
Intestine
Colon
Pancreas (total)
Pancreas Acinus
Salivary Glands
Pathophysiology/Disease
OMIM
Gastric acid secretion
is reduced and
gastric mucosa is
hyperplastic in
KCNQ1 knockout
mice (334, 638).
Human mutations
of KCNQ1 cause
“long QT
syndrome” (442,
650), “short QT
syndrome” (29),
and familial atrial
fibrillation (77).
607542,
607554,
192500,
220400,
609621
Human: ⫹⫹
Rat: ⫹⫹
KCNN4 knockout
602754
Mouse: ⫹⫹ Rat;
Localization:
mice are of normal
⫹⫹ Localization:
basolateral
appearance and
acinar cells.
and luminal
fertility. Volume
Function:
membrane of
regulation of T
activated by
pancreatic
lymphocytes and
cholinergic
duct cells.
erythrocytes is
stimulation;
Function:
impaired. Fluid
secretion of
electrolyte
secretion from
primary saliva?
secretion. IF
parotid glands is
N, P (27, 437,
(618); P
normal (27). In
441, 523, 602);
(217)
colonic mucosa
QP (75); IS
carbachol(441); IF
stimulated CI⫺
intercalated
secretion is
ducts of
decreased (146,
submandibulary
400). Knockout
gland (618); EST
mice show virtually
normal saliva
secretion (27, 523).
Pancreas Duct
Human: ⫹⫹
Human: ⫹
Human: ⫹⫹⫹
Mouse: ⫹⫹ Rat: ⫹⫹ Mouse: ⫺ P, IS Human: ⫹ DB
Human:
Mouse: ⫹⫹
Mouse: ⫹⫹
Mouse: ⫹⫹ N
Localization: islets
(103)
(684); EST
⫹⫹⫹
Localization:
Rat: ⫹⫹
(79, 539); EST
and basolateral
Mouse:
basolateral,
Guinea pig:
membrane of
⫹⫹⫹
⫹⫹
acinar cells
Localization: (associated with
KCNE3).
Localization:
(associated with
gastric
Function:
basolateral,
KCNE1). Function:
parietal
driving force for
(associated
providing driving
cells
electrogenic
with
force for
(luminal,
transport. N (79,
KCNE3).
secretion? P, IS
associated
96); P, IS (103);
Function:
(103); IF (663); F
with
P (334); IF (638,
driving force
(284, 302, 333)
KCNE2).
663); EST
for luminal
Function:
CI⫺
K⫹
recycling
secretion. N
required
(79, 96); P
for H⫹/K⫹
(311); S
ATPase
(184); IF
activity. P
(348, 663); IS
(183, 334);
(549); EST
N, IF (96)
P, IS (103);
IF (220);
EST
Voltage-gated channels, KQT-like subfamily
Human: ⫹⫹ Human: ⫹ Mouse: Human: ⫹⫹⫹ Human: ⫹/⫺
Rat: ⫹⫹
Mouse:
⫹⫹
Mouse: ⫹⫹
Mouse: ⫹⫹
Localization:
⫹⫹
Localization:
Rat: ⫹⫹
Rat: ⫹ DP
basolateral
Localization: probably in the
Localization:
(259); N
membrane of
basolateral
basolateral (and
basolateral
(244); P (607),
pancreatic acinar
membrane
luminal?)
(and luminal
EST
cells. Function:
of surface
membrane of
?) membrane
electrolyte and
cells. N
crypt cells,
of crypt
enzyme secretion.
(244); P
endocrine cells,
cells,
IF (618)
(640) IF
neurons.
neurons.
(163); EST
Function:
Function:
providing
driving force
driving force for
for
electrolyte
electrolyte
secretion. DP
secretion.
(259); N (244);
DP (259),P
EST
(244, 356,
640, 665); IF,
W, P (618,
163); EST
1—Continued
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TABLE
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1141
Physiol Rev • VOL
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Aliases
KIAA1422,
Kca4.1,
SLO2.2
Kca4.2,
SLICK,
SLO2.1
KCNT1
KCNV1
Kv8.1
KCNU1 Kca5.1, SLO3
KCNT2
Kv9.1
Kv9.2
Kv9.3
Human: ⫹
EST
Human: ⫹
Rat: ⫹ N
(485); EST
Human: ⫹
Mouse: ⫹
EST
KCNQ5 Kv7.5
KCNS1
KCNS2
KCNS3
Human: ⫹
EST
Stomach
KCNQ4 Kv7.4
KCNQ3 Kv7.3
KCNQ2 ENB1, BFNC,
Kv7.2,
KCNA11,
HNSPC
HUGO
Symbol
1—Continued
Mouse: ⫹ EST
Human: ⫹⫹ Rat:
⫹ N (485); EST
Mouse: ⫹ EST
Human: ⫹⫹ EST
Intestine
Human: ⫹
Mouse: ⫹⫹
EST
Human: ⫹ EST
Pancreas (total)
Pancreas Acinus
Pancreas Duct
Potassium channels, subfamily V
Rat: ⫺ P (217)
Potassium channels, subfamily U
Rat: ⫺ P (217)
Human: ⫹ EST Human: ⫹⫹
Mouse: ⫹
Localization:
islet ␤-cell.
Function:
insulin
secretion? P,
IF, IS (682)
Potassium channels, subfamily T
Rat: ⫺ P (217)
Voltage-gated channels, delayed-rectifier, subfamily S
Human: ⫹ EST
Human: ⫹ EST
Colon
Human ⫹ EST
Salivary Glands
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TABLE
Mutations of human
KCNQ2 cause
“benign familial
neonatal
convulsions” (579)
and “myokymia
with neonatal
epilepsy” (95).
Mutations of human
KCNQ3 are
associated with
“benign neonatal
epilepsy” (72).
Mutations of human
KCNQ4 cause
“autosomal
dominant
sensorineural
deafness” (305).
Pathophysiology/Disease
608164
?
610044
608167
602905
602906
603888
607357
603537
602232
602235
OMIM
1142
DIRK HEITZMANN AND RICHARD WARTH
607604
Pancreas Duct
Human: ⫺ P (464) Human: ⫹⫹
Human: ⫹⫹⫹
Function:
Function:
KCNV2 alone
KCNV2 alone
is not
is not
functional,
functional,
only in
only in
association
association
with KCNB1.
with KCNB1.
P (464)
P (464)
Pancreas Acinus
Pancreas (total)
Colon
Intestine
Kv8.2, Kv11.1
KCNV2
Stomach
Aliases
HUGO
Symbol
1—Continued
TABLE
P, PCR; QP, quantitative PCR; N, Northern blot; DB, RNA dot blot; IS, in situ hybridization; IF, immunfluorescence; F, functional evidence; W, Western blot; IP, immunoprecipitation;
BA, binding assay; EST, UniGene EST data.
Physiol Rev • VOL
1143
2. Schematic illustration of K⫹ channel function in epithelia. A:
K channels hyperpolarize the membrane voltage, thereby fueling electrogenic transport mechanisms such as Na⫹-coupled reabsorption of
nutrients (not depicted) or luminal Cl⫺ secretion. Basolateral K⫹ channels can hyperpolarize also the luminal membrane if the paracellular
pathway allows ion currents to flow. In addition, they contribute to the
establishment of a transepithelial voltage (Vte), which drives ions
through the paracellular pathway. B: K⫹ channels as recycling pathways
for K⫹: Na⫹-K⫹-ATPase and H⫹-K⫹-ATPase take up K⫹ in exchange for
Na⫹ and H⫹, respectively. For ongoing activity of these ATPases, recycling of K⫹ is required to avoid depletion of K⫹ in the external fluid.
Therefore, activity of the ATPases and K⫹ channels is often tightly
coupled. C: luminal K⫹ channels in distal nephron and the colon are
direct ways to eliminate K⫹. They hyperpolarize the luminal membrane
and lead in concert with luminal Cl⫺ channels to electroneutral KCl
secretion. The driving force for paracellular transport, e.g., of Na⫹, is
reduced (Vte in this model is only ⫺12 mV compared with ⫺20 mV in A).
D: swelling-induced K⫹ channels participate in cell volume regulation.
Many K⫹ channels are directly or indirectly (via swelling-induced increase in Ca2⫹) activated by cell swelling. K⫹ leaves the cell together
with its counterion, and water follows these osmolytes: the cells perform regulatory volume decrease.
⫹
FIG.
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Salivary Glands
Pathophysiology/Disease
OMIM
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1144
DIRK HEITZMANN AND RICHARD WARTH
3. K⫹ and salt handling
4. Cell volume regulation
Transcellular transport of salt and substrates paralleled by osmotic water flow represents a continuous challenge for epithelial cells of the gastrointestinal tract to
keep their cell volume constant. To achieve this goal, the
precise adjustment of cellular uptake on the one hand and
elimination of osmolytes on the other hand is necessary to
avoid large changes of the cell volume with the risk of
cellular damage. To stabilize normal cell volume, several
types of transport proteins are regulated by cell swelling/
shrinkage and, therefore, are able to counteract volume
changes, e.g., Na⫹-2Cl⫺-K⫹ cotransporters, Cl⫺ channels,
and K⫹ channels (115, 203, 230, 322, 459). In intestinal
epithelial cells, several types of volume-sensitive K⫹ channels are strongly expressed, e.g., TASK2 (KCNK5, Ref.
447), SK4 (KCNN4, Refs. 535, 669), and Kv7.1 (KCNQ1,
Ref. 191). Activation of those channels by cell swelling
results in the exit of K⫹ and the same amount of negatively charged counterions, which decreases the osmolality of the cytosol and induces water flux out of the cell:
“regulatory volume decrease.”
5. Proliferation, differentiation, and cell death
Proliferation, differentiation, and apoptosis of cells
are essential processes for every multicellular organism.
During these processes, K⫹ channel expression and K⫹
channel activity is tightly controlled to adapt membrane
voltage and cell volume to the needs. On the other hand,
changes of the expression pattern of K⫹ channels and
their activity can have severe impact on the ability of cells
to go through distinct parts of the cell cycle or to perform
apoptosis (323). Therefore, it is not surprising that severe
disturbances such as cancer can be accompanied by upPhysiol Rev • VOL
6. Cell migration and wound healing
Cell migration and movement of cells is required to
reseal mucosal defects after injury. Over the last years,
there has been growing evidence for an important role of
K⫹ channels during cell migration (558) and wound healing of epithelial cells (179, 365, 512, 572). Apparently, K⫹
channels and ion transporters are required for localized
volume changes that play a role for single cell migration.
However, the precise mechanisms by which K⫹ channels
affect wound healing, and vice versa, still need to be
elucidated.
7. Functions of K⫹ channel proteins independent from
K⫹ permeation?
Very recently, evidence has been provided that interaction of KCNB1 (Kv2.1) K⫹ channels with the SNARE
protein syntaxin facilitates exocytosis. Interestingly, this
facilitation was not dependent on the function of KCNB1
as a K⫹ channel, because it could be observed even after
disruption of the pore function of the channel (578). A
qualitatively similar observation has been made for
KCNK1 associated with ARF6/EFA6: KCNK1 expression
interfered with the endocytosis of transferrin receptors
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K⫹ channels in the luminal membrane of epithelial
cells are an evident pathway for the exit of K⫹ out of the
cell, and if not reabsorbed later on, for elimination of K⫹
from the body. Since plasma K⫹ homeostasis is an absolute crucial parameter for the survival of mammalian
organisms, the elimination of K⫹ from the body is tightly
controlled by several mechanisms. Among those, the regulation of luminal colonic K⫹ channels by the mineralocorticoid aldosterone has been the focus of research. In
surface cells of colonic crypts, aldosterone leads to stimulation of Na⫹ reabsorption and concomitant K⫹ secretion; the latter one stabilizes the driving force for ongoing
Na⫹ uptake. Additionally, there exist aldosterone-independent ways of regulation, which allow handling of K⫹
balance independent from the Na⫹ balance. However, the
precise nature of the aldosterone-dependent and -independent regulation of intestinal K⫹ excretion still awaits
detailed characterization.
or downregulation of certain K⫹ channels genes (308, 472,
474, 484). So far, five different K⫹ channel genes have
been the focus of most studies investigating the effect of
K⫹ channel function on proliferation and tumorigenesis:
KCNA3, KCNN4, KCNK9, KCNH1, and KCNH2 (591). In
tissues such as muscle or the nervous system, the rate of
proliferating cells is very low, and most of the cells live
for many years in a postmitotic, terminal differentiated
status. In intestinal epithelial cells, however, proliferation
rate is very high, and renewal of the epithelium occurs in
2–3 days and 3– 8 days in small and large intestine, respectively (352). The short life span of intestinal cells
requires very precise and timely adjusted mechanisms for
fine tuning of the cellular processes including ionic conductances which affect proliferation, differentiation, and
finally apoptosis. As a consequence, pharmacological inhibition or overexpression of K⫹ channels can modify cell
growth (474). In addition, blockade of K⫹ channels diminishes apoptotic K⫹ efflux which normally takes place as
an early event during apoptosis and which is needed for
the execution of later parts of the apoptotic program
(IEC-6 cell line) (189). Disturbances of the cellular processes underlying growth, differentiation, and cell death
have implications for diseases such as inflammatory
bowel disease, adenoma formation, and carcinogenesis.
Therefore, knowledge of the role of K⫹ channels for these
basic processes shall lead to better understanding for the
control of cell growth, cell fate, and cell death and finally
could offer new therapeutic strategies for diseases of
gastrointestinal epithelia.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1145
irrespective of its function as an ion channel (94). It is
possible that similar ion permeation-independent functions of channels as part of protein complexes will be
discovered for other K⫹ channels in the future.
Over the last years, our knowledge about K⫹ channel
genetics, structure, and molecular aspects of their various
cellular functions has largely improved. In the following
sections, we will provide an overview about the molecular
physiology of K⫹ channels in epithelial cells of the gastrointestinal tract.
II. Kⴙ CHANNELS ACTING IN CONCERT WITH
Hⴙ-Kⴙ-ATPase IN GASTRIC PARIETAL
CELLS
The stomach is important for storage, for milling and
first digestion of the ingested food, and for appropriate
delivery of the gastric content into the small intestine.
Digestion and denaturation of food proteins is initiated by
pepsins and acidic pH of the gastric juice, which also
serves to diminish the number of possibly harmful microorganisms. In addition, intrinsic factor secreted by parietal cells promotes the absorption of vitamin B12 in the
terminal ileum. As an important protective measure
against the acidic luminal content, gastric surface cells
produce a bicarbonate-rich mucous secretion. During the
Physiol Rev • VOL
last years, molecular techniques have allowed the identification of several K⫹ channels that are specifically expressed in the stomach. In this section, we discuss the
functional role of those K⫹ channels during ion transport
of gastric epithelial cells.
A. Histology of Gastric Mucosa
The stomach mucosa consists of so-called gastric
glands, which are composed of several specialized cell
types (Fig. 3). The luminal surface is covered by a layer of
epithelial cells that secrete alkaline mucus to protect the
mucosa against the acidic gastric juice. Secretion of protective mucus is the predominant function of the relatively short “cardiac” glands. Oxyntic glands in the “fundus” and the “corpus” of the stomach are longer, and they
contain many parietal cells (50 – 60% of the cells) and
chief cells. This type of gastric gland produces the vast
majority of the gastric juice. Chief cells produce precursors for the protease pepsin and are located at the base of
the gland. As a self-protection mechanism, surface mucous cells secrete gel-forming glycoproteins together with
NaHCO3, thereby forming an unstirred layer of acid-neutralizing mucous. Additionally, endocrine and paracrine
cells within the epithelium play important regulatory
roles for the gastric secretory function. In the “antrum,”
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FIG. 3. Ion transport in gastric mucosal cells. A: histology of mouse gastric mucosa. Mucous-producing cells cover the surface of the gastric
mucosa. Acid-producing parietal cells are shown as dark cells within the gastric glands. Chief cells (gray color) are mainly located in the lower part
of the gland. The arrows point to cell type for which models are depicted in B and C. B: hypothetical model for bicarbonate secretion in gastric
⫺
surface cells. In the luminal membrane, Cl⫺ and HCO⫺
channels. Luminal anion exchangers replace
3 leave the cell through CFTR-dependent Cl
⫹
luminal Cl⫺ by HCO⫺
.
Luminal
anion
exit
through
CFTR
is
energized
by
basolateral
K
channels.
KCNE3/KCNQ1
K⫹ channels are probably together
3
⫹
⫹
with others localized in the basolateral membrane. Basolateral Na⫹/HCO⫺
cotransporter
and
Na
/H
exchanger
serve
the uptake of HCO⫺
3
3 and exit
of H⫹, respectively. C: cell model for acid secretion of parietal cells. H⫹ is secreted by the H⫹-K⫹-ATPase in the luminal membrane in exchange for
K⫹ which recycles through apical K⫹ channels. KCNE2/KCNQ1 (E2/Q1) and members of the KCNJ inward rectifier family (Jx) have been identified
⫺
as luminal K⫹ channels. Cl⫺ is secreted through apical Cl⫺ channels. Basolateral anion exchanger exports HCO⫺
3 in exchange for Cl .
1146
DIRK HEITZMANN AND RICHARD WARTH
pyloric glands are the predominant gland type which contain (besides surface epithelial cells and mucous neck
cells) gastrin-producing G cells. The population of small
undifferentiated stem cells is located in the upper third of
the gland (the so-called “neck region”). These stem cells
are the progenitor cells of all gastric cell types (223, 224).
motility is mediated by several hormones including secretin, cholecytokinin (CCK), and gastric inhibitory polypeptide (GIP). Secretin and GIP indirectly inhibit gastric acid
secretion via a release of somatostatin. At higher doses,
CCK acts as an antagonist of gastrin (88, 231, 237, 550).
C. Cellular Mechanisms of HCl Secretion by
Parietal Cells
B. Composition of Gastric Juice
Physiol Rev • VOL
The stimulation of secretion involves two major signaling pathways: acetylcholine via M3 receptors and gastrin via CCK-2 receptors lead to an increase of the cytosolic Ca2⫹ activity, whereas histamine via H2 receptors
increases cAMP. Both pathways end up in protein phosphorylation by protein kinase A or protein kinase C. In
addition to these “classical” ways of activation of acid
secretion, very recently evidence was provided for a role
of calcium-sensing receptor (515) and amino acid transport in the modulation of acid secretion (60, 289). The
activation process of parietal cells is accompanied by
dramatic morphological changes (461, 636). During the
transition from the resting to the stimulated state, H⫹-K⫹ATPase-containing tubulovesicles fuse with each other
and gain access to the apical surface. This impressive
prolongation and extension of these secretory canaliculi
largely increases the apical membrane compartment. By
fusion of the tubulovesicles, the H⫹-pumping P-type
ATPase, which consists of a catalytic ␣- and a regulatory
␤-subunit, is translocated into the luminal membrane
compartment (125). Because of the strict coupling of H⫹
export to uptake of K⫹, replenishment of luminal K⫹ is an
absolute requirement for the activity of the H⫹-K⫹ATPase. In the following, the mechanisms guaranteeing
sufficient luminal K⫹ concentration for ongoing H⫹-K⫹ATPase activity will be discussed in detail (686, 387).
1. Luminal K⫹ recycling: a pivotal step for gastric
acid secretion
Starting in the 1930s, gastric acid secretion and the
role of different ions for this process have been studied in
vitro (100, 186). It has been observed that gastric acid
secretion strongly depends on the presence of Ca2⫹ and
K⫹. Although the importance of K⫹ for gastric acid secretion was evident, it was not yet clear “what aspect of
potassium in the tissue is the determinant of secretion”
(92). The gastric mucosa secretes hydrochloric acid
against
an
enormous
electrochemical
gradient
(1:1,000,000 from the cytosol to the luminal fluid). Therefore, it was postulated that an ATP-consuming protein is
involved in this process. In 1967, purification and characterization of H⫹-K⫹-ATPase and later on the cloning of its
␣- and ␤-subunits revolutionized our understanding of
acid secretion in parietal cells (65, 150, 151, 574). The
strict coupling of H⫹ secretion to K⫹ uptake by the H⫹-
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The adult human stomach secretes 2–3 liters of gastric juice per day with differing acidity and ionic composition dependent on the secretory rate. The acidic, mucous-rich, and enzyme-containing fluid is secreted by different specialized cell types located in the so-called
gastric glands. After stimulation, gastric parietal cells are
able to produce the most acidic fluid found in human
body, with a proton concentration up to 150 –160 mM. The
acid denaturates food proteins, promotes cleavage of pepsinogens to the active pepsins, and reduces the number of
microorganisms ingested by the food (393). During stimulated secretion of parietal cells, the increase in H⫹ concentration of the secreted fluid is paralleled by a decline
in Na⫹ concentration, a moderate increase in K⫹, and an
enhanced output of intrinsic factor (451).
The control of gastric secretion can be divided into
three phases: 1) cephalic phase, 2) gastric phase, and 3)
intestinal phase. The cephalic phase is initiated by the
brain through afferent stimuli from taste and smell receptors, which converge on the vagal nucleus in the medulla
oblongata. Efferent fibers of the vagal nerve excite neurons in the myenteric and submucous plexus, leading to
the liberation of acetylcholine, which in turn promotes
the release of histamine from enterochromaffin-like cells
in the gastric mucosa. In addition, gastrin is released from
antral G cells. All three hormones lead to the stimulation
of gastric secretion. The gastric phase is initiated mainly
by the distension of the stomach by the food and the
chemical nature of the nutrients. The distension leads to
an intramural local and an extramural vago-vagal reflex
response which supports secretion via the same mechanisms as the cephalic phase. G cells and the release of
gastrin are activated by partially digested proteins and
support ongoing HCl secretion. A decrease in luminal pH
activates a negative-feedback mechanism via somatostatin produced by D cells in the antral and pyloric mucosa.
Somatostatin acts as a paracrine hormone and turns off
gastric acid secretion. Moreover, prostaglandin E2 also
inhibits acid secretion by activation of inhibitory Gi proteins. The predominant regulatory aspect of the intestinal
phase is associated with inhibition of gastric secretion
and regulated emptying of the stomach. Acidic pH, fat,
and osmolality of the gastric content entering the duodenum are the major stimuli for a negative-feedback mechanism. This feedback inhibition of gastric secretion and
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
K⫹-ATPase explained the necessity of sufficient amounts
of K⫹ in the luminal fluid, but still the way that K⫹ enters
the lumen was not clear (167, 331, 531). Good evidence
has been provided that Cl⫺ and K⫹ are secreted across
the luminal membrane through specific conductive pathways that are activated during stimulation of acid secretion (514, 671, 101, 385, 386). It was suggested that the
luminal K⫹ conductance is a rate-limiting step for H⫹
secretion (671).
D. Basolateral Kⴙ Channels of Parietal Cells
E. Luminal Kⴙ Channels of Parietal Cells
Although the number of reports on basolateral K⫹
channels in parietal cells is very limited, the basolateral
membrane is at least easily accessible with the patchclamp pipette. For the luminal membrane, the situation is
much more difficult, and access to the luminal membrane
of parietal cells of intact glands is not possible. Over the
last 6 years, several possible candidates for luminal K⫹
channels have been identified by molecular biology and
immunofluorescence techniques. In addition, genetically
modified animals and specific channel inhibitors have
provided important information concerning the physiological significance of luminal K⫹ channels.
Physiol Rev • VOL
1. The KCNQ1/KCNE2 channel: a major player for
parietal cell function
The first study suggesting a significant contribution
of a K⫹ channel for parietal cell function was published in
2000 by Lee et al. (334). They reported that targeted
disruption of the KCNQ1 gene causes deafness and gastric
hyperplasia in mice (334). Originally, KCNQ1 (KvLQT1)
has been cloned as a K⫹ channel responsible for a certain
form of cardiac arrhythmia, the so-called “long QT syndrome type 1” (650). KCNQ1 belongs to a five memberscontaining subfamily of the 6/7TM-1P K⫹ channels, and it
is expressed in the heart and a variety of epithelial tissues.
The gastric mucosa of KCNQ1 ⫺/⫺ animals shows dramatic changes: severe mucosal hyperplasia and disorganization, hypertrophia of mucous cells, reduced parietal
cell number, and vacuolation of parietal cells with a loss
of H⫹-K⫹-ATPase staining. In addition, KCNQ1 ⫺/⫺ mice
exhibited hypochlorhydria and had elevated plasma gastrin levels that likely reflects the impairment of gastric
acid secretion. This study pointed to a pivotal function of
KCNQ1 for gastric mucosa and acid secretion; however,
the localization and cellular function of KCNQ1 in gastric
mucosa was not yet elucidated. Shortly after, KCNQ1 was
immunolocalized in the luminal membrane compartment
of mouse parietal cells where it partially colocalized with
the H⫹-K⫹-ATPase (96, 183). With the use of pharmacological inhibitors of KCNQ1, in a variety of species acid
secretion can be almost completely blocked (183). Together with the observations made in KCNQ1 knockout
mice, these reports clearly demonstrated the physiological significance of KCNQ1 for gastric acid secretion. For
the first time, these reports convincingly unraveled the
molecular identity and functional importance of a luminal
K⫹ channel of parietal cells. In the luminal membrane of
parietal cells, KCNQ1 assembles with its ␤-subunit
KCNE2 (96, 183, 220). This assembly severely changes the
biophysical properties of KCNQ1: the voltage-dependent
and slowly activating KCNQ1 is transformed into a constitutively open, voltage-insensitive, and acid-resistant
channel which is activated by cAMP and phospholipids
(96, 220, 221, 621). Recently, it was shown by a gene chip
analysis on cell-sorted rat parietal cells that KCNQ1 and
KCNE2 are both strongly expressed in gastric mucosa and
enriched in the parietal cell fraction. Moreover, pharmacological inhibition of KCNQ1 in isolated gastric glands
led to similar blockade of acid secretion as it was observed with inhibitors of the H⫹-K⫹-ATPase or histamine
receptor (H2) blockers (319). The final proof for the importance of the assembly of KCNQ1 with KCNE2 for
parietal cell function has been recently provided by a nice
study with a KCNE2 knockout mouse model: KCNE2
knockout mice display a severe gastric phenotype with
impaired acid secretion, gastric mucosal hyperplasia, and
an abnormal distribution of KCNQ1 (522).
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With regard to the K⫹ conductance, hyperpolarization of the luminal and basolateral membrane was observed upon stimulation (102, 460). With the use of the
patch-clamp technique, several different K⫹ channels
have been measured in the basolateral membrane of Necturus oxyntic cells, among them a 40- to 70-pS K⫹ channel
and an inwardly rectifying 30-pS K⫹ channel. The 40- to
70-pS K⫹ channel is activated by rises in cytosolic Ca2⫹;
the open probability of the 30-pS K⫹ channel is increased
by cAMP (597, 634). Similar channels have also been
found in the basolateral membrane of oxyntic cells of the
bullfrog (Rana catesbeiana). A frequently observed 60-pS
K⫹ channel is Ca2⫹ regulated and stimulated by Mg2⫹/
ATP from the cytosolic side (294, 418). Like oxyntic cells
from Necturus, frog oxyntic cells have a 30-pS K⫹ channel
that shows Mg2⫹-dependent inward rectification and activation by cAMP (418). Interestingly, those K⫹ channels
were inhibited by the H⫹-K⫹-ATPase inhibitor omeprazole (294, 418). Relatively little is known about K⫹ channels of mammalian parietal cells. In the basolateral membrane of rabbit parietal cells, a 230-pS K⫹ channels has
been observed as well as nonselective cation channels
(532). In parietal cells from guinea pig, three types of K⫹
conductances have been observed in whole cell experiments: voltage-dependent inwardly and outwardly rectifying K⫹ conductances and a Ca2⫹-activated K⫹ conductance (298).
1147
1148
DIRK HEITZMANN AND RICHARD WARTH
FIG. 4. Working model for acid secretion. Under resting
conditions, the H⫹-K⫹-ATPase has no access to the luminal
membrane. After stimulation of acid secretion, vesicles containing the H⫹-K⫹-ATPase fuse with the luminal membrane,
and the H⫹-K⫹-ATPase is targeted to the apical pole. In the
depth of the canaliculi, KCNE2/KCNQ1 channels in concert
with Cl⫺ channels secrete a KCl-rich fluid. Then H⫹-K⫹-ATPase
activity leads to replacement of K⫹ by H⫹. [Model adapted
from Heitzmann et al. (220).]
2. Regulation of heteromeric KCNE2/KCNQ1 channels
in the luminal membrane of parietal cells
Physiol Rev • VOL
3. Other candidates for luminal K⫹ channels of
parietal cells
Over the last 6 years, good evidence has been provided for an important role of luminal KCNE2/KCNQ1 K⫹
channels as a limiting factor for gastric acid secretion in
various species. However, there is also evidence for other
K⫹ channels in the luminal membrane of parietal cells.
Several members of the inward rectifier family (2TM-1P)
are expressed in stomach mucosa, and inwardly rectifying
K⫹ channels have been described as candidates for luminal K⫹ channels: KCNJ1 (Kir1.1, ROMK) (4), KCNJ2
(Kir2.1) (388), KCNJ10 (Kir4.1) (159), KCNJ15 (Kir4.2)
(172), KCNJ13 (Kir7.1) (171), and KCNJ16 (Kir5.1) (319).
With the use of immunofluorescence and immunoelectron
microscopy, KCNJ10 has been found to colocalize with
the H⫹-K⫹-ATPase in the luminal membrane compartment (159). In a recent gene expression study on stomach
mucosa and parietal cell-enriched cell fractions, several
K⫹ channels appeared to be specifically enriched in parietal cells compared with whole stomach mucosa. With the
use of array and real-time PCR techniques, three K⫹ channel genes were the most promising parietal cell-specific
candidates: KCNQ1, KCNE2, and KCNJ16 (319). It might
well be that heteromeric KCNJ15/KCNJ16 channels or
other members of the inward rectifier family are involved
in luminal K⫹ recycling of parietal cells. Supporting that,
very recently it has been suggested that CFTR plays a role
in gastric acid secretion by modulating a KATP-like K⫹
conductance (575). The functional data on KCNE2/
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As mentioned above, a key step during activation of
acid secretion is the exocytotic event leading to the fusion
of H⫹-K⫹-ATPase-carrying vesicles with the luminal membrane compartment. Since KCNQ1 colocalizes partially
with the H⫹-K⫹-ATPase, it was evident to suggest a similar type of regulation for KCNQ1. Under resting conditions, KCNQ1 and H⫹-K⫹-ATPase show a distribution pattern suggestive for a localization in intracellular vesicles.
Interestingly, KCNQ1 and H⫹-K⫹-ATPase are only partially colocalized, indicating that KCNQ1- and H⫹-K⫹-ATPase-carrying vesicles are not, or only to some extent, overlapping (319, 220). Upon stimulation of acid secretion, the
H⫹-K⫹-ATPase is directed to the apical pole of the parietal
cells and the distal parts of the canaliculi. The KCNQ1
staining does not show a similar strong redistribution. Although KCNQ1 and H⫹-K⫹-ATPase partially colocalize in the
canaliculi compartment, the KCNQ1 staining appears to be
less focused to the apical pole, and it is stronger in the distal
part (close to the dead end) of the canaliculi (220). Therefore, we propose the following working model (Fig. 4): upon
activation of secretion, parietal cells start to secrete a K⫹and Cl⫺-rich fluid at the end of the canaliculi. H⫹-K⫹ATPases located at the apical pole of canaliculi then
exchange K⫹ by H⫹. If this model is correct, high and
potentially harmful concentrations of HCl are formed
only at the very apical pole. This would lower the risk
for parietal cell damage due to accidental leak of the
canalicular membrane. The significance of such a leakage, however, has not yet been established. Probably,
there is not only an intracellular gradient for the distribution of KCNQ1 and the H⫹-K⫹-ATPase but also a
gradient along the gland axis. In most sections of
mouse stomach, we observed a stronger staining for
KCNQ1 in basal parietal cells and a more pronounced
staining for H⫹-K⫹-ATPase in the apically localized
parietal cells (unpublished data).
If apparently KCNE2/KCNQ1 is not regulated by a
targeting event to the luminal membrane, how is it regulated? Heterologously expressed KCNE2/KCNQ1 are activated by increases in intracellular cAMP concentration,
by PIP2, and by acidic extracellular pH (220). The activa-
tion by acidic pH is conferred on KCNQ1 by the assembly
with its parietal cell ␤-subunit KCNE2. Apparently, the
extracellular NH2 terminus and at least part of the transmembrane region of KCNE2 are needed to transmit extracellular acidification into activation of KCNQ1 current
(221). All evidence considered, KCNE2/KCNQ1 is a physiologically important luminal K⫹ channel that is activated
during stimulation of acid secretion. Inactivation of
KCNE2/KCNQ1 results in severe impairment of acid secretion. Probably indirectly via compensatory high
plasma gastrin levels, the KCNE2/KCNQ1 defect leads to
significant hyperplasia of stomach mucosa and disturbed
parietal cell morphology (117).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
KCNQ1 indicate that this channel complex is absolutely
necessary for physiological acid output under stimulated
conditions. Therefore, KCNE2/KCNQ1 could act in concert with inward rectifiers. Or the predominant role of
inward rectifiers is to support secretion at basal conditions or sustained secretion. Moreover, some of the channels mentioned above, for which the subcellular distribution is not yet known, might be localized in the basolateral
membrane. Ongoing studies on knockout mice will probably shed some light on the physiological role of the
various K⫹ channels in gastric parietal cells.
The mechanism of bicarbonate secretion in gastric
surface cells probably resembles very much those of bicarbonate secretion in small intestine. Therefore, the
principles of cellular bicarbonate transport will be discussed in more detail in section IIIB. In the stomach,
secretion of the bicarbonate-rich mucus is the most important line of defense against the aggressive gastric
juice. Unfortunately, very little is known about the role of
K⫹ channels for gastric bicarbonate secretion. On the
basis of immunofluorescence data, KCNQ1 appears to be
present in gastric surface cells. Probably associated with
its “intestinal”-type ␤-subunit KCNE3, KCNQ1 is localized
in the basolateral membrane (183). In the basolateral
membrane of surface cells, the Ca2⫹-regulated KCNN4
channel is expressed (163). Probably, KCNQ1 channels
are activated after stimulation of the cAMP pathway and
KCNN4 after increases of cytosolic Ca2⫹. When activated,
both K⫹ conductances hyperpolarize the basolateral
membrane, thereby providing the driving force for luminal Cl⫺ exit which augments Cl⫺/HCO⫺
3 exchange resulting in net secretion of HCO⫺
3 across the luminal membrane (Fig. 3B).
III. TRANSPORT ACROSS THE EPITHELIUM OF
THE SMALL INTESTINE
The small intestine is the part of the gastrointestinal
tract where most of the ingested food is digested into its
constituents. Cleavage by enzymes of the pancreatic juice
and of small intestinal enterocytes leads to the breakdown of macromolecules into reabsorbable units. Moreover, there is an impressive movement of water across the
epithelia of the gastrointestinal tract: 2–3 liters of water
are ingested by the food per day, and 7– 8 liter of water
from secretions enter the lumen of the gastrointestinal
tract. The majority of these 10 liters of water is reabsorbed by the epithelial cells of the small intestine, 1.5–2
liters are reabsorbed in the large intestine, and only 0.15–
0.2 liters are excreted by feces (18). Most of the water
Physiol Rev • VOL
reabsorption probably occurs passively driven by the osmotic gradient that is generated by reabsorption of nutrients and salt. In addition, a substantial amount of water
might be directly reabsorbed by solute transporters cotransporting water together with their substrates, e.g., the
Na⫹-dependent glucose transporter (414, 326, 362). However, more recent studies have questioned the concept of
secondarily active water transport through cotransporters (73, 165). The passive component of water reabsorption occurs paracellularly and probably transcellularly
through aquaporins (a very good overview on intestinal
aquaporins is provided by Matsuzaki et al., Ref. 402). The
molecular identification of proteins forming cell-to-cell
contacts and tight junctions has largely improved our
understanding of the paracellular pathway. Among those
proteins, claudins form the most diverse group with some
20 members. Several claudins show very specific expression patterns along the crypt-surface-villus axis and vary
in the different segments of the gastrointestinal tract.
Thus claudins are probably important structural determinants underlying the specific functional properties of the
paracellular pathway (161, 505, 164, 233).
In addition to reabsorptive processes that take place
mainly in the enterocytes of villus cells, intestinal crypt
cells produce a bicarbonate- and Cl⫺-rich secretion. For
neutralization of the luminal contents of the stomach,
bulk secretion of bicarbonate into the lumen by Brunner’s
glands, pancreas, and liver are of importance. In addition
to that, bicarbonate secretion that is derived from surface
cells ensures a neutral juxtamucosal pH within the mucus-bicarbonate barrier. To understand the physiological
regulation of transport processes in the small intestine, an
integrative approach is required taking into account the
complex and multifaceted interactions between mucosal
cells, endocrine cells, neurons, cells of the immune system, blood and lymphatic vessels, and smooth muscles
which are responsible for gastrointestinal motility (18). In
many cases, mediators and hormones affect more than
one of those cell types, and therefore, the in vivo response
upon a given stimulus might substantially differ from the
response of an isolated mucosal preparation in vitro.
Nevertheless, studies on ex vivo epithelial preparations
are the basis for understanding function and regulation of
epithelial transport. In the following, we will discuss the
mechanisms of Cl⫺ and bicarbonate secretion and electrogenic nutrient reabsorption.
A. Mechanisms of Clⴚ Secretion in Crypts of Small
Intestine
Although the small intestinal mucosa performs net
reabsorption, secretion formed by crypt cells is of physiological and especially pathophysiological relevance. Cl⫺
and to a lesser extent HCO⫺
3 are the ions whose transcel-
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F. Bicarbonate Secretion of Surface Cells in
Gastric Mucosa
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DIRK HEITZMANN AND RICHARD WARTH
lular transport dominates the secretion of crypt cells. The
basic concept of transcellular Cl⫺ transport in crypt cells
of small intestine resembles the one for the colon (Fig. 5):
basolaterally, Cl⫺ is taken up by the Na⫹-2Cl⫺-K⫹ cotransporter (NKCC1) and the A2 anion exchanger (645,
679). At the luminal side, Cl⫺ leaves the cell through
cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR)-dependent Cl⫺ channels. The
cAMP pathway is activated by a variety of hormones and
mediators, e.g., prostaglandin E2, serotonin, vasoactive
intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), and by bacterial toxins, e.g., cholera toxin (for review, see Refs. 143, 312).
Interestingly, the effect of cholera toxin is not restricted
to epithelial cells, but it also increases intestinal blood
supply and affects the gut nervous system. The importance of the enteric nervous system for the effect of
cholera toxin is highlighted by the fact that blockade of
the enteric nervous system inhibits cholera toxin-mediated fluid secretion (67, 68). Although the villi are probably still absorbing during cholera secretion (369), cholera
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⫺
FIG. 5. Cl secretion in crypt cells of small intestine. A: section
through mouse duodenum. Reabsorption occurs in enterocytes of the
large villi; Cl⫺ secretion occurs mainly in the short duodenal crypts at
the bottom of the mucosa. B: model for Cl⫺ secretion in crypt cells. For
transcellular Cl⫺ transport, Cl⫺ is taken up mainly by the Na⫹-2Cl⫺-K⫹
cotransporter (NKCC1) and to some extent by Cl⫺/anion exchanger
(AE2). Cl⫺ exits the cell predominantly through cAMP-stimulated CFTR
Cl⫺ channels. The role of Ca2⫹-activated Cl⫺ channels, e.g., Bestrophin
1 (Vmd2), for secretion in small intestinal crypt cells is still a matter of
debate. The luminal Cl⫺ exit is driven by the hyperpolarized membrane
voltage generated by basolateral and possibly luminal K⫹ channels.
From functional studies, heteromeric KCNE3/KCNQ1 channels substantially contribute to the basolateral K⫹ conductance during cAMP-stimulated secretion. During Ca2⫹-activated secretion, activity of Ca2⫹-dependent KCNN4 tightly follows the changes of cytosolic Ca2⫹. Probably,
KCNE3/KCNQ1 channels are also active during Ca2⫹-induced secretion.
The role of luminal channels is still questionable, because K⫹ secretion
through channels appears to be very low in the small intestine (70, 629).
toxin, by this “combined approach” on epithelial cells and
enteric nervous system, leads to overwhelming and sustained activation of secretion. This results in a severe
impairment of the net absorptive function of the small
intestine (18, 182, 501, 696, 143).
In addition to the cAMP-mediated CFTR Cl⫺ conductance, there is some evidence for alternative (mainly
Ca2⫹-regulated) pathways, but the physiological contribution of those “non-CFTR” Cl⫺ channels is still a matter of
debate (162, 313): ClC-2 Cl⫺ channels are expressed in
murine small intestine, but they localize to the tight junction complex (202) and/or to the basolateral membrane,
and they are not involved in luminal Cl⫺ secretion (69,
490, 694). A Ca2⫹-regulated Cl⫺ channel expressed in
small intestine is ClCA1, but its expression seems to be
restricted to goblet cells (168, 687). Bestrophin 1 (VMD2)
is a third candidate which has very recently been proposed to underlie the Ca2⫹-activated Cl⫺ conductance in
proximal colon and intestinal tumor cell lines (23). Taken
together, CFTR is the principal cAMP-activated Cl⫺ conductance; the functional contribution of Ca2⫹-activated
Cl⫺ channels in small intestine awaits to be established. It
might well be that the Ca2⫹-activated Cl⫺ conductance is
especially important for goblet cell function. In crypt
enterocytes, stimulation of the cAMP pathway strongly
increases luminal CFTR Cl⫺ conductance, which leads to
Cl⫺ exit into the lumen and depolarization of the luminal
membrane. For ongoing Cl⫺ secretion, a sufficient
amount of Cl⫺ has to be taken up via basolateral transport
systems (NKCC1 and AE2; Fig. 5B), and the luminal membrane needs to have a potential that is more negative than
the equilibrium potential of Cl⫺. The small intestinal epithelium is relatively leaky, and the luminal and basolateral
membranes are not electrically isolated from each other.
Therefore, a luminal hyperpolarization can be accomplished by activation of basolateral K⫹ channels, which
then fuel luminal Cl⫺ exit. In the colon, KCNE3/KCNQ1
K⫹ channels play the key role as basolateral K⫹ conductance during cAMP-mediated secretion (their function is
discussed in detail in sect. IVC). In small intestinal crypts,
KCNE3/KCNQ1 contribute substantially to cAMP-induced
Cl⫺ secretion (some 50%), but they are not the only active
K⫹ channels (638, 663). McNicholas et al. (411) described
a large-conductance (84 –99 pS) K⫹ channel in human
duodenum that was activated by cAMP (411). Because of
its large single-channel conductance, this channel is
clearly different from KCNE3/KCNQ1. Besides agonists
acting via cAMP (e.g., prostaglandin E2, serotonin), agonists increasing cytosolic Ca2⫹ also stimulate secretion.
Although Ca2⫹-rising agonists do not stimulate the luminal CFTR Cl⫺ conductance, they increase secretion by
hyperpolarizing the basolateral membrane, and they lead
to discharge of mucus from goblet cells. Probably, basolateral KCNN4 K⫹ channels are the major (but not only)
contributors to induce Ca2⫹-mediated secretion (the func-
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
B. Bicarbonate Secretion in Small Intestinal Villus
Cells
FIG. 6. Mechanisms of bicarbonate secretion in small intestine.
Bicarbonate secretion takes place in small intestinal crypt and villus
⫹
cells. HCO⫺
3 is taken up by basolateral Na -dependent transporters.
Basolateral K⫹ channels fuel electrogenic bicarbonate uptake and recy⫹
cle K⫹ taken up by the Na⫹-K⫹-ATPase. In addition, HCO⫺
are
3 and H
generated from CO2 and H2O; Na⫹/H⫹ exchanger activity guarantees
⫺
intracellular pH homeostasis. Luminal HCO⫺
3 exit occurs through Cl
channels and Cl⫺/bicarbonate exchangers (AE4; DRA⫽SLC26A3; PAT1⫽SLC26A6). HCO⫺
3 enters the lumen across the paracellular pathway
fueled by hydrostatic pressure and by the chemical gradient for HCO⫺
3.
Transport processes that probably are of minor importance are depicted
with dotted arrows.
The acidic pH and peptic activity of the gastric contents entering the small intestine are a severe challenge
for the enterocytes and mucosal integrity. The duodenal
protection against gastric acid consist of two major components: the unstirred gel layer of mucus reducing the
penetration of acid and pepsins and neutralization of the
acidic contents by secreted bicarbonate. The mucus layer
consists of a loosely adherent superficial layer (thickness:
⬃150 ␮m), mainly acting as lubricant and a firmly adherent layer, acting as a stable and protective line of defense
(thickness: ⬃15 ␮m). An excellent review on the gastrointestinal mucus and bicarbonate barrier has been provided by Allen and Flemström (7). In the following, we
will discuss the cellular mechanisms of bicarbonate secretion in small intestine.
Bicarbonate is taken up via basolateral Na⫹-dependent transporters in electroneutral (NBCn1) and electrogenic (NBC1) ways (Fig. 6). Basolateral K⫹ channels are
needed to restore the driving force for sustained bicarbonate uptake by electrogenic NBC1 transporters, and
they serve as a recycling pathway for K⫹ taken up by the
Na⫹-K⫹-ATPase. Ca2⫹-activated KCNN4 channels (e.g.,
activated via cholinergic stimulation, Ref. 119) and members of the inward rectifier family (KCNJ) have been
found in villus cells. Additionally, data from KCNQ1
knockout mice suggest a basolateral localization of
KCNQ1 channels in small intestinal enterocytes (638);
however, expression of KCNQ1 channels in villus cells is
very low compared with crypt cells (96, 663). With the use
of patch-clamp on enterocytes, several different K⫹ channels have been observed: Ca2⫹-dependent ones (427, 571),
inward rectifiers (566), Ca2⫹-independent large- (422) and
small-conductance K⫹ channels (119, 611), and ATP-sensitive large-conductance K⫹ channels (405). Besides electrogenic NBC1 transporters, bicarbonate and protons can
be generated by the conversion of CO2 and H2O catalyzed
by intracellular carbonic anhydrase. Basolateral and luminal Na⫹/H⫹ exchangers are engaged in the maintenance of the cellular pH homeostasis.
Bicarbonate export across the luminal membrane
occurs via Cl⫺ channels (probably mainly via CFTR, Refs.
81, 232, 310, 502) and via Cl⫺/HCO⫺
3 exchangers [AE4
(⫽SLC4A9); DRA (⫽SLC26A3), PAT-1 (⫽SLC26A6)] (7,
577, 655, 677). Recent studies have highlighted the functional importance of SLC26A6 transporters (577, 656). In
vitro data suggest that bicarbonate might also enter the
luminal space via the paracellular pathway driven by hydrostatic pressure and by the chemical gradient when an
acidic gastric content has entered the duodenum (7).
Several physiological and pathophysiological stimuli
are involved in the complex regulation of duodenal bicarbonate secretion, e.g., prostaglandin E2, VIP, and cholera
toxin via the cAMP pathway (628); heat-stable enterotoxin of Escherichia coli and guanylin via the cGMP
pathway (631, 196); acetylcholine and prostaglandin EP4
by stimulation of the Ca2⫹ pathway (560); capsaicin via
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tion of KCNN4 channels is discussed in sect. IVC). Moreover, KCNN4 also participates in Ca2⫹-mediated secretion
of Brunner’s gland of the duodenum (299). In human
duodenum, KCNN4 could underlie the 19- to 28-pS K⫹
channel that was activated by Ca2⫹ and (in 2/3 of the
patches) by cAMP (411). In mouse jejunum, large-conductance (92 pS), intermediate-conductance (38 pS), and
small-conductance (5–20 pS) K⫹ channels have been observed in the basolateral membrane (62). In cell-attached
patches, the intermediate-conductance K⫹ channel, probably KCNN4, is activated by 1-EBIO and DCEBIO (205,
206). In conclusion, cAMP (and similarly cGMP) leads to
strong and sustained Cl⫺ secretion of small intestinal
crypt cells. The chain of events comprises activation of
luminal CFTR, basolateral K⫹ channels (KCNE3/KCNQ1
and others), and basolateral uptake systems for Cl⫺
(mainly NKCC1). Ca2⫹-increasing agonists mainly stimulate basolateral K⫹ channels (KCNN4, KCNE3/KCNQ1
and others?); they do not or only weakly affect luminal
Cl⫺ conductance. Under physiological and pathophysiological conditions, costimulation of the Ca2⫹ and cAMP
pathways leads to potentiation of secretion (19).
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DIRK HEITZMANN AND RICHARD WARTH
C. Function of Kⴙ Channels for Reabsorption and
Secretion in Small Intestine
Na⫹-dependent solute transporters fueled by the
chemical gradient of Na⫹ and by the hyperpolarized membrane voltage are powerful mechanisms to reabsorb nutrients almost completely, even against the concentration
gradient of the respective substrate (403, 469). The entry
of a positive net charge by these transport systems depolarizes the luminal membrane resulting in a transepithelial
voltage difference (Vte; see Fig. 7) which consecutively
drives paracellular electrogenic transport, i.e., transport
of Cl⫺ (33, 202). On the other hand, increasing depolarization by electrogenic transport reduces the driving force
for further transcellular transport. Moreover, the uptake
of substrates, Na⫹, and water leads to osmotic cell swelling. Under these conditions, concomitant activation of K⫹
channels restores a hyperpolarized membrane voltage
and the transepithelial voltage. The efflux of K⫹ as an
osmolyte counteracts cell swelling. Therefore, it is not
surprising that K⫹ channel activity in the small intestine
appears to follow the transport activity of the enterocytes
(185, 199, 377, 378, 405, 556). Due to the low electrical
resistance of the paracellular pathway, luminal and basolateral K⫹ channels are able to repolarize the luminal
membrane in a similar way. In other respects, the consequences of activation of luminal versus basolateral K⫹
channels are not identical: luminal K⫹ channel activation
directly hyperpolarizes the luminal membrane and
thereby reduces the difference between the luminal and
basolateral potential (i.e., a low transepithelial voltage,
which cannot drive paracellular voltage-dependent reabsorption); and K⫹ is secreted into the lumen. Basolateral
K⫹ channel activation primarily hyperpolarizes the basolateral membrane and increases the transepithelial voltage that drives an ionic current across the paracellular
pathway. Dependent on the ion selectivity of the paracellular pathway, the transepithelial voltage can drive reabsorption of anions or secretion of cations. This paracelPhysiol Rev • VOL
FIG. 7. Reabsorptive function of small intestinal villus cells. Villus
enterocytes reabsorb glucose and neutral amino acids in a Na⫹-dependent manner leading to depolarization of the luminal membrane (218,
292). On the basolateral side, glucose and amino acids leave the cells by
Na⫹-independent carriers (510, 619). Since the basolateral pathway in
small intestine has a relatively high permeability for ions and does not
lead to electrical separation of luminal and basolateral membranes (24,
144, 158, 328), basolateral and luminal K⫹ channels are able to repolarize
the luminal membrane. The transepithelial voltage preferentially drives
reabsorption of anions through the paracellular pathway; water fluxinduced solvent drag can lead to reabsorption of anions and cations.
Likely candidates for basolateral K⫹ channels are KCNN4, KCNK5,
KCNE3/KCNQ1, and inward rectifiers (KCNJ family). Functionally,
MaxiK channels have been observed too. Basolateral K⫹ channels are
activated during substrate transport leading to stabilization of membrane voltage and cell volume, generation of the transepithelial voltage,
and recycling of K⫹ which has been taken up by the Na⫹-K⫹-ATPase.
Candidates for luminal channels could be KCNK1, KCNE1/KCNQ1, and
inward rectifiers. However, so far no data are available supporting the
functional relevance of luminal K⫹ channels. Therefore, relevant expression of K⫹ channels in the luminal membrane of villus cells is questionable.
lular current decreases the Vte; it leads to hyperpolarization of the luminal membrane and depolarization of the
basolateral one. In contrast to luminal K⫹ channels, basolateral K⫹ channel activity increases the K⫹ concentration in the basolateral space, but K⫹ is not “lost” into the
lumen. Since luminal application of substrates, which are
reabsorbed in a Na⫹-dependent manner, results in a substantial increase of the transepithelial voltage, activation
of the basolateral K⫹ conductance probably supports this
transepithelial voltage effect (185, 638).
Relatively little is known about the molecular identity of the K⫹ channels involved in glucose and amino acid
reabsorption. Disruption of the KCNQ1 gene leads to a
decreased short-circuit current upon luminal addition of
glucose and phenylalanine, indicating that basolateral
KCNQ1 (probably coassembling with KCNE3) are required for physiological repolarization of the cell membrane during electrogenic transport (638). In an immunofluorescence study, a KCNJ13 (Kir7.1) staining pattern
was observed in the basolateral membrane of villus cells
of rat small intestine (438). In human small intestine,
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stimulation of vanilloid receptors (272); and luminal acid
and sham feeding (7, 595). The most powerful way of
stimulation of bicarbonate secretion appears to occur via
activation of the cGMP-dependent kinase II; activation of
secretion via protein kinase A and Ca2⫹-dependent pathways is less potent (497). Probably, basolateral K⫹ channels are directly involved in this regulation of bicarbonate
secretion. Blockers of Ca2⫹-activated KCNN4 channels,
such as clotrimazole and TRAM34, inhibit duodenal bicarbonate transport induced by stimulation of the Ca2⫹ pathway; however, these blockers have no effect on cAMP and
cGMP-activated secretion. On the other hand, Ca2⫹ ionophores and 1-EBIO, an activator of Ca2⫹-activated KCNNx
channels, stimulated bicarbonate secretion (119).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
KCNJ13 also appears to be strongly expressed (479). Unfortunately, functional data highlighting the physiological
significance of KCNJ13 are not yet available.
1. What are the mechanisms underlying K⫹ channel
activation during reabsorptive activity of small
intestinal enterocytes?
Physiol Rev • VOL
IV. Kⴙ CHANNEL OF THE LARGE INTESTINE
The main physiological task of the colonic mucosa is
reabsorption of Na⫹, Cl⫺, short-chain fatty acids (SCFA,
derived from bacterial fermentation), and water as well as
secretion of K⫹, HCO⫺
3 , and mucus (36, 662). The transport of these electrolytes is closely linked to the function
of K⫹ channels in the basolateral and luminal membranes
of colonic enterocytes. Under normal conditions, the colon performs net reabsorption: from the 1.5–2 liter of
water per day entering the colon, only some 0.1– 0.2 liter
of water is finally excreted via the feces. Under pathophysiological states, such as secretory diarrhea, colonic
secretion strongly increases. As a consequence, vectorial
transport of Na⫹, Cl⫺, HCO⫺
3 , and water is reversed and
stool volume can increase up to sixfold and more: the
body loses salt, water, and bicarbonate. In colonic mucosa, K⫹ channels are a prerequisite for electrogenic
transport. In addition, they are involved in cell volume
regulation and influence very important cellular functions
such as proliferation, differentiation, apoptosis, and carcinogenesis. Over the last decades, colonic K⫹ channels
have been studied extensively, which is mirrored by more
than 500 publications on that specific issue. Nevertheless,
a variety of K⫹ channel-related functions are still a matter
of debate, e.g., 1) contribution of specific K⫹ channels to
K⫹ secretion and vectorial transport; 2) missing function
of channels which are strongly expressed, e.g., KCNH8; or
3) changes in K⫹ channel expression: cause or consequence of carcinogenesis? In this section, we outline the
role of K⫹ channels for the function of colonic enterocytes.
A. Anatomy of the Colon
Cecum, proximal, and distal colon exhibit different
functional properties. Cecum and proximal colon have an
intermediate resistance of ⬃100 ⍀䡠cm2, and the distal
colon has a fourfold higher resistance (83, 158). In the
cecum, Na⫹ is reabsorbed electrogenically and electroneutrally. Na⫹ or cation-selective channels that are different from the ENaC are believed to underlie the electrogenic reabsorption (82, 563–565). Electroneutral reabsorption involves Na⫹/H⫹ and Cl⫺/HCO⫺
3 exchange in the
luminal membrane. In the small intestine and colonic
crypt surface cells, the Na⫹/H⫹ exchanger type 3 (NHE3)
is the major isoform (170); in colonic crypt cells, NHE2 is
the dominant isoform in the luminal membrane (195) (Fig.
8). In proximal colon, also KCl cotransport has been
proposed as a luminal K⫹ secretory pathway. In the proximal colon, Na⫹ is predominantly reabsorbed in an electroneutral fashion, again via luminal Na⫹/H⫹ exchange in
concert with Cl⫺/HCO⫺
3 exchangers. The major luminal
Cl⫺/HCO⫺
exchanger
is
SLC26A3 (DRA) (559). As a ba3
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To fulfill varying physiological needs, the reabsorptive capacity of small intestinal epithelial cells is regulated
by transcriptional and nontranscriptional mechanisms.
The expression of transporters can vary over a broad
range depending on the functional requirements (45, 238,
301, 467, 470, 646). To our knowledge, nothing is known
about adaptive changes of K⫹ channel expression in small
intestinal enterocytes, and most of the studies have focused on nontranscriptional mechanisms of intestinal K⫹
channel regulation. There is good evidence for upregulation of K⫹ channels in response to increased transcellular
reabsorption and stimulated basolateral Na⫹-K⫹-ATPase
activity (“pump-leak parallelism,” Ref. 185). Also, pharmacological activation of basolateral K⫹ channels by cromakalim (543), pinacidil, BRL 38227 (234), and diazoxide
(405) has been shown to enhance Na⫹-coupled transport.
Physiologically, the basolateral K⫹ conductance is stimulated by reduction of the cytosolic ATP concentration
(405), by swelling-induced membrane stretch, and interaction with the cytoskeleton (379, 185), intracellular alkalinization (378), stimulation of Ca2⫹/calmodulin kinase
II, cytosolic Ca2⫹ (377), and the cGMP pathway (543).
Schultz and Dubinsky (556) have suggested that cell
swelling might be a key event for the upregulation of
basolateral K⫹ channels because swelling itself induces
several cellular changes such as reorganization of the
cytoskeleton, membrane stretch, and changes in cytosolic
Ca2⫹, which all by itself stimulate the K⫹ conductance.
Therefore, coordinated activation of K⫹ channels and
Na⫹-K⫹-ATPase possibly contributes to the phenomenon
of the “pump-(K⫹)-leak parallelism” (556). In the luminal
membrane of small intestinal cells, K⫹ channels probably
play no or only a minor role. It has been suggested that K⫹
secretion detectable in rat jejunum does not occur
through luminal K⫹ channels but via a pH-regulated and
channel-independent process. This process potentially involves K⫹/H⫹ exchange mechanism that is H⫹-K⫹-ATPase
independent (35, 70). Taken together, K⫹ channel regulation in small intestinal villus cells appears to be modulated dependent on the reabsorptive activity of the enterocytes. By this mechanism, the basolateral K⫹ conductance guarantees 1) a stable driving force for voltagedependent transport activity, 2) it serves cell volume
homeostasis, and 3) it recycles K⫹ which is constantly
taken up by the Na⫹-K⫹-ATPase.
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DIRK HEITZMANN AND RICHARD WARTH
solateral export system for Na⫹ and HCO⫺
a
3,
Na⫹(HCO⫺
)
cotransporter
has
been
proposed
that
is
3 x
stimulated by epinephrine (153, 561, 562). Na⫹ reabsorption through apical Na⫹ channels is of minor importance.
Moreover, aldosterone apparently increases only electroneutral reabsorption of Na⫹ but not the electrogenic one
(124, 153). In proximal colon, Ca2⫹-regulated K⫹ channels
have been found in the luminal and basolateral membrane. As in the distal colon, the total basolateral K⫹
conductance is decreased by agonists stimulating the
cAMP pathway (554). The distal colon is responsible for
fine tuning of the salt and water reabsorption and, when
stimulated, the colonic mucosa secretes mucus and fluid
to facilitate the passage of the feces. As the distal nephron
and sweat gland ducts, this segment of the gut is a target
tissue of mineralocorticoids that control Na⫹ reabsorption and K⫹ secretion. Additionally, a variety of other
hormones and mediators modulate colonic transport (Table 2). The colonic mucosa consists of crypts, which can
be divided into crypt surface, crypt middle, and crypt
base. Along the crypt axis, the differences in transport
properties reflect a differentiation process that occurs in
the short life span (3– 8 days in human, Refs. 320, 352) of
the crypt cells. The colonic crypt encompasses at least
three cell lineages: enterocytes, endocrine cells, and mucus-producing goblet cells. Renewal of crypt cells by proliferation of stem cells (located in a niche at the crypt
base), migration and differentiation, apoptosis, and exfoliation have to be tightly controlled to avoid ulceration on
the one hand and carcinogenesis on the other hand (226,
Physiol Rev • VOL
623). With their migration (4.5 ␮m/h) from the crypt base
towards the surface, the functional properties of the enterocytes change (520, 626). At the crypt base, cells predominantly perform electrogenic Cl⫺ secretion. The major task of surface cells is to reabsorb Na⫹ and SCFA and
⫹
to secrete HCO⫺
3 and K . However, this “classical view” of
a strict functional gradient along the crypt axis is probably not correct: under certain conditions, surface cells
also contribute to Cl⫺ secretion, and crypt cells can fulfill
reabsorptive tasks, e.g., Na⫹ reabsorption via NHE2 (172,
195).
Besides the net reabsorption of electrolytes and
SCFA, colonic mucosa reabsorbs water. Interestingly, the
precise mechanism of colonic water reabsorption is still
not well understood. Up to 1.5–2 liters of water are reabsorbed per day, but it is at present not clear how much of
the water passes transcellularly and paracellularly. Several aquaporins (AQP) are expressed in the colonic epithelium: AQP1, AQP3, AQP4, and AQP8 (373, 397). In
surface cells, AQP8 is located in the luminal membrane
and probably contributes to transcellular water transport
(317). AQP8 knockout mice only have a very mild phenotype, probably because other aquaporins or reabsorption
across the paracellular pathway compensate for the AQP8
defect. (683). AQP4 is mainly localized in the basolateral
membranes of the upper half of colonic crypts and at
higher levels in proximal than in distal colon. AQP4
knockout mice displayed reduced water permeability in
the proximal colon and a slightly increased water content
of the feces. Interestingly, cAMP-mediated secretion is
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FIG. 8. Principles of colonic ion transport. A: picture of an isolated colonic crypt. The arrows point to cells which correspond to the cell models
shown in B–D. B: transport model of a colonic crypt cell. Cl⫺ secretion in colonic crypt cells has three major components: luminal cAMP-activated
CFTR-dependent Cl⫺ channels, basolateral K⫹ channels (predominantly KCNE3/KCNQ1 and KCNN4), and Na⫹-2Cl⫺-K⫹ cotransporter (NKCC1) as
⫹
⫹
main Cl⫺ uptake system. HCO⫺
3 transporters are found in the luminal and basolateral membrane and the Na /H exchanger type 2 (NHE2) in the
luminal membrane. K⫹ channels are also localized in the luminal membrane. C: ion transport in surface cells of proximal colon. Na⫹ is mainly
⫺
reabsorbed electroneutrally via apical Na⫹/H⫹ exchangers (mainly NHE3). Cl⫺/HCO⫺
3 exchangers (mainly DRA) and Cl /small-chain fatty acid
(SCFA) exchangers have been observed in the luminal membrane, too. KCNMA1 (MaxiK) K⫹ channels appear to be a major pathway for luminal
K⫹ secretion. In the basolateral membrane, KCNE3/KCNQ1, KCNN4, and probably KCNK5 support electrogenic transport by hyperpolarizing the
membrane voltage. D: in surface cells of distal colon, Na⫹ reabsorption mainly occurs in an electrogenic way through epithelial sodium channels
(ENaC) in exchange for K⫹ (leaving the cell through apical K⫹ channels). Luminal H⫹-K⫹-ATPases (colonic type) are engaged in K⫹ reabsorption,
which is of importance during K⫹ deprivation (416).
1155
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
TABLE
2.
Agonists modulating colonic transport
Agonist
Eicosanoids
PGE2
PGF2␣
PGI2
PGD2
HETE, HPETE
Amines
Serotonin
Origin
M
M
M
M, EC
Norepinephrine/epinephrine
N
Adenosine
Peptides
VIP
M
N
M
N
GRP (gastrin-releasing peptide)
Tachykinins (substance P,
N
neurokinin A and B,
neuropeptide B)
Opioids
Endothelins
Prolactin
Guanylin/uroguanylin
Proteases
Trypsin, thrombin, tryptase
EE
N
cAMP
secretion
secretion
variable
secretion 2
secretion
110, 116, 425
157
157
114, 178
25, 86
E
SM
N
E
ET (SM)
N
SM
N
E(s)
E(s)
N
E
N
5-HT(x)
cAMP
182, 533
Ca2⫹
secretion
contraction
secretion
secretion
relaxation
secretion
contraction
cAMP2, Ca2⫹
cAMP
absorption
K⫹ secretion
Ca2⫹
PGE2
secretion
secretion
407, 654
Ca2⫹
Ca2⫹
K⫹ secretion
contraction
secretion
182, 336, 337, 399, 542
58, 182, 278
cAMP
secretion
relaxation
secretion
secretion
cAMP2
variable
absorption
VIP
IP3, Ca2⫹
NO
M3
M1
nicotinic
␣1
␣2
␣2
␤1
␤2
H1
P2Y2⫹4
P2X
E
SM
E
E
N/SM
N
E
cAMP
Y1
NA(␣2)
N
E
N
N
E, N
E
E
relaxation
absorption
secretion 2
Absorption
Secretion
KCl secretion 2
secretion
SSTR1, 2, 5
Jak/STAT
cGMP
M, feces E
PAR1-4
G protein-coupled
Gas
NO (nitric oxide)
N, M, L
PGE2,
cGMP
Cytokines
Tumor necrosis factor ␣
L
Bacterial toxins
Cholera toxin
Toxin of Y. enterocolitica
Heat-stable E. coli toxin
Heat-labile E. coli toxin
Toxin A of C. difficile
Laxatives
Ricinoleic acid
Anthraquinones
Bile salts
Ref. Nos.
EP4
ET1R
PRL-R
GC-C
P
Effect
E, N
N
N
N
N
E
NPY (neuropeptide Y), PYY
(peptide YY)
Somatostatin
Messenger
N
E
N
(E, SM)
E
E
SubE
E
M
GM1
SM
E, N, SubE
cAMP
5-HT, VIP
cGMP
cGMP
PGE2
cAMP
113, 251, 278, 457
98, 236, 278, 583, 598
46
142, 624, 625
85, 182, 278, 315
47, 278, 589
111, 141, 278, 598, 657
278, 598
307
155, 503
290
secretion, inhibition 87, 390
of Na⫹ reabsorption
secretion
182, 670
secretion,
inflammation
546
secretion
secretion
relaxation
secretion
secretion
67, 68, 182, 368, 501, 696
secretion
secretion,
inflammation
contraction
PGE2, histamine, 5-HT, NO secretion
secretion
240
450, 501
696
182
182
256
135
N, neurons; E, enterocytes; M, mast cells; EC, enterochromaffin cells; EE, enteroendocrine cells; SubE, subepithelial cells; ET, endothelial
cells; SM, smooth muscle cells; L, leukocytes; P, pituitary; “(s)”, species differences
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N
Purines
ATP
Receptor
E, SubE
Acetylcholine
Histamine
Target
1156
DIRK HEITZMANN AND RICHARD WARTH
not affected by the AQP4 inactivation (649). The model of
colonic water reabsorption driven by an osmotic gradient
is challenged by the fact that osmolality of the feces is
probably rather high. Therefore, a special model of water
absorption in distal colon has been proposed: crypt cells
and pericryptal sheath surrounding colonic crypts act in
concert to perform effective water reabsorption (435,
436). In the future, integrative research on the axial gradients of aquaporin expression and the peculiar properties and composition of the paracellular pathway will help
to further elucidate colonic water reabsorption.
B. Pathways of Luminal Kⴙ Secretion
1. Luminal KCNMA1 (MaxiK) channels
Among the above-mentioned presumably luminal K⫹
channels, KCNMA1 is the one for which localization and
function in the luminal membrane is documented best. By
immunofluorescence, a KCNMA1-specific staining was
consistently observed in colonic surface cells (146), especially in the apical membrane (210, 503, 542). However,
the localization of KCNMA1 in the luminal membrane of
crypt cells described in these studies is controversial.
Recent studies provided evidence for alteration of KCNMA1 localization by ulcerative colitis and end-stage renal disease. In normal tissue, KCNMA1 was restricted to
surface cells; however, in ulcerative colitis and end-stage
renal disease, the KCNMA1 signal was also detected in
crypt cells. The authors concluded that the changes in
KCNMA1 expression might contribute to the fecal loss of
Physiol Rev • VOL
2. Luminal KCNN4 (IK1, SK4, KCa3.1) channels?
In two studies, the localization of KCNN4 in rat colonic mucosa has been investigated; however, the staining
pattern differed. Using isolated crypts, Joiner et al. (268)
observed a strong basolateral staining in crypt cells and a
more diffuse pattern in surface cells. Furness et al. (163)
used tissue sections for immunohistochemistry. They observed a KCNN4 staining at the luminal and basolateral
membrane of enterocytes with a weaker signal at the
crypt base. Unfortunately, tissues from KCNN4 knockout
mice were not used as negative controls. Is KCNN4 a
pathway for luminal K⫹ secretion? Based on pharmacology and immunofluorescence, it has been concluded that
KCNN4 contributes to K⫹ secretion (268). However, two
other studies are questioning this conclusion. In colonic
mucosa of KCNN4 knockout mice, carbachol was still
able to activate luminal K⫹ channels, but the activation of
basolateral K⫹ channels was absent (146, 147, 400). The
data from KCNN4 knockout mice clearly point to the
relevance of KCNN4 as a basolateral channel. A major
contribution of KCNN4 to Ca2⫹-induced K⫹ secretion in
surface cells appears to be unlikely because this type of
secretion was virtually absent in KCNMA1 but not in
KCNN4 knockout mice (400).
3. Evidence for other K⫹ channels in the luminal
membrane?
Analysis of K⫹ channel gene expression in colonic
mucosa suggests that, besides KCNN4 and KCNMA1,
members of the KCND, KCNH, KCNJ, and KCNK families
are also expressed (406). At present, functional data indicating a role for one or several of those channels for K⫹
secretion in the native tissue are not yet available.
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During the last years, much attention has been paid
to the regulation of colonic K⫹ secretion. This function of
colonocytes, which is controlled by mineralocorticoids, is
important for the maintenance of body K⫹ homeostasis.
In addition, luminal K⫹ channels are necessary to establish a sufficient driving force for Na⫹ reabsorption
through ENaC channels (210, 312, 359). However, the
molecular identity of the luminal K⫹ channels underlying
this K⫹ secretion is still a question of debate. The investigation of luminal K⫹ channels in the colon is hampered
by the fact that patch-clamp experiments of luminal membrane patches of native crypts are extremely difficult
because mucus and microvilli strongly impair seal formation. Therefore, most data have been obtained from isolated cells, cultured cells, or from Ussing chamber experiments. At present, several K⫹ channels are “hot” candidates as luminal K⫹ channels: 1) KCNMA1 (MaxiK) (63,
210, 400, 542), 2) KCNN4 (IK1 or SK4) (97, 163, 268), 3) a
chromanol 293B-sensitive K⫹ conductance (112) (which
was not observed in another study, Ref. 391), 4) a inwardly rectifying K⫹ channel probably belonging to the
KCNJ family (662), and 5) perhaps members of the KCNK
family (unpublished data).
K⫹ observed in patients suffering from ulcerative colitis
and end-stage renal disease (398, 536). The functional
importance of KCNMA1 as luminal K⫹ channel of colonic
crypts has been highlighted by numerous studies. In the
luminal membrane of colonic crypt cells, a large-conductance (200 –240 pS) K⫹ channel has been described that is
voltage dependent and regulated by pH, Ca2⫹, and the
cholesterol content of the membrane. Its abundance is
increased by high dietary K⫹ load, by aldosterone, and
probably also by glucocorticoids (63, 359, 537, 34, 318).
Moreover, KCNMA1 channels mediate K⫹ secretion upon
stimulation with luminal purines. This type of Ca2⫹-mediated K⫹ secretion is missing in KCNMA1 knockout mice
(542). These data are suggestive of a prominent role of
KCNMA1 during K⫹ secretion across the luminal membrane of colonocytes. However, there is also evidence
that luminal K⫹ secretion is more complex and probably
consists of several components (552).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1157
C. Role of Kⴙ Channels for Clⴚ Secretion in
Colonic Crypt Cells
1. cAMP-mediated secretion
In crypt cells of large and small intestine, stimulation
of the cAMP pathway leads to sustained and strong secretion of electrolytes and water (Fig. 9). The primary ion
that is transported transcellularly is Cl⫺ and, therefore,
this type of secretion is called Cl⫺ secretion. The key
event for Cl⫺ secretion is the activation of the CFTRdependent Cl⫺ conductance in the luminal membrane. In
cystic fibrosis patients, whose CFTR is defective, this type
of secretion is strongly diminished or absent (312). Upon
activation of the Cl⫺ conductance, Cl⫺ leaves the cell into
the lumen, thus depolarizing the luminal membrane towards the equilibrium potential of Cl⫺. At the equilibrium
potential of Cl⫺, further Cl⫺ exit would be impossible.
Basolateral (and luminal) K⫹ channels hyperpolarize the
membrane, thereby energizing further luminal Cl⫺ exit.
There is evidence from KCNQ1 knockout mice and pharmacological data obtained from rat, rabbit, and human
tissue indicating that cAMP-activated Cl⫺ secretion
largely depends on the activity of basolateral heteromeric
KCNE3/KCNQ1 channels (357, 38, 112, 309, 380, 389, 549,
638). Only in guinea pig colon, no such function for
KCNE3/KCNQ1 has been observed (348).
Why is KCNE3/KCNQ1 in most species examined so
important for cAMP-mediated secretion? KCNE3/KCNQ1
is not the only K⫹ channel in the basolateral membrane of
crypt cells. Another major contributor under control conditions is the Ca2⫹-dependent KCNN4 K⫹ channel. However, after stimulation with cAMP, the cytosolic Ca2⫹
activity drops (probably due to voltage dependence of
Physiol Rev • VOL
Ca2⫹ influx pathways), and KCNN4 activity is shut off
(40). For this reason, the basolateral KCNE3/KCNQ1 K⫹
conductance is the bottleneck during cAMP-induced secretion, and inhibition of KCNE3/KCNQ1 almost completely abolishes electrogenic secretion. In small intestinal crypts, the contribution of KCNE3/KCNQ1 to electrogenic Cl⫺ secretion is less pronounced, and it accounts
only for ⬃50% (638, 663). The biophysical properties of
KCNE3/KCNQ1 are remarkable: homomeric KCNQ1 or
heteromeric KCNE1/KCNQ1 are voltage-sensitive and
slowly activating K⫹ channels (21, 539). Assembly of
KCNQ1 with its intestinal (KCNE3) or gastric (KCNE2)
subunits changes the biophysical properties completely:
KCNE3/KCNQ1 channels are much less voltage dependent and do not show slow activation, but they are constitutively open (549). Moreover, the assembly with different KCNE subunits modifies the pharmacological properties of KCNQ1 (59, 220, 221, 338, 339). The singlechannel conductance of KCNQ1 channels is very small
(221, 526, 567, 685), and from noise analysis, it was estimated to be below 3 pS in colonic epithelium (666).
Interestingly, KCNE3/KCNQ1 channels are stimulated in a
cAMP-dependent way, and they are able to generate a
hyperpolarized basolateral membrane voltage in colonic
crypt cells. The paracellular pathway between colonic
crypt cells is probably permeable for cations such as Na⫹.
Thus luminal and basolateral membranes are not electrically isolated from each other, and basolateral hyperpolarization drives a paracellular Na⫹ flux into the lumen
and hyperpolarizes the luminal membrane (659). By this
mechanism, the basolateral K⫹ conductance repolarizes
the luminal membrane and supports ongoing luminal Cl⫺
exit. In addition to CFTR-dependent Cl⫺ conductance and
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2⫹
⫺
⫺
FIG. 9. cAMP- and Ca -stimulated Cl secretion of colonocytes. A: cAMP-mediated Cl secretion, e.g., by stimulation with prostaglandin E2
(PGE2). A primary event of cAMP-induced secretion is the activation of the luminal CFTR-dependent Cl⫺ conductance. In the basolateral membrane,
KCNE3/KCNQ1 channels are activated and hyperpolarize the basolateral membrane, thereby fueling luminal Cl⫺ exit. Na⫹ follows through the
paracellular pathway. In colonocytes, increases in cAMP lead to reduction of cytosolic Ca2⫹ activity. By this mechanism, luminal and basolateral
⫺
2⫹
Ca2⫹-regulated K⫹ channels close. HCO⫺
-mediated secretion after stimulation with
3 can be secreted through CFTR or in exchange for Cl . B: Ca
acetylcholine. In contrast to cAMP stimulation, Ca2⫹ is not able to activate CFTR. Activity of basolateral KCNN4 K⫹ channels mirrors the time
2⫹
course of acetylcholine-induced Ca increase. KCNE3/KCNQ1 channels are also activated by increased cytosolic Ca2⫹ activity. In the luminal
membrane, Ca2⫹-regulated K⫹ channels are stimulated and lead to electroneutral transcellular secretion of KCl. As a consequence of luminal K⫹
channel activity, the transepithelial voltage difference is small, and paracellular Na⫹ transport decreases.
1158
DIRK HEITZMANN AND RICHARD WARTH
2. cGMP-stimulated secretion
Stimulation of proximal colonic mucosa by agonists
acting via cGMP, e.g., guanylin (6, 152), leads to strong
secretion due to activation of CFTR Cl⫺ conductance. The
Escherichia coli heat-stable enterotoxin apparently also
activates secretion as an exogenous agonist of guanylin
receptors. The effects of guanylin are virtually absent in
mice lacking intact CFTR (90). The effect of guanylin on
K⫹ channels in colonic mucosa has not yet been directly
tested, but presumably, KCNE3/KCNQ1 is responsible for
cGMP-mediated secretion too.
3. Secretion in response to increases in cytosolic Ca2⫹
Upon stimulation with agonists raising intracellular
Ca2⫹, colonic crypt cells hyperpolarize close to the equilibrium potential of K⫹ (Fig. 9B). The hyperpolarization is
due to a large increase in whole cell K⫹ conductance:
Ca2⫹ strongly activates Ca2⫹-sensitive basolateral (and to
lesser extent also luminal) K⫹ channels (662). With the
use of the patch-clamp technique, the most frequently
observed K⫹ channel in the basolateral membrane of
mammalian colonic crypts is a 10- to 25-pS small- to
intermediate-conductance K⫹ channel that is steeply regulated by Ca2⫹ in the physiological range (half-maximal
activation at 300 nM free Ca2⫹, Hill coefficient of 3) (40,
57, 106, 538). In cell-attached recordings, open probability
of this channel is increased by agonists increasing cytosolic Ca2⫹, e.g., carbachol, or by cell swelling (535, 669).
In excised patches, the channels show a run-down, but
channel activity can be refreshed by application of ATP,
suggesting that phosphorylation/dephosphorylation might
regulate the channel. The nature of the respective protein
kinase is still a matter of debate: the human channel has
been reported to be activated by protein kinase A (360,
538); however, this has not been observed for the rat
channel (446). Moreover, protein kinase C appears to be
Physiol Rev • VOL
not involved in this regulation (107, 446). Probably, the
ATP effect is rather complex: a COOH-terminal domain of
the channel confers the ATP sensitivity without being
phosphorylated itself (173). Interestingly, aldosterone has
been claimed to inhibit the human Ca2⫹-activated K⫹
channel by a nongenomic mechanism (48, 49). Pharmacologically, the Ca2⫹-activated K⫹ channel of colonic
crypts is blocked by Ba2⫹ (90% inhibition at 100 ␮M),
charybdotoxin, TEA, clotrimazole (IC50 60 nM), quinine,
and quinidine. The channel is insensitive to the chromanol
293B (inhibitor of KCNQ1 channels) and activated by
1-EBIO (probably by shifting the Ca2⫹ sensitivity) (40,
108, 109, 128, 644, 662, 665). The functional properties of
the colonic Ca2⫹-activated K⫹ channel resemble those of
cloned human and mouse KCNN4 (SK4, IK1, KCa3.1) channels (244, 270, 355, 356, 640), and in fact, the rat KCNN4
was cloned from colonic crypts (644, 665). Interestingly,
the KCNN4 protein itself is not sensing Ca2⫹, but it becomes Ca2⫹-regulated by association with calmodulin
(134, 269, 281). The relevance of KCNN4 as basolateral K⫹
channel has been highlighted by recent studies on two
knockout models for this channel gene. Disruption of
KCNN4 severely impaired carbachol-induced short-circuit
current in Ussing chamber experiments. In wild-type animals, carbachol leads to a strong (and transient) lumennegative transepithelial voltage (induced by the large increase in basolateral KCNN4 conductance). In KCNN4
knockout mice, this lumen-negative transepithelial voltage deflection is strongly reduced (400) or even absent
(146), but carbachol induced a lumen-positive transepithelial voltage deflection due to activation of luminal
Ca2⫹-regulated K⫹ channels (probably KCNMA1) (400).
Besides hyperpolarization for energizing the transport, a luminal Cl⫺ conductance is needed for the induction of electrogenic Cl⫺ secretion. Ca2⫹-activated Cl⫺
channels are not expressed in normal mucosa of distal
colon, or only at very low levels. However, there appears
to be expression of Ca2⫹-regulated Cl⫺ channels in proximal colon, e.g., members of the ClCa family (132). Very
recently, it was shown that bestrophin 1 is another good
candidate to underlie this conductance (23, 312, 313).
Under experimental conditions allowing detection of
small increases in luminal Cl⫺ conductance, Schultheiss
et al. (553) have observed activation of luminal Cl⫺ channels by cholinergic stimulation. This Cl⫺ conductance
was NO dependent and had pharmacological characteristics different from CFTR (553). Ca2⫹-activated Cl⫺ channels can be hardly detected in normal distal colon, but
expression of those channels is increased after induction
of carcinogenesis, and a variety of cell lines derived from
intestinal tumors exhibit Ca2⫹-activated Cl⫺ channels (23,
39). If Ca2⫹-activated Cl⫺ channels are very weakly expressed under physiological conditions, how do Ca2⫹stimulating agonists stimulate Cl⫺ secretion in distal colon? The Ca2⫹-rising agonists predominantly activate ba-
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basolateral KCNE3/KCNQ1 channels, basolateral uptake
of Cl⫺ has also to be stimulated during secretion to provide sufficient intracellular Cl⫺. The major basolateral
Cl⫺ uptake system is the Na⫹-2Cl⫺-K⫹ cotransporter
(NKCC1), which is stimulated by low intracellular Cl⫺,
cell shrinkage, and cAMP (91, 98, 188, 222, 371, 521).
Besides transcellular Cl⫺ transport, the colonic mucosa is
able to secrete HCO⫺
3 as anion, be it through CFTR or by
exchanging luminal SCFA (or Cl⫺) against HCO⫺
3 via luminal anion exchangers (SCFA/HCO⫺
exchanger
or Cl⫺/
3
⫺
HCO3 exchanger, Fig. 9A) (36, 137, 138). Stimulation of
the cAMP pathway does not only increase electrolyte and
water secretion into the lumen, but it also activates production and secretion of mucus by enterocytes. Mucus
secretion by goblet cells is believed to occur mainly after
increases in cytosolic Ca2⫹ (for review, see Refs. 149,
204).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
D. Do Kⴙ Channels Influence Cell Fate,
Proliferation, and Carcinogenesis?
Over the last years, changes of K⫹ channel expression have been shown to be associated with cancer in a
growing number of publications. Apparently, the control
of the cell voltage and cell volume by K⫹ channels greatly
affects the regulation of the cell cycle, proliferation, and
apoptosis (189, 324, 456, 672). With regard to determination of cellular fate and cell differentiation, only a few
examples of primary involvement of K⫹ channels have
been described so far (30, 219).
In the colon, stem cells in the crypt base region
exhibit a very high proliferation rate; the daughter cells
differentiate and lose their proliferative capacity during
their migration to the surface. Finally, the surface cells
undergo apoptosis and are replaced by their successors.
In normal colon, exfoliation of nonapoptotic cells is believed to be a rare event. In tumor tissue, cells do not lose
their capacity to proliferate, and the initiation of apoptosis appears to be retarded: transformed colonocytes accumulate and large numbers of not yet apoptotic cells are
exfoliated into the lumen (320, 358). In renal proximal
tubular cells, KCNK5 (TASK2) K⫹ channels are required
Physiol Rev • VOL
for apoptotic volume decrease, which is a key event during the process of apoptosis (316). So far, it is not known
whether KCNK5 plays a similar role for apoptotic volume
decrease in small and large intestine, where the channel is
also expressed. The changes in the cellular program during carcinogenesis go along with changes of protein expression and electrical properties. Several K⫹ channels
have been found to be overexpressed in cancer tissue,
e.g., members of the “EAG” family (KCNH1 and KCNH2)
(76, 473, 474), KCNC1 and KCNC4 (Kv3.1 and Kv3.4) (465,
586), KCNA5 (Kv1.5) (465, 586), KCNMA1 (MaxiK) (43),
and KCNK9 (TASK3) (329, 432, 484). Although the
changes in K⫹ channel expression are well documented, it
is often not clear whether those changes are causative for
carcinogenesis or an epiphenomenon reflecting dedifferentiation and ongoing proliferation. Analysis of gene expression profiles including K⫹ channels will help to improve our knowledge about the cellular phenomena underlying carcinogenesis. Moreover, tumor-associated K⫹
channels could serve as useful tumor markers and possible targets for local treatment of colonic cancer (591).
V. EXOCRINE PANCREAS AND SALIVARY
GLANDS: PARADIGMS FOR EXOCRINE
SECRETION
Over the past decades, studies of ion transport mechanisms in exocrine pancreas and salivary glands have
promoted our understanding of the principles underlying
exocrine secretion of epithelial cells. In the following, we
will delineate the putative roles of K⫹ channels in acinar
and duct cells of exocrine pancreas and salivary glands
and their contribution to transepithelial ion transport.
A. Enzyme and Clⴚ Secretion in Pancreatic Acinar
Cells
In humans, the epithelial cells of the exocrine pancreas secrete ⬃2 liters of alkaline and enzyme-rich fluid
per day. During the interdigestive phases, the secretory
rate is rather low (0.2– 0.3 ml/min). After ingestion of
food, the secretion rate increases 10-fold. Morphologically and functionally, the exocrine pancreas consists of
two parts, the acinar cells forming a NaCl- and enzymerich fluid and duct epithelial cells that produce bicarbonate-rich secretion. The major task of pancreatic acinar
cells is the secretion of digestive enzymes and zymogens
via exocytosis of enzyme-containing vesicles (so-called
zymogen granules, Fig. 10A) and transepithelial transport
of NaCl and water (496). The mechanisms by which zymogen granules fuse with the apical membrane and release their content have been studied extensively (for
review, see Ref. 257). Upon the fusion event, activation of
ion conductances and water channels in the granule mem-
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solateral K⫹ channels (and to less extent luminal K⫹
channels). Thereby, they increase the driving force for
luminal Cl⫺ exit through open Cl⫺ channels. The major
luminal Cl⫺ conductance is CFTR dependent, but CFTR is
not Ca2⫹ stimulated in colonocytes. Therefore, Ca2⫹-stimulated Cl⫺ secretion necessitates residual costimulation
with cAMP to keep CFTR active. Inhibition of the endogenous cAMP production by indomethacin (indomethacin
inhibits the generation of the cAMP-rising prostaglandin
E2) abolishes cholinergic Cl⫺ secretion. In the absence of
a relevant luminal Cl⫺ conductance, only the Ca2⫹-induced activation of luminal K⫹ channels can be observed
in transepithelial voltage measurements (391).
What is the physiological significance of Ca2⫹-induced Cl⫺ secretion in colonic mucosa? Compared with
cAMP-stimulated secretion, the effect of increased Ca2⫹
appears to be less important, because it is transient, and
it needs cAMP costimulation. Under physiological conditions, stimulation with acetylcholine leads to Ca2⫹-activated flush secretion of electrolytes, water, and mucus. In
addition, acetylcholine stimulates contraction of colonic
muscle and propulsion of the feces. In this regard, Ca2⫹induced secretion is probably important to guarantee low
friction for the propulsion of feces. Longer lasting or
repetitive activation of the Ca2⫹ pathway probably leads
to modification of the composition of the secreted fluid
due to activation of luminal K⫹ channels and reduction of
the paracellular Na⫹ flux: under such conditions, the mucosa secretes a KCl-rich fluid instead of NaCl.
1159
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DIRK HEITZMANN AND RICHARD WARTH
brane is believed to facilitate the wash-out of the vesicle,
thereby discharging zymogens and enzymes into the lumen (258) (however, it should be stated that the major
component of the luminal agonist-elicited Cl⫺ conductance is independent from vesicular conductances, Ref.
253). With the use of molecular and biochemical approaches, ClC-2 and ClC-3 Cl⫺ channels, aquaporin-1 water channels KCNJ8 (⫽Kir6.1), and KCNQ1 K⫹ channels
have been identified in the vesicle membrane (614, 615). A
recent patch-clamp study has highlighted the putative role
of KCNJ8 K⫹ channels and ClC-2 and ClC-3 Cl⫺ channels
in freshly isolated zymogen granules (279). The regulation
of zymogen granule release is mainly triggered by agonists
leading to an IP3-mediated rise of cytosolic Ca2⫹, e.g.,
acetylcholine (via M1 and M3 muscarinic receptors, Refs.
169, 252) and CCK (via CCK1 and CCK2 receptors; however, the role of CCK in stimulating human acinar cells
has been questioned, Refs. 261, 517, 647).
In contrast to the few studies on ion channels located
on secretory vesicles, the cellular mechanism of transepithelial NaCl transport in acinar cells has been investigated extensively. The basic mechanisms are depicted in
Figure 10B. Cl⫺ is taken up across the basolateral memPhysiol Rev • VOL
brane via several transporters, i.e., the Cl⫺/HCO⫺
3 exchanger (AE2, Ref. 529), the Na⫹-2Cl⫺-K⫹ cotransporter
(NKCC1), and the thiazide-sensitive NaCl cotransporter
(NCC, Ref. 697). In response to increases in cytosolic
Ca2⫹, the Cl⫺ conductance of the luminal membrane is
strongly enhanced (145, 394, 478, 693). K⫹ channels hyperpolarize the basolateral membrane, thereby creating
the driving force for luminal Cl⫺ exit through open channels (493). Na⫹ follows across the paracellular pathway
driven by the transepithelial voltage difference (492, 580).
As for enzyme release, hormonal stimulation by acetylcholine or CCK, which leads to rises of cytosolic Ca2⫹,
plays the central role for activating electrogenic Cl⫺ secretion (175, 423, 493, 496). In fact, the acetylcholine
signaling cascade involving a pivotal contribution of IP3
as a messenger releasing Ca2⫹ from internal stores has
been described for the first time in this tissue (590).
Increases in cytosolic Ca2⫹ activity induce impressive
changes of the ion conductance of pancreatic acinar cells.
In the relatively small surface of the luminal membrane, a
large number of Cl⫺ channels open in response to the rise
of Ca2⫹ (478), thus depolarizing the membrane voltage
from some ⫺40 to ⫺20 mV (580). The luminal Cl⫺ chan-
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FIG. 10. Ion transport in exocrine pancreas. A: histology of a pancreatic acinus cells. Zymogen-containing vesicles are localized at the apical
pole of the cells. B: model for Cl⫺ secretion in pancreatic acinar cells. Agonists raising cytosolic Ca2⫹ induce the opening of luminal Ca2⫹-regulated
Cl⫺ channels which depolarize the membrane close to the equilibrium potential of Cl⫺. Basolateral K⫹ channels [KCNE1/KCNQ1, KCNMA1 (MaxiK),
and others] hyperpolarize the membrane voltage below the equilibrium potential of Cl⫺, thus powering luminal Cl⫺ exit. Stimulation of the cAMP
pathway stimulates basolateral KCNQ1 channels. Ca2⫹-regulated nonselective cation channels probably play a minor role (478). Cl⫺/HCO⫺
3
exchanger (AE2), Na⫹-2Cl⫺-K⫹ (NKCC1), and NaCl (NCC) cotransporters serve as Cl⫺ uptake mechanisms in the basolateral membrane. C: model
⫹
⫺
of transepithelial bicarbonate in pancreatic duct cells. At the basolateral membrane, bicarbonate is taken up by a Na -2HCO3 cotransporter (NBC).
Additionally, intracellular carbonic anhydrase accelerates formation of bicarbonate from CO2. Na⫹/H⫹ exchangers (NHE) extrude the H⫹ across the
basolateral membrane. Ca2⫹-activated KCNN4 (IK1) and large-conductance K⫹ channels (MaxiK) hyperpolarize the basolateral membrane and
create the driving force for luminal anion exit. In the luminal membrane, Cl⫺/HCO⫺
3 exchangers (SLC26A3 and SLC26A6; Ref. 431) secrete
bicarbonate in exchange for Cl⫺, which leaves the cell through luminal CFTR-type Cl⫺ channels. In addition, non-CFTR-like channels might be also
present. During stimulated secretion, bicarbonate transport probably does not occur via Cl⫺/HCO⫺
3 exchangers but predominantly through a
2⫹
CFTR-dependent luminal HCO⫺
-regulated Cl⫺ channels appear to play a role during Ca2⫹-mediated secretion. Na⫹
3 conductance. In addition, Ca
follows through the paracellular pathway fueled by the transepithelial voltage.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
Physiol Rev • VOL
and prostaglandin E2 (probably via EP3 receptors), likely
because those receptors reduce the intracellular cAMP
concentration via inhibitory G proteins (330, 332). Although the above-mentioned studies suggest a substantial
contribution of KCNE1/KCNQ1 to Cl⫺ secretion of acinar
cells, KCNQ1 inhibitors do not have a relevant impact on
fluid and enzyme secretion of rat exocrine pancreas (333).
Therefore, KCNE1/KCNQ1 channels are not the bottle
neck limiting acetylcholine-induced secretion, and their
inhibition can be compensated. Further studies are
needed to identify and to characterize other basolateral
K⫹ channels. Taken together, Ca2⫹ and cAMP pathways
act, at least in part, in concert for inducing a strong
electrolyte secretion in pancreatic acinar cells.
B. Role of the Kⴙ Conductance for Bicarbonate
Secretion in Pancreatic Ducts
Pancreatic duct cells secrete a very alkaline fluid that
contains up to 140 mM bicarbonate under stimulated
conditions. Under resting conditions, the bicarbonate
concentration is in the range of 30 – 60 mM. Although the
composition of pancreatic juice during stimulated secretion has been known for a long time, it is still a matter of
debate by which mechanisms the ducts cells achieve such
high bicarbonate secretion (Fig. 10C). An excellent overview about the current knowledge of bicarbonate transport in pancreatic ducts is provided by Steward, Ishiguro,
and Case (588). Under resting conditions with relatively
low luminal concentrations of bicarbonate, a luminal Cl⫺/
HCO⫺
3 exchanger (working in a 1:1 stoichiometry) is able
to transport HCO⫺
3 into the lumen energized by the concentration gradient of Cl⫺. Under stimulated conditions
with high luminal bicarbonate and low Cl⫺ concentrations, however, such a Cl⫺/HCO⫺
3 exchanger would import bicarbonate. Therefore, other transport mechanisms
are needed to explain the secretion of HCO⫺
3 against the
chemical gradient (243, 588). One possibility is the presence of electrogenic Cl⫺/HCO⫺
3 exchangers with a stoichiometry of 1:2 (e.g., SLC26A6), which are fueled by the
membrane voltage (243, 588). Such a secretion mode is
possible, if 1) Cl⫺ taken up by the Cl⫺/HCO⫺
3 exchanger
does not accumulate in the cytosol (luminal Cl⫺ channels
are required as exit or recycling pathway) and 2) the
luminal membrane voltage is sufficiently hyperpolarized
(probably in the range of ⫺45 mV) to drive the negative
net charge out of the cell. Which mechanisms are responsible for hyperpolarizing the luminal membrane? Most
likely, the luminal membrane is hyperpolarized below the
equilibrium potential of Cl⫺ by basolateral K⫹ channels
(454). Those basolateral K⫹ channels can also induce
luminal hyperpolarization because the luminal and basolateral membrane are not electrically separated but connected via a Na⫹-permeable paracellular pathway (454).
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nels have been shown to have a very small single-channel
conductance (1–2 pS, Ref. 394), and they are not inhibited
by typical Cl⫺ channel inhibitors such as DIDS, NPPB,
and glibenclamide (693). From the halide permeability
sequence it was deduced that the CFTR Cl⫺ channel does
not underlie this conductance (693). In another study on
pig pancreatic acini, a ClC-2-like Cl⫺ channel has been
described (66). In parallel to activation of luminal Cl⫺
channels, Ca2⫹ stimulates K⫹ channels in the basolateral
membrane. This K⫹ conductance is required to hyperpolarize the membrane voltage below the equilibrium potential to fuel luminal Cl⫺ exit. In pancreatic acinar cells of
various species, a Ca2⫹-regulated large-conductance K⫹
channel (200 pS) has been observed upon stimulation
with the Ca2⫹ agonists acetylcholine, CCK, and bombesin
(254, 255, 396, 492, 494, 495, 599). In rodents, this largeconductance K⫹ channel appears to be expressed in an
age-dependent manner with low expression levels in
young and increased expression in adult animals (463). A
less frequent 50-pS K⫹ channel, which is voltage and Ca2⫹
activated, has been found in human and guinea pig pancreatic acinar cells (495, 599). In mouse pancreatic acini,
voltage-activated K⫹ channels (620) as well as pH-regulated inwardly rectifying K⫹ channels have been observed
that were not regulated by cAMP and cytosolic Ca2⫹
activity (545). It has been suggested that besides members
of the inward rectifier family also 2-P domain K⫹ channels
contribute to the pH-regulated K⫹ conductance of pancreatic acinar cells (126). Apparently different from the
K⫹ channels described above, a slowly activating and
voltage-dependent component of the K⫹ conductance in
pancreatic acinar cells is augmented after cholinergic
stimulation. This current can be inhibited by the KCNQ1
blocker 293B, and single-channel amplitude is very small,
both suggesting that KCNQ1 underlies this voltage-dependent K⫹ conductance of acinar cells (284, 302). The peculiar current kinetics and the fact that this current is
diminished in KCNE1 knockout mice speak in favor for an
assembly of KCNQ1 with its ␤-subunit KCNE1 (663).
In addition to hormone receptors coupling to the
IP3/Ca2⫹ pathway, pancreatic acinar cells express receptors whose stimulation leads to generation of cAMP, e.g.,
receptors for secretin and VIP. Compared with the prominent regulation by cytosolic Ca2⫹, stimulation of the
cAMP pathway is considered to be of minor importance
for the activation of Cl⫺ secretion (496). Interestingly, the
increase of cytosolic cAMP concentration strongly augments the voltage-dependent and slowly activating K⫹
current carried by heteromeric KCNE1/KCNQ1 K⫹ channels, but cAMP is not able to stimulate luminal Ca2⫹regulated Cl⫺ channels (286). Therefore, cAMP on its own
is not capable to induce transcellular Cl⫺ secretion, but it
probably enhances Ca2⫹-activated Cl⫺ secretion by increasing the driving force for luminal Cl⫺ exit. The
KCNE1/KCNQ1 K⫹ current is inhibited by somatostatin
1161
1162
DIRK HEITZMANN AND RICHARD WARTH
cells can be inhibited by ATP via purinergic receptor
stimulation (probably P2Y2 or P2Y4, Refs. 216, 584). ATP
is released from acinar cells after cholinergic stimulation
and might act as a paracrine factor coordinating acinar
and duct cell function (585). In contrast to basolateral
receptors, luminal puringeric receptors (probably P2X7
and P2X4) lead to depolarization of the membrane and
increases in whole cell conductance (216).
Taken together, sufficient activity of basolateral K⫹
channels is a prerequisite to drive apical electrogenic Cl⫺
and HCO⫺
3 secretion. Furthermore, hyperpolarization of
the basolateral membrane and depolarization of the luminal membrane establish a transepithelial voltage difference that in turn leads to paracellular Na⫹ flux into the
lumen. By these mechanisms, apical, basolateral, and
paracellular ways of ion transport cooperate to establish
secretion of HCO⫺
3 up to 150 mM.
1. What are the properties of the basolateral K⫹
conductance?
C. Fluid and Electrolyte Secretion in Salivary
Glands
According to impalement studies on isolated perfused rat pancreatic ducts, resting pancreatic duct cells
have a hyperpolarized basolateral membrane voltage of
⫺60 to ⫺70 mV due to a high K⫹ conductance leading to
a basolateral resistance of 90 –120 ⍀䡠 cm2 (453, 454). The
luminal membrane of resting duct cells has a very high
electrical resistance of ⬃2,000 ⍀䡠cm2 and probably no
significant K⫹ conductance. The paracellular pathway, as
mentioned in the last paragraph, is Na⫹ permeable with
an estimated resistance of 50 – 80 ⍀䡠cm2. Several hormones stimulating secretion in acinar cells via increases
in cytosolic Ca2⫹ such as CCK, bombesin, and substance
P have no effect on duct cells (468). However, cholinergic
stimulation of the Ca2⫹ pathway and, more importantly,
increases in cAMP by stimulation with secretin, VIP, and
adrenaline (via ␤-receptors) lead to dramatic changes of
the electrical properties of duct cells: the basolateral K⫹
conductance is increased leading to a small hyperpolarization which is followed by depolarization caused by
strong activation of a luminal Cl⫺ conductance (452, 468).
The impressive increase in luminal ion conductance is
mirrored by a drop of the luminal resistance from 2,000 to
80 ⍀䡠cm2. There is experimental evidence for activation
of the luminal Cl⫺ conductance by cAMP and Ca2⫹ pathways (148, 468, 664). The cAMP-induced increase in basolateral K⫹ conductance is probably caused by activation of MaxiK channels via cAMP-dependent phosphorylation. It has been suggested that phosphorylation of
MaxiK channels alters the Ca2⫹ responsiveness of the
channel (187). Additional candidates for basolateral K⫹
channels are Ca2⫹-regulated KCNN4 (IK1) and pH- and
cell volume-sensitive KCNK5 (TASK2) channels (148,
618). Interestingly, the K⫹ conductance of pancreatic duct
In humans, per day more than 1 liter of saliva is
produced mainly by three pairs of large salivary glands,
i.e., sublingual, submandibular, and parotid glands. The
saliva is a watery secretion containing electrolytes, proteins, and mucus. The secretion of saliva is a highly
regulated process (via autonomic innervation) with relatively low rates between the meals and a very high secretion after stimulation, which is initiated by food-related
thoughts, smell and taste of food, and by mastication.
Cholinergic stimulation is a major way for activation
(547), but a variety of other factors and hormones also
modulate saliva production, e.g., ␤-adrenergic stimulation
(104, 264), substance P (265), and purinergic signaling
(680). Saliva is required to hydrate and to protect the
mucosa of the oral cavity, to facilitate milling and transport of the ingested food, to dissolve gustatory substances, to initiate digestion, and to protect against microbial, mechanical, and chemical insults (415, 548). The
physiological importance of saliva is highlighted by diseases of the salivary glands which result in reduced saliva
production, e.g., Sjögren’s syndrome (OMIM no. 270150),
cystic fibrosis (OMIM no. 219700), and chemotherapy
and irradiation for head and neck tumors. Clinical
symptoms encompass oral dryness (xerostomia), dysphagia, adherence of food to the oral mucosa, oral
burning, dental caries, changes in taste, inability to eat
dry food, intolerance to spicy food, inability to speak
for long periods, and chronic esophagitis due to reduced
clearance and buffering of gastric acid leaking back into
the esophagus (53). Like the secretory mechanism in
exocrine pancreas, saliva secretion involves two stages
(613). First, a fluid of plasmalike electrolyte composition
is formed by salivary acinar cells. Afterwards, the secre-
Physiol Rev • VOL
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Another possibility for achieving high luminal HCO⫺
3
concentrations would be a transport model with a HCO⫺
3permeable ion conductance in the luminal membrane.
The likely candidate for such a luminal HCO⫺
3 -permeable
channel is CFTR, which has been shown to conduct not
only Cl⫺ but also HCO⫺
3 (502, 582). Moreover, patients
suffering from cystic fibrosis display reduced alkalinization of pancreatic fluid (266, 297). Also for this model of
HCO⫺
3 secretion, hyperpolarization of the luminal membrane below the equilibrium potential of HCO⫺
3 is required to energize luminal HCO⫺
exit.
Again,
basolateral
3
K⫹ channels are probably responsible for hyperpolarizing
the luminal membrane. Interestingly, data from knockout
mice suggest a functional interplay between CFTR and
the Cl⫺/HCO⫺
3 exchanger SLC26A6 (653). Further work is
needed to elucidate the exciting and complex interactions
of Cl⫺- and HCO⫺
3 -transporting membrane proteins in the
luminal membrane of pancreatic duct cells.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
1163
tion is modified during its passage through the ducts:
NaCl is reabsorbed and K⫹ and HCO⫺
3 are secreted by the
duct epithelial cells (392). Below, the basic principles of
saliva formation and its modification along the ducts will
be outlined.
D. Formation of Primary Saliva by Acinus Cells
The principles of saliva production have been the
focus of several excellent reviews (392, 410, 415, 439, 504,
548, 609, 630), and useful lists of salivary gland-specific
gene expression and protein localization have been provided (214, 437). For primary saliva formation, the transcellular movement of Cl⫺ represents a pivotal step (Fig.
11). For this purpose, Cl⫺ is taken up basolaterally via the
Na⫹-2Cl⫺-K⫹ cotransporter [NKCC1 (424) and the Cl⫺/
HCO⫺
3 exchanger AE2 (214, 443)]. NKCC1 activity is increased during muscarinergic and ␤-adrenergic stimulation (131, 488). Data from NKCC1-deficient mice have
highlighted the importance of NKCC1 as Cl⫺ uptake
mechanism: saliva flow of the parotid gland was reduced
by some 60% in knockout mice, although these mice
showed a compensatory increase in basolateral Cl⫺/
⫺
HCO⫺
3 exchange (130). At the luminal pole, Cl leaves the
Physiol Rev • VOL
cell through Ca2⫹-activated Cl⫺ channels. The BEST2
(vitelliform macular dystrophy 2-like protein 1) gene
product has been proposed to underlie this Ca2⫹-activated Cl⫺ conductance, but this is still a matter of debate
(415, 437). Other Cl⫺ channels that expressed salivary
glands are ClC2 and ClC3 (437, 440). The luminal Cl⫺ exit
is energized by basolateral K⫹ channels that hyperpolarize the membrane voltage below the Cl⫺ equilibrium potential. With the use of patch-clamp techniques, Ca2⫹- and
voltage-activated K⫹ channels of large conductance (KCNMA1 ⫽ MaxiK ⫽ BK ⫽ Slo1, associated with the ␤-subunits KCNMB1 and KCNMB4) have been described in the
basolateral membrane of parotid and submandibular acinus cells (395, 441, 475). A second type of K⫹ channel
frequently observed in salivary glands is the Ca2⫹-activated K⫹ channel of intermediate single-channel conductance (KCNN4 ⫽ IK1 ⫽ SK4) (213, 246, 259, 441, 602).
Besides Ca2⫹, KCNN4 has been proposed to be activated
by protein kinase A in submandibular acinus cells (212).
Only in bovine parotid glands, an additional inwardly
rectifying K⫹ channel (KCNJ2) has been found (211). For
a long time, the relative contributions of the major channels, MaxiK and IK1, for the basolateral K⫹ conductance
was a matter of debate (245, 247, 592). In recent years,
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FIG. 11. Mechanisms of saliva formation. A: simplified scheme of saliva formation. In acinus cells, a NaCl-rich fluid is secreted. Duct cells
⫺
reabsorb Na⫹ and Cl⫺ transcellularly and secrete K⫹ and HCO⫺
is taken up by the basolateral
3 . B: transport model of a salivary acinus cells. Cl
Na⫹-2Cl⫺-K⫹ cotransporter (NKCC1) and by the anion exchanger (AE2) (214). HCO⫺
3 is formed from CO2 in a carbonic anhydrase-dependent way
(not shown); the H⫹ leaves the cell through a basolateral Na⫹/H⫹ exchanger (NHE1). Additionally, a basolateral Na⫹-HCO⫺
3 cotransporter has been
described (NBC1, Ref. 476; not shown in the model). Ca2⫹-activated Cl⫺ channels (perhaps BEST2, Ref. 437) serve as luminal Cl⫺ exit pathway. Na⫹
enters the lumen across the paracellular pathway driven by the transepithelial voltage; water follows probably transcellularly through aquaporins
(probably mainly AQP5, Ref. 99) [Adapted from Nakamoto et al. (437) and Turner and Sugiya (630).] C: working model of salivary duct function
during stimulated saliva production. Na⫹ is reabsorbed through ENaC and luminal Na⫹/H⫹ exchangers; Cl⫺ is reabsorbed by CFTR. HCO⫺
3 is taken
⫹
⫹
up by basolateral Na⫹-HCO⫺
exchanger (NHE1) is
3 cotransporters (NBC) secreted into the lumen via CFTR (370, 570). The basolateral Na /H
involved in the regulation of the cytosolic pH. The molecular nature of the luminal K⫹ channels is not precisely known. Ducts are relatively
impermeable to water; therefore, net absorption of ions results in hypotonic saliva.
1164
DIRK HEITZMANN AND RICHARD WARTH
E. Modification of the Primary Saliva by Duct
Epithelia
The major task of salivary gland duct epithelia is to
modify the plasmalike fluid secreted by acinar cells. Final
saliva composition and ion transport in ducts are dependent on the secretory status of the gland. At “low flow”
resting conditions, the ionic composition of the final saliva is (in mM): 3 Na⫹, 25 K⫹, 24 Cl⫺, and 3 HCO⫺
3 , pH 6.5;
after stimulation of saliva secretion by the autonomic
Physiol Rev • VOL
nervous system, the saliva flow largely increases and the
ionic composition changes (in mM): 45 Na⫹, 21 K⫹, 40
Cl⫺, 26 HCO⫺
3 , pH 7.5 (410). This modification of primary
saliva during the passage through the duct system encompasses reabsorption of Na⫹ and Cl⫺ and secretion of K⫹
and HCO⫺
3 (613). Water is not reabsorbed or only very
little. Since the reabsorption of NaCl exceeds the secretion of K⫹ and HCO⫺
3 , the final saliva becomes hypotonic.
In the luminal membrane, Na⫹ is reabsorbed through
ENaC (84, 123). Cl⫺ enters the cells probably mainly via
the CFTR-dependent Cl⫺ conductance (695). In addition,
ClCA Cl⫺ channels have been described (242, 681). Basolaterally, Na⫹ is extruded by the Na⫹-K⫹-ATPase; Cl⫺
leaves the cell most likely through Cl⫺ channels. For the
luminal secretion of HCO⫺
3 , it has been suggested that
similar to pancreatic ducts luminal CFTR is involved in
this process (570, 695). In the luminal and basolateral
membrane of duct cells, several Na⫹-HCO⫺
3 cotransporting systems (NBC family, Ref. 525) have been found
whose expression patterns appear to vary in a gland-,
segment-, and species-dependent manner (3, 296, 347, 433,
476, 528, 530). Basolateral NBC transporters act as uptake
systems for HCO⫺
3 , and luminal NBC transporters have
been suggested to work as salvage mechanism: in the
resting gland, ducts appear to reabsorb HCO⫺
3 rather than
secreting it, resulting in a relatively low pH (6.5) of the
final saliva at these conditions (370, 613). Electrogenic
NBC transporters (229), e.g., NBC1 in the luminal membrane of ducts of guinea pig parotid gland, could, in
principle, participate in luminal HCO⫺
3 secretion (dependent on a sufficiently hyperpolarized luminal membrane)
(347, 525). Relatively little is known about the K⫹ channels underlying luminal K⫹ secretion (486) (for an overview of the expression of K⫹ channel in salivary glands,
see Table 1). In duct cells, K⫹ channels are needed to
energize voltage-dependent transport processes, e.g., lu⫹
uptake as well as basolateral
minal HCO⫺
3 exit and Na
⫺
uptake of HCO3 by electrogenic members of the NBC
transporter family. Furthermore, luminal K⫹ channels are
the likely pathway for K⫹ secretion, and basolateral K⫹
channels are needed to recycle K⫹ that has been taken up
by the Na⫹-K⫹-ATPase. As such a way for luminal K⫹
secretion, KCNJ1 (ROMK)-like channels have been described in human submandibular cells (353). With the use
of immunofluorescence techniques, a KCNN4 (IK1, SK4)specific strong signal was observed in intercalated ducts
of the submandibular gland (618); however, functional
data evaluating the significance of KCNN4 in salivary
ducts have not yet been published. Further studies are
needed to evaluate the functional contribution of KCNJ1
and KCNN4 channels and to identify additional K⫹ channel candidates supporting the ion transport in salivary
ducts.
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several interesting studies on genetically modified mice
have shed light on the role of these channels during
secretion. Interestingly, KCNN4 (IK1) knockout mice displayed normal activated fluid secretion in parotid glands,
although the linear (KCNN4-specific) K⫹ current component was diminished (27). Also KCNMA1 (MaxiK) knockout mice showed a mild phenotype with a normal secretion rate and slight changes of the ionic composition of
the saliva (523). However, KCNMA1/KCNN4 double
knockout mice exhibited a severely reduced secretion
rate of parotid (523) and submandibular glands (524),
indicating that both channels are important. The membrane voltage of acinar cells of double knockout mice was
depolarized. Upon cholinergic stimulation, the cells depolarized further, which is indicative of the activation of
Ca2⫹-regulated Cl⫺ channels in the absence of Ca2⫹-regulated K⫹ conductance (523, 524). In conclusion, MaxiK
and IK1 K⫹ channels underlie the Ca2⫹-regulated basolateral K⫹ conductance in salivary glands and contribute to
the electrical driving force for luminal Cl⫺ exit. The Cl⫺
channel-induced depolarization of the luminal membrane
and the K⫹ channel-induced hyperpolarization of the basolateral membrane establish a lumen-negative Vte that
drives Na⫹ through the paracellular pathway into the
lumen (492, 630). Parallel to the Ca2⫹-induced cellular
changes leading to NaCl secretion, rises in Ca2⫹ stimulate
the insertion of AQP5 into the luminal membrane (249,
401). The increased cellular water permeability and the
osmotic gradient built by the secretion of NaCl result in a
water flux into the lumen. Although a variety of different
aquaporins are expressed in salivary glands (99), the severely impaired water flux observed in AQP5-deficient
mice underlines the importance of AQP5 for fluid secretion of acinar cells (303, 372). Additionally, there is evidence for a paracellular water flux in submandibular
gland (434). Taken together, the Ca2⫹-induced concerted
activation of luminal and basolateral transport systems
results in the secretion of large amounts of isotonic NaClrich fluid. Additionally, salivary proteins are secreted in
acinar cells via exocytosis of zymogen-containing granules. The secretion of salivary proteins is stimulated in
response to rises of cAMP, e.g., after VIP or ␤-adrenergic
stimulation (248, 415).
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
VI. CONCLUSIONS AND PERSPECTIVES
Physiol Rev • VOL
covery of small interfering RNAs (siRNA) as a novel way
of posttranscriptional regulation of gene expression and
the availability of the siRNA technique to knock-down
already synthesized RNA offer new perspectives for basic
and applied research. In the future, the integrative use of
molecular and functional techniques and of modern methods of the postgenome era will further improve our
knowledge about the multifaceted functions of gastrointestinal K⫹ channels and their potential clinical implications.
ACKNOWLEDGMENTS
We thank Dr. Weber for critically reading the manuscript
and Prof. Dr. Kunzelmann for fruitful discussions.
Address for reprint requests and other correspondence: R.
Warth, Institute of Physiology, Universitaetstrasse 31, 93053
Regensburg, Germany (e-mail: [email protected]).
GRANTS
This work was supported by Deutsche Forschungsgemeinschaft Grant SFB699.
REFERENCES
1. Abbott GW, Butler MH, Bendahhou S, Dalakas MC, Ptacek
LJ, Goldstein SA. MiRP2 forms potassium channels in skeletal
muscle with Kv3.4 and is associated with periodic paralysis. Cell
104: 217–231, 2001.
2. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH,
Timothy KW, Keating MT, Goldstein SA. MiRP1 forms IKr
potassium channels with HERG and is associated with cardiac
arrhythmia. Cell 97: 175–187, 1999.
3. Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A,
Kurtz I. Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J Biol Chem 273: 17689 –17695,
1998.
4. Aihara T, Nakamura E, Amagase K, Tomita K, Fujishita T,
Furutani K, Okabe S. Pharmacological control of gastric acid
secretion for the treatment of acid-related peptic disease: past,
present, and future. Pharmacol Ther 98: 109 –127, 2003.
5. Alabi AA, Bahamonde MI, Jung HJ, Kim JI, Swartz KJ. Portability of paddle motif function and pharmacology in voltage sensors. Nature 450: 370 –375, 2007.
6. Albano F, de Marco G, Canani RB, Cirillo P, Buccigrossi V,
Giannella RA, Guarino Guanylin A. E. coli heat-stable enterotoxin induce chloride secretion through direct interaction with
basolateral compartment of rat and human colonic cells. Pediatr
Res 58: 159 –163, 2005.
7. Allen A, Flemstrom G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin. Am J Physiol Cell Physiol
288: C1–C19, 2005.
8. Aller MI, Veale EL, Linden AM, Sandu C, Schwaninger M,
Evans LJ, Korpi ER, Mathie A, Wisden W, Brickley SG. Modifying the subunit composition of TASK channels alters the modulation of a leak conductance in cerebellar granule neurons. J Neurosci 25: 11455–11467, 2005.
9. Alloui A, Zimmermann K, Mamet J, Duprat F, Noel J, Chemin
J, Guy N, Blondeau N, Voilley N, Rubat-Coudert C, Borsotto
M, Romey G, Heurteaux C, Reeh P, Eschalier A, Lazdunski M.
TREK-1, a K⫹ channel involved in polymodal pain perception.
EMBO J 25: 2368 –2376, 2006.
10. Amberg GC, Baker SA, Koh SD, Hatton WJ, Murray KJ,
Horowitz B, Sanders KM. Characterization of the A-type potas-
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Advances in electrophysiological and molecular techniques as well as genomics and proteomics approaches
have enormously improved our understanding of K⫹
channels over the last 25 years. In the epithelia of the
gastrointestinal tract, K⫹ channels serve a variety of important functions, and their large molecular diversity allows precise adaptation to the complex needs. Such vital
functions of K⫹ channels encompass 1) the K⫹ channelmediated hyperpolarization as a prerequisite of vectorial
transport across the epithelial cells. By this mechanism,
many different K⫹ channels energize voltage-driven transport processes, e.g., electrogenic glucose reabsorption in
small intestine, colonic Na⫹ reabsorption by epithelial
Na⫹ channels, and Cl⫺ secretion in crypt cells or exocrine
glands. Moreover, the polarized activation of K⫹ channels
in basolateral or luminal membranes is a critical factor for
the establishment of a transepithelial voltage difference
that is needed to drive ion transport across the paracellular pathway. 2) Luminal MaxiK channels in the colonic
surface cells act as an exit pathway for K⫹. These mineralocorticoids-controlled channels play a significant role
for the fine-tuning of the electrolyte homeostasis. 3) Several K⫹ channels act in concert with K⫹-transporting
ATPases by allowing K⫹ recycling across the plasma
membrane. A prominent example for this function is the
KCNE2/KCNQ1 heteromeric K⫹ channel, whose activity is
indispensable for gastric acid secretion by the H⫹-K⫹ATPase. 4) K⫹ channels play a role in cellular volume
regulation. During reabsorption of nutrients, epithelial
cells transport vast amounts of osmolytes and, therefore,
they are continuously challenged by changes of cell volume. Cell volume-dependent activation of K⫹ channels is
needed to counterbalance the cellular increase in osmolytes and induces regulatory volume decrease after
cell swelling. 5) K⫹ channels are involved in the control of
cell differentiation, proliferation, and carcinogenesis. Unfortunately, in many cases it is not clear whether changes
in K⫹ function are causative or secondary. Nevertheless,
few examples have illustrated the potential of K⫹ channels to play a crucial role for differentiation, apoptosis,
and carcinogenesis.
The information about the expression, function, and
regulation of gastrointestinal K⫹ channels is still incomplete and fragmentary, not at least because the experimental approach is complicated by the functional and
morphological diversity of the tissues (e.g., crypt and
villus cells) and the high fragility of freshly isolated tissues and cells. Generation and phenotypical analysis of
transgenic and knockout mice have turned out to be very
powerful tools to study the relevance of K⫹ channels in
gastrointestinal epithelia. Data from genetically modified
animals enabled us to bridge the gap between physiology
and clinically relevant pathophysiology. The exciting dis-
1165
1166
11.
12.
13.
14.
15.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
sium current in murine gastric antrum. J Physiol 544: 417– 428,
2002.
Amberg GC, Koh SD, Hatton WJ, Murray KJ, Monaghan K,
Horowitz B, Sanders KM. Contribution of Kv4 channels toward
the A-type potassium current in murine colonic myocytes.
J Physiol 544: 403– 415, 2002.
Arrighi I, Bloch-Faure M, Grahammer F, Bleich M, Warth R,
Mengual R, Drici MD, Barhanin J, Meneton P. Altered potassium balance and aldosterone secretion in a mouse model of
human congenital long QT syndrome. Proc Natl Acad Sci USA 98:
8792– 8797, 2001.
Arrighi I, Lesage F, Scimeca JC, Carle GF, Barhanin J. Structure, chromosome localization, tissue distribution of the mouse
twik K⫹ channel gene. FEBS Lett 425: 310 –316, 1998.
Ashcroft FM. Adenosine 5⬘-triphosphate-sensitive potassium
channels. Annu Rev Neurosci 11: 97–118, 1988.
Ashmole I, Goodwin PA, Stanfield PR. TASK-5, a novel member
of the tandem pore K⫹ channel family. Pflügers Arch 442: 828 – 833,
2001.
Atkinson NS, Robertson GA, Ganetzky B. A component of
calcium-activated potassium channels encoded by the Drosophila
slo locus. Science 253: 551–555, 1991.
Bang H, Kim Y, Kim D. TREK-2, a new member of the mechanosensitive tandem-pore K⫹ channel family. J Biol Chem 275: 17412–
17419, 2000.
Banks MR, Farthing MJ. Fluid and electrolyte transport in the
small intestine. Curr Opin Gastroenterol 18: 176 –181, 2002.
Banks MR, Golder M, Farthing MJ, Burleigh DE. Intracellular
potentiation between two second messenger systems may contribute to cholera toxin induced intestinal secretion in humans. Gut 53:
50 –57, 2004.
Bao L, Kaldany C, Holmstrand EC, Cox DH. Mapping the BKCa
channel’s “Ca2⫹ bowl”: side-chains essential for Ca2⫹ sensing.
J Gen Physiol 123: 475– 489, 2004.
Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M,
Romey G. KvLQT1 and IsK (minK) proteins associate to form the
IKs cardiac potassium current. Nature 384: 78 – 80, 1996.
Barriere H, Belfodil R, Rubera I, Tauc M, Lesage F, Poujeol C,
Guy N, Barhanin J, Poujeol P. Role of TASK2 potassium channels regarding volume regulation in primary cultures of mouse
proximal tubules. J Gen Physiol 122: 177–190, 2003.
Barro SR, Spitzner M, Schreiber R, Kunzelmann K. Bestrophin
1 enables Ca2⫹ activated Cl⫺ conductance in epithelia. J Biol Chem
2006.
Barry RJC, Smyth DH, Wright EM. Short-circuit current and
solute transfer by rat jejunum. J Physiol 181: 410 – 431, 1965.
Battu S, Clement G, Heyman M, Wal JM, Cook-Moreau J,
Desjeux JF, Beneytout JL. Production of arachidonic acid metabolites by the colon adenocarcinoma cell line HT29 cl.19A and
their effect on chloride secretion. Cancer Lett 116: 213–223, 1997.
Bayliss DA, Sirois JE, Talley EM. The TASK family: two-pore
domain background K⫹ channels. Mol Interv 3: 205–219, 2003.
Begenisich T, Nakamoto T, Ovitt CE, Nehrke K, Brugnara C,
Alper SL, Melvin JE. Physiological roles of the intermediate
conductance, Ca2⫹-activated potassium channel Kcnn4. J Biol
Chem 279: 47681– 47687, 2004.
Behrens R, Nolting A, Reimann F, Schwarz M, Waldschutz R,
Pongs O. hKCNMB3 and hKCNMB4, cloning and characterization
of two members of the large-conductance calcium-activated potassium channel beta subunit family. FEBS Lett 474: 99 –106, 2000.
Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande
D, Mannens MM, Baro I, Wilde AA. Mutation in the KCNQ1 gene
leading to the short QT-interval syndrome. Circulation 109: 2394 –
2397, 2004.
Bendahhou S, Fournier E, Sternberg D, Bassez G, Furby A,
Sereni C, Donaldson MR, Larroque MM, Fontaine B, Barhanin J. In vivo and in vitro functional characterization of Andersen’s
syndrome mutations. J Physiol 565: 731–741, 2005.
Benson MD, Li QJ, Kieckhafer K, Dudek D, Whorton MR,
Sunahara RK, Iniguez-Lluhi JA, Martens JR. SUMO modification regulates inactivation of the voltage-gated potassium channel
Kv1.5. Proc Natl Acad Sci USA 104: 1805–1810, 2007.
Physiol Rev • VOL
32. Bezanilla F. The voltage-sensor structure in a voltage-gated channel. Trends Biochem Sci 30: 166 –168, 2005.
33. Bijlsma PB, Bakker R, Groot JA. The chloride conductance of
tight junctions of rat ileum can be increased by cAMP but not by
carbachol. J Membr Biol 157: 127–137, 1997.
34. Binder HJ, McGlone F, Sandle GI. Effects of corticosteroid
hormones on the electrophysiology of rat distal colon: implications
for Na⫹ and K⫹ transport. J Physiol 410: 425– 441, 1989.
35. Binder HJ, Murer H. Potassium/proton exchange in brush-border
membrane of rat ileum. J Membr Biol 91: 77– 84, 1986.
36. Binder HJ, Rajendran V, Sadasivan V, Geibel JP. Bicarbonate
secretion: a neglected aspect of colonic ion transport. J Clin Gastroenterol 39: S53–S58, 2005.
37. Blank T, Nijholt I, Kye MJ, Radulovic J, Spiess J. Smallconductance, Ca2⫹-activated K⫹ channel SK3 generates age-related
memory and LTP deficits. Nat Neurosci 6: 911–912, 2003.
38. Bleich M, Briel M, Busch AE, Lang HJ, Gerlach U, Gögelein H,
Greger R, Kunzelmann K. KvLQT channels are inhibited by the
K⫹ channel blocker 293B. Pflügers Arch 434: 499 –501, 1997.
39. Bleich M, Ecke D, Schwartz B, Fraser G, Greger R. Effects of
the carcinogen dimethylhydrazine (DMH) on the function of rat
colonic crypts. Pflügers Arch 433: 254 –259, 1997.
40. Bleich M, Riedemann N, Warth R, Kerstan D, Leipziger J, Hör
M, Van Driessche W, Greger R. Ca2⫹-regulated K⫹ and nonselective cation channels in the basolateral membrane of rat colonic crypt base cells. Pflügers Arch 432: 1011–1022, 1996.
41. Bleich M, Schlatter E, Greger R. The luminal K⫹ channel of the
thick ascending limb of Henle’s loop. Pflügers Arch 415: 449 – 460,
1990.
42. Bleich M, Shan QX. Epithelial K(⫹) channels: driving force generation and K(⫹) recycling for epithelial transport with physiological and clinical implications. Sheng Li Xue Bao 59: 443– 453, 2007.
43. Bloch M, Ousingsawat J, Simon R, Schraml P, Gasser TC,
Mihatsch MJ, Kunzelmann K, Bubendorf L. KCNMA1 gene
amplification promotes tumor cell proliferation in human prostate
cancer. Oncogene 12: 2525–2534, 2007.
44. Bond CT, Sprengel R, Bissonnette JM, Kaufmann WA, Pribnow D, Neelands T, Storck T, Baetscher M, Jerecic J, Maylie
J, Knaus HG, Seeburg PH, Adelman JP. Respiration and parturition affected by conditional overexpression of the Ca2⫹-activated
K⫹ channel subunit, SK3. Science 289: 1942–1946, 2000.
45. Boudry G, Cheeseman CI, Perdue MH. Psychological stress
impairs Na⫹-dependent glucose absorption and increases GLUT2
expression in the rat jejunal brush-border membrane. Am J Physiol
Regul Integr Comp Physiol 292: R862–R867, 2007.
46. Bouritius H, Groot JA. Apical adenosine activates an amiloridesensitive conductance in human intestinal cell line HT29cl.19A
Am J Physiol Cell Physiol 272: C931–C936, 1997.
47. Bouritius H, Oprins JC, Bindels RJ, Hartog A, Groot JA.
Neuropeptide Y inhibits ion secretion in intestinal epithelium by
reducing chloride and potassium conductance. Pflügers Arch 435:
219 –226, 1998.
48. Bowley KA, Linley JE, Robins GG, Kopanati S, Hunter M,
Sandle GI. Role of protein kinase C in aldosterone-induced nongenomic inhibition of basolateral potassium channels in human
colonic crypts. J Steroid Biochem Mol Biol 104: 45–52, 2007.
49. Bowley KA, Morton MJ, Hunter M, Sandle GI. Non-genomic
regulation of intermediate conductance potassium channels by
aldosterone in human colonic crypt cells. Gut 52: 854 – 860, 2003.
50. Bradley KK, Hatton WJ, Mason HS, Walker RL, Flynn ER,
Kenyon JL, Horowitz B. Kir3.1/3.2 encodes an I(KACh)-like current in gastrointestinal myocytes. Am J Physiol Gastrointest Liver
Physiol 278: G289 –G296, 2000.
51. Brenner R, Jegla TJ, Wickenden A, Liu Y, Aldrich RW. Cloning
and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and
hKCNMB4. J Biol Chem 275: 6453– 6461, 2000.
52. Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC,
Wiler SW, Patterson AJ, Nelson MT, Aldrich RW. Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature 407: 870 – 876, 2000.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
16.
DIRK HEITZMANN AND RICHARD WARTH
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
Physiol Rev • VOL
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
tion in human tissues and differential cellular localisation in the
colon and corpus cavernosum. Naunyn-Schmiedebergs Arch Pharmacol 369: 602– 615, 2004.
Chen SZ, Jiang M, Zhen YS. HERG K⫹ channel expressionrelated chemosensitivity in cancer cells and its modulation by
erythromycin. Cancer Chemother Pharmacol 56: 212–220, 2005.
Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin
HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ,
Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1
gain-of-function mutation in familial atrial fibrillation. Science 299:
251–254, 2003.
Chik CL, Li B, Karpinski E, Ho AK. Ceramide inhibits the
outward potassium current in rat pinealocytes. J Neurochem 79:
339 –348, 2001.
Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G,
Barhanin J. Properties of KvLQT1 K⫹ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J 16: 5472–5479, 1997.
Chu PJ, Rivera JF, Arnold DB. A role for Kif17 in transport of
Kv4.2. J Biol Chem 281: 365–373, 2006.
Clarke LL, Harline MC. Dual role of CFTR in cAMP-stimulated.
Am J Physiol Gastrointest Liver Physiol 274: G718 –G726, 1998.
Clauss W, Hoffmann B, Schafer H, Hornicke H. Ion transport
and electrophysiology in rabbit cecum. Am J Physiol Gastrointest
Liver Physiol 256: G1090 –G1099, 1989.
Clauss W, Schaefer H, Horch I, Hoernicke H. Segmental differences in electrical properties and Na-transport of rabbit caecum,
proximal and distal colon in vitro. Pflügers Arch 403: 278 –282,
1985.
Cook DI, Dinudom A, Komwatana P, Kumar S, Young JA.
Patch-clamp studies on epithelial sodium channels in salivary duct
cells. Cell Biochem Biophys 36: 105–113, 2002.
Cooke HJ, Sidhu M, Fox P, Wang YZ, Zimmermann EM. Substance P as a mediator of colonic secretory reflexes. Am J Physiol
Gastrointest Liver Physiol 272: G238 –G245, 1997.
Craven PA, DeRubertis FR. Profiles of eicosanoid production by
superficial and proliferative colonic epithelial cells and sub-epithelial colonic tissue. Prostaglandins 32: 387–399, 1986.
Cuffe JE, Bertog M, Velazquez-Rocha S, Dery O, Bunnett N,
Korbmacher C. Basolateral PAR-2 receptors mediate KCl secretion and inhibition of Na⫹ absorption in the mouse distal colon.
J Physiol 539: 209 –222, 2002.
Cui G, Waldum HL. Physiological and clinical significance of
enterochromaffin-like cell activation in the regulation of gastric
acid secretion. World J Gastroenterol 13: 493– 496, 2007.
Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED,
Keating MT. A molecular basis for cardiac arrhythmia: HERG
mutations cause long QT syndrome. Cell 80: 795– 803, 1995.
Cuthbert AW, Hickman ME, MacVinish LJ, Evans MJ, Colledge WH, Ratcliff R, Seale PW, Humphrey PP. Chloride secretion in response to guanylin in colonic epithelial from normal and
transgenic cystic fibrosis mice. Br J Pharmacol 112: 31–36, 1994.
D’Andrea L, Lytle C, Matthews JB, Hofman P, Forbush B3,
Madara JL. Na:K:2Cl cotransporter (NKCC) of intestinal epithelial
cells. Surface expression in response to cAMP. J Biol Chem 271:
28969 –28976, 1996.
Davenport HW. Sodium space and acid secretion in frog gastric
mucosa. Am J Physiol 204: 213–216, 1963.
Decher N, Maier M, Dittrich W, Gassenhuber J, Bruggemann
A, Busch AE, Steinmeyer K. Characterization of TASK-4, a novel
member of the pH-sensitive, two-pore domain potassium channel
family. FEBS Lett 492: 84 – 89, 2001.
Decressac S, Franco M, Bendahhou S, Warth R, Knauer S,
Barhanin J, Lazdunski M, Lesage F. ARF6-dependent interaction of the TWIK1 K⫹ channel with EFA6, a GDP/GTP exchange
factor for ARF6. EMBO Rep 5: 1171–1175, 2004.
Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ,
Steinlein OK. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K⫹ channel. Proc Natl
Acad Sci USA 98: 12272–12277, 2001.
Dedek K, Waldegger S. Colocalization of KCNQ1/KCNE channel
subunits in the mouse gastrointestinal tract. Pflügers Arch 442:
896 –902, 2001.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
53. Brosky ME. The role of saliva in oral health: strategies for prevention and management of xerostomia. J Support Oncol 5: 215–
225, 2007.
54. Brown AM, Birnbaumer L. Direct G protein gating of ion channels. Am J Physiol Heart Circ Physiol 254: H401–H410, 1988.
55. Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA,
Kramer P, Litt M. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene,
KCNA1. Nature Genet 8: 136 –140, 1994.
56. Buckler KJ, Williams BA, Honore E. An oxygen-, acid- and
anaesthetic-sensitive TASK-like background potassium channel in
rat arterial chemoreceptor cells. J Physiol 525: 135–142, 2000.
57. Burckhardt BC, Gögelein H. Small and maxi K⫹ channels in the
basolateral membrane of isolated crypts from rat distal colon.
Pflügers Arch 420: 54 – 60, 1992.
58. Burleigh DE, Furness JB. Distribution and actions of galanin and
vasoactive intestinal peptide in the human colon. Neuropeptides
16: 77– 82, 1990.
59. Busch AE, Busch GL, Ford E, Suessbrich H, Lang HJ, Greger
R, Kunzelmann K, Attali B, Stühmer W. The role of the IsK
protein in the specific pharmacological properties of the IKs channel complex. Br J Pharmacol 122: 187–189, 1997.
60. Busque SM, Kerstetter JE, Geibel JP, Insogna K. L-type amino
acids stimulate gastric acid secretion by activation of the calciumsensing receptor in parietal cells. Am J Physiol Gastrointest Liver
Physiol 289: G664 –G669, 2005.
61. Butler A, Wei AG, Baker K, Salkoff L. A family of putative
potassium channel genes in Drosophila. Science 243: 943–947,
1989.
62. Butt AG, Hamilton KL. Ion channels in isolated mouse jejunal
crypts. Pflügers Arch 435: 528 –538, 1998.
63. Butterfield I, Warhurst G, Jones MN, Sandle GI. Characterization of apical potassium channels induced in rat distal colon during
potassium adaptation. J Physiol 501: 537–547, 1997.
64. Calmels TP, Faivre JF, Cheval B, Javre JL, Rouanet S, Bril A.
hKv4.3 channel characterization and regulation by calcium channel
antagonists. Biochem Biophys Res Commun 281: 452– 460, 2001.
65. Canfield VA, Okamoto CT, Chow D, Dorfman J, Gros P, Forte
JG, Levenson R. Cloning of the H,K-ATPase beta subunit. Tissuespecific expression, chromosomal assignment, relationship to
Na,K-ATPase beta subunits. J Biol Chem 265: 19878 –19884, 1990.
66. Carew MA, Thorn P. Identification of ClC-2-like chloride currents
in pig pancreatic acinar cells. Pflügers Arch 433: 84 –90, 1996.
67. Cassuto J, Fahrenkrug J, Jodal M, Tuttle R, Lundgren O.
Release of vasoactive intestinal polypeptide from the cat small
intestine exposed to cholera toxin. Gut 22: 958 –963, 1981.
68. Cassuto J, Jodal M, Lundgren O. The effect of nicotinic and
muscarinic receptor blockade on cholera toxin induced intestinal
secretion in rats and cats. Acta Physiol Scand 114: 573–577, 1982.
69. Catalan M, Niemeyer MI, Cid LP, Sepulveda FV. Basolateral
ClC-2 chloride channels in surface colon epithelium: regulation by
a direct effect of intracellular chloride. Gastroenterology 126:
1104 –1114, 2004.
70. Cermak R, Evelgünne A, Lawnitzak C, Scharrer E. K⫹ secretion in rat distal jejunum. J Membr Biol 171: 235–243, 1999.
71. Chapman H, Ramstrom C, Korhonen L, Laine M, Wann KT,
Lindholm D, Pasternack M, Tornquist K. Downregulation of the
HERG (KCNH2) K(⫹) channel by ceramide: evidence for ubiquitinmediated lysosomal degradation. J Cell Sci 118: 5325–5334, 2005.
72. Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ,
Leppert M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet 18: 53–55,
1998.
73. Charron FM, Blanchard MG, Lapointe JY. Intracellular hypertonicity is responsible for water flux associated with Na⫹/glucose
cotransport. Biophys J 90: 3546 –3554, 2006.
74. Chavez RA, Gray AT, Zhao BB, Kindler CH, Mazurek MJ,
Mehta Y, Forsayeth JR, Yost CS. TWIK-2, a new weak inward
rectifying member of the tandem pore domain potassium channel
family. J Biol Chem 274: 7887–7892, 1999.
75. Chen MX, Gorman SA, Benson B, Singh K, Hieble JP, Michel
MC, Tate SN, Trezise DJ. Small and intermediate conductance
Ca2⫹-activated K⫹ channels confer distinctive patterns of distribu-
1167
1168
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
120. Doyle DA, Cabral JM, Pfuetzner RA, Kuo A, Gulbis JM, Cohen
SL, Chait BT, MacKinnon R. The structure of the potassium
channel: molecular basis of K⫹ conduction and selectivity. Science
280: 69 –77, 1998.
121. Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang
L, Kotagal P, Luders HO, Shi J, Cui J, Richerson GB, Wang
QK. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 37: 733–738,
2005.
122. Dubinsky WP, Mayorga-Wark O, Schultz SG. Potassium channels in basolateral membrane vesicles from Necturus enterocytes:
stretch and ATP sensitivity. Am J Physiol Cell Physiol 279: C634 –
C638, 2000.
123. Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC.
Cell-specific expression of epithelial sodium channel alpha, beta,
gamma subunits in aldosterone-responsive epithelia from the rat:
localization by in situ hybridization and immunocytochemistry.
J Cell Biol 127: 1907–1921, 1994.
124. Dudeja PK, Harig JM, Baldwin ML, Cragoe EJJ, Ramaswamy
K, Brasitus TA. Na⫹ transport in human proximal colonic apical
membrane vesicles. Gastroenterology 106: 125–133, 1994.
125. Duman JG, Pathak NJ, Ladinsky MS, McDonald KL, Forte JG.
Three-dimensional reconstruction of cytoplasmic membrane networks in parietal cells. J Cell Sci 115: 1251–1258, 2002.
126. Duprat F, Girard C, Jarretou G, Lazdunski M. Pancreatic two
P domain K⫹ channels TALK-1 and TALK-2 are activated by nitric
oxide and reactive oxygen species. J Physiol 562: 235–244, 2005.
127. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski
M. TASK, a human background K⫹ channel to sense external pH
variations near physiological pH. EMBO J 16: 5464 –5471, 1997.
128. Ecke D, Bleich M, Lohrmann E, Hropot M, Englert HC, Lang
HJ, Warth R, Rohm W, Schwartz B, Fraser G, Greger R. A
chromanol type of K⫹ channel blocker inhibits forskolin- but not
carbachol mediated Cl⫺ secretion in rat and rabbit colon. Cell
Physiol Biochem 5: 204 –210, 1995.
129. Elkins T, Ganetzky B, Wu CF. A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc Natl Acad Sci
USA 83: 8415– 8419, 1986.
130. Evans RL, Park K, Turner RJ, Watson GE, Nguyen HV, Dennett MR, Hand AR, Flagella M, Shull GE, Melvin JE. Severe
impairment of salivation in Na⫹/K⫹/2Cl⫺ cotransporter (NKCC1)deficient mice. J Biol Chem 275: 26720 –26726, 2000.
131. Evans RL, Turner RJ. Upregulation of Na⫹-K⫹-2Cl⫺ cotransporter activity in rat parotid acinar cells by muscarinic stimulation.
J Physiol 499: 351–359, 1997.
132. Evans SR, Thoreson WB, Beck CL. Molecular and functional
analyses of two new calcium-activated chloride channel family
members from mouse eye and intestine. J Biol Chem 279: 41792–
41800, 2004.
133. Ewald DA, Williams A, Levitan IB. Modulation of single Ca2⫹dependent K⫹-channel activity by protein phosphorylation. Nature
315: 503–506, 1985.
134. Fanger CM, Ghanshani S, Logsdon NJ, Rauer H, Kalman K,
Zhou J, Beckingham K, Chandy KG, Cahalan MD, Aiyar J.
Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1. J Biol Chem 274: 5746 –
5754, 1999.
135. Farack UM, Loeschke K. Inhibition by loperamide of deoxycholic
acid induced intestinal secretion. Naunyn-Schmiedebergs Arch
Pharmacol 325: 286 –289, 1984.
136. Farrelly AM, Ro S, Callaghan BP, Khoyi MA, Fleming N,
Horowitz B, Sanders KM, Keef KD. Expression and function of
KCNH2 (HERG) in the human jejunum. Am J Physiol Gastrointest
Liver Physiol 284: G883–G895, 2003.
137. Feldman GM. HCO⫺
3 secretion by rat distal colon: effects of inhibitors and extracellular Na⫹. Gastroenterology 107: 329 –338,
1994.
138. Feldman GM, Stephenson RL. H⫹ and HCO⫺
3 flux across apical
surface of rat distal colon. Am J Physiol Cell Physiol 259: C35–C40,
1990.
139. Feliciangeli S, Bendahhou S, Sandoz G, Gounon P, Reichold
M, Warth R, Lazdunski M, Barhanin J, Lesage F. Does sumoy-
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
97. Del Castillo JR, Burguillos L. Pathways for K⫹ efflux in isolated
surface and crypt colonic cells. Activation by calcium. J Membr
Biol 205: 37– 47, 2005.
98. Del Castillo J, Arevalo JC, Burguillos L, Sulbaran-Carrasco
MC. Beta-adrenergic agonists stimulate Na⫹-K⫹-Cl⫺ cotransport
by inducing intracellular Ca2⫹ liberation in crypt cells. Am J
Physiol Gastrointest Liver Physiol 277: G563–G571, 1999.
99. Delporte C, Steinfeld S. Distribution and roles of aquaporins in
salivary glands. Biochim Biophys Acta 1758: 1061–1070, 2006.
100. Delrue G. Etude de la sécrétion acide de l’estomac. Arch Intern
Physiol 33: 196 –216, 1930.
101. Demarest JR, Loo DD, Sachs G. Activation of apical chloride
channels in the gastric oxyntic cell. Science 245: 402– 404, 1989.
102. Demarest JR, Machen TE. Microelectrode measurements from
oxyntic cells in intact Necturus gastric mucosa. Am J Physiol Cell
Physiol 249: C535–C540, 1985.
103. Demolombe S, Franco D, de Boer P, Kuperschmidt S, Roden
D, Pereon Y, Jarry A, Moorman AF, Escande D. Differential
expression of KvLQT1 and its regulator IsK in mouse epithelia.
Am J Physiol Cell Physiol 280: C359 –C372, 2001.
104. Denniss AR, Schneyer LH, Sucanthapree C, Young JA. Actions
of adrenergic agonists on isolated excretory ducts of submandibular glands. Am J Physiol Renal Fluid Electrolyte Physiol 235:
F548 –F556, 1978.
105. Derst C, Hirsch JR, Preisig-Muller R, Wischmeyer E, Karschin
A, Doring F, Thomzig A, Veh RW, Schlatter E, Kummer W,
Daut J. Cellular localization of the potassium channel Kir7.1 in
guinea pig and human kidney. Kidney Int 59: 2197–2205, 2001.
106. Devor DC, Frizzell RA. Calcium-mediated agonists activate an
inwardly rectified K⫹ channel in colonic secretory cells. Am J
Physiol Cell Physiol 265: C1271–C1280, 1993.
107. Devor DC, Frizzell RA. Modulation of K⫹ channels by arachidonic acid in T84 cells. I. Inhibition of the Ca2⫹-dependent K⫹
channel. Am J Physiol Cell Physiol 274: C138 –C148, 1998.
108. Devor DC, Singh AK, Frizzell RA, Bridges RJ. Modulation of
Cl⫺ secretion by benzimidazolones. I. Direct activation of a Ca2⫹dependent K⫹ channel. Am J Physiol Lung Cell Mol Physiol 271:
L775–L784, 1996.
109. Devor DC, Singh AK, Gerlach AC, Frizzell RA, Bridges RJ.
Inhibition of intestinal Cl⫺ secretion by clotrimazole: direct effect
on basolateral membrane K⫹ channels. Am J Physiol Cell Physiol
273: C531–C40, 1997.
110. Diener M, Bridges RJ, Knobloch SF, Rummel W. Neuronally
mediated and direct effects of prostaglandins on ion transport in
rat colon descendens. Naunyn-Schmiedebergs Arch Pharmacol
337: 74 –78, 1988.
111. Diener M, Gartmann V. Effect of somatostatin on cell volume,
Cl⫺ currents and transepithelial Cl⫺ transport in rat distal colon.
Am J Physiol Gastrointest Liver Physiol 266: G1043–G1052, 1994.
112. Diener M, Hug F, Strabel D, Scharrer E. Cyclic AMP-dependent
regulation of K⫹ transport in the rat distal colon. Br J Pharmacol
118: 1477–1487, 1996.
113. Diener M, Knobloch SF, Bridges RJ, Keilmann T, Rummel W.
Cholinergic-mediated secretion in the rat colon: neuronal and epithelial muscarinic responses. Eur J Pharmacol 168: 219 –229, 1989.
114. Diener M, Nobles M, Schmitt C, Rummel W. Characterization of
the antisecretory action of prostaglandin D2 in the rat colon. Acta
Physiol Scand 145: 19 –24, 1992.
115. Diener M, Scharrer E. Swelling-activated conductances for chloride, potassium and amino acids in the rat colon: a whole-cell
study. Exp Physiol 80: 411– 428, 1995.
116. Ding M, Kinoshita Y, Kishi K, Nakata H, Hassan S, Kawanami
C, Sugimoto Y, Katsuyama M, Negishi M, Narumiya S,
Ichikawa A, Chiba T. Distribution of prostaglandin E receptors in
the rat gastrointestinal tract. Prostaglandins 53: 199 –216, 1997.
117. Dockray GJ. Topical review. Gastrin and gastric epithelial physiology. J Physiol 518: 315–324, 1999.
118. Dolphin AC. G protein modulation of voltage-gated calcium channels. Pharmacol Rev 55: 607– 627, 2003.
119. Dong H, Smith A, Hovaida M, Chow J. Role of Ca2⫹-activated K⫹
channels in duodenal mucosal ion transport and bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol 291: G1120 –
G1128, 2006.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
140.
141.
142.
143.
144.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
Physiol Rev • VOL
161. Fujita H, Chiba H, Yokozaki H, Sakai N, Sugimoto K, Wada T,
Kojima T, Yamashita T, Sawada N. Differential expression and
subcellular localization of claudin-7, -8, -12, -13, -15 along the
mouse intestine. J Histochem Cytochem 54: 933–944, 2006.
162. Fuller CM, Benos DJ. Ca2⫹-activated Cl⫺ channels: a newly
emerging anion transport family. News Physiol Sci 15: 165–171,
2000.
163. Furness JB, Robbins HL, Selmer IS, Hunne B, Chen MX, Hicks
GA, Moore S, Neylon CB. Expression of intermediate conductance potassium channel immunoreactivity in neurons and epithelial cells of the rat gastrointestinal tract. Cell Tissue Res 314:
179 –189, 2003.
164. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: novel integral membrane proteins localizing at tight
junctions with no sequence similarity to occludin. J Cell Biol 141:
1539 –1550, 1998.
165. Gagnon MP, Bissonnette P, Deslandes LM, Wallendorff B,
Lapointe JY. Glucose accumulation can account for the initial
water flux triggered by Na⫹/glucose cotransport. Biophys J 86:
125–133, 2004.
166. Gamper N, Li Y, Shapiro MS. Structural requirements for differential sensitivity of KCNQ K⫹ channels to modulation by Ca2⫹/
calmodulin. Mol Biol Cell 16: 3538 –3551, 2005.
167. Ganser AL, Forte JG. K⫹-stimulated ATPase in purified microsomes of bullfrog oxyntic cells. Biochim Biophys Acta 307: 169 –
180, 1973.
168. Gaspar KJ, Racette KJ, Gordon JR, Loewen ME, Forsyth GW.
Cloning a chloride conductance mediator from the apical membrane of porcine ileal enterocytes. Physiol Genomics 3: 101–111,
2000.
169. Gautam D, Han SJ, Heard TS, Cui Y, Miller G, Bloodworth L,
Wess J. Cholinergic stimulation of amylase secretion from pancreatic acinar cells studied with muscarinic acetylcholine receptor
mutant mice. J Pharmacol Exp Ther 313: 995–1002, 2005.
170. Gawenis LR, Stien X, Shull GE, Schultheis PJ, Woo AL,
Walker NM, Clarke LL. Intestinal NaCl transport in NHE2 and
NHE3 knockout mice. Am J Physiol Gastrointest Liver Physiol
282: G776 –G784, 2002.
171. Geibel JP. Role of potassium in acid secretion. World J Gastroenterol 11: 5259 –5265, 2005.
172. Geibel JP. Secretion and absorption by colonic crypts. Annu Rev
Physiol 67: 471– 490, 2005.
173. Gerlach AC, Syme CA, Giltinan L, Adelman JP, Devors DC.
ATP-dependent activation of the intermediate conductance, Ca2⫹activated K⫹ channel, hIK1, is conferred by a C-terminal domain.
J Biol Chem 276: 10963–10970, 2001.
174. Ghosh S, Nunziato DA, Pitt GS. KCNQ1 assembly and function
is blocked by long-QT syndrome mutations that disrupt interaction
with calmodulin. Circ Res 98: 1048 –1054, 2006.
175. Giovannucci DR, Bruce JI, Straub SV, Arreola J, Sneyd J,
Shuttleworth TJ, Yule DI. Cytosolic Ca(2⫹) and Ca(2⫹)-activated Cl(⫺) current dynamics: insights from two functionally distinct mouse exocrine cells. J Physiol 540: 469 – 484, 2002.
176. Girard C, Duprat F, Terrenoire C, Tinel N, Fosset M, Romey
G, Lazdunski M, Lesage F. Genomic and functional characteristics of novel human pancreatic 2p domain K⫹ channels. Biochem
Biophys Res Commun 282: 249 –256, 2001.
177. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ,
Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J,
Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP,
Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT.
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
N Engl J Med 350: 1838 –1849, 2004.
178. Goerg KJ, Diener C, Diener M, Rummel W. Antisecretory effect
of prostaglandin D2 in rat colon in vitro: action sites. Am J Physiol
Gastrointest Liver Physiol 260: G904 –G910, 1991.
179. Gojova A, Barakat AI. Vascular endothelial wound closure under
shear stress: role of membrane fluidity and flow-sensitive ion channels. J Appl Physiol 98: 2355–2362, 2005.
180. Gong Q, Keeney DR, Molinari M, Zhou Z. Degradation of trafficking-defective long QT syndrome type II mutant channels by the
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
145.
lation control K2P1/TWIK1 background K⫹ channels? Cell 130:
563–569, 2007.
Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, Marrugat J, Valverde MA. Gain-of-function
mutation in the KCNMB1 potassium channel subunit is associated
with low prevalence of diastolic hypertension. J Clin Invest 113:
1032–1039, 2004.
Ferrar JA, Cuthbert AW, Cox HM. The antisecretory effects of
somatostatin and analogues in rat descending colon mucosa. Eur
J Pharmacol 184: 295–303, 1990.
Ferris HA, Carroll RE, Rasenick MM, Benya RV. Constitutive
activation of the gastrin-releasing peptide receptor expressed by
the nonmalignant human colon epithelial cell line NCM460. J Clin
Invest 100: 2530 –2537, 1997.
Field M. Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest 111: 931–943, 2003.
Fihn BM, Sjoqvist A, Jodal M. Permeability of the rat small
intestinal epithelium along the villus-crypt axis: effects of glucose
transport. Gastroenterology 119: 1029 –1036, 2000.
Findlay I, Petersen OH. Acetylcholine stimulates a Ca2⫹-dependent Cl⫺ conductance in mouse lacrimal acinar cells. Pflügers Arch
403: 328 –330, 1985.
Flores CA, Melvin JE, Figueroa CD, Sepulveda FV. Abolition
of Ca2⫹-mediated intestinal anion secretion and increased stool
dehydration in mice lacking the intermediate conductance Ca2⫹dependent K⫹ channel Kcnn4. J Physiol 583: 705–717, 2007.
Flores CA, Melvin JE, Sepulveda FV. Cl⫺ secretion induced by
Ca2⫹ agonists is impaired in distal colon of a Kcnn4 null mouse
(Abstract). J Physiol 565P: C7, 2005.
Fong P, Argent BE, Guggino WB, Gray MA. Characterization of
vectorial chloride transport pathways in the human pancreatic duct
adenocarcinoma cell line, HPAF. Am J Physiol Cell Physiol 285:
C433–C445, 2003.
Forstner G. Signal transduction, packaging and secretion of mucins. Annu Rev Physiol 57: 585– 605, 1995.
Forte JG, Forte GM, Saltman P. K⫹-stimulated phosphatase of
microsomes from gastric mucosa. J Cell Physiol 69: 293–304, 1967.
Forte JG, Ganser A, Beesley R, Forte TM. Unique enzymes of
purified microsomes from pig fundic mucosa. K⫹-stimulated adenosine triphosphatase and K⫹-stimulated pNPPase. Gastroenterology 69: 175–189, 1975.
Forte LR, Eber SL, Turner JT, Freeman RH, Fok KF, Currie
MG. Guanylin stimulation of Cl⫺ secretion in human intestinal T84
cells via cyclic guanosine monophosphate. J Clin Invest 91: 2423–
2428, 1993.
Foster ES, Budinger ME, Hayslett JP, Binder HJ. Ion transport
in proximal colon of the rat. Sodium depletion stimulates neutral
sodium chloride absorption. J Clin Invest 77: 228 –235, 1986.
Freeman LC, Lippold JJ, Mitchell KE. Glycosylation influences
gating and pH sensitivity of I(sK). J Membr Biol 177: 65–79, 2000.
Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, regulation of secretion. Physiol Rev 80: 1523–1631,
2000.
Frey BW, Lynch FT, Kinsella JM, Horowitz B, Sanders KM,
Carl A. Blocking of cloned and native delayed rectifier K channels
from visceral smooth muscles by phencyclidine. Neurogastroenterol Motil 12: 509 –516, 2000.
Frieling T, Rupprecht C, Dobreva G, Haussinger D, Schemann
M. Effects of prostaglandin F2 alpha (PGF2 alpha) and prostaglandin I2 (PGI2) on nerve-mediated secretion in guinea-pig colon.
Pflügers Arch 431: 212–220, 1995.
Frömter E, Diamond J. Route of passive ion permeation in epithelia. Nature 235: 9 –13, 1972.
Fujita A, Horio Y, Higashi K, Mouri T, Hata F, Takeguchi N,
Kurachi Y. Specific localization of an inwardly rectifying K⫹ channel, Kir4.1, at the apical membrane of rat gastric parietal cells; its
possible involvement in K⫹ recycling for the H⫹-K⫹-pump.
J Physiol 540: 85–92, 2002.
Fujita A, Takeuchi T, Saitoh N, Hanai J, Hata F. Expression of
Ca2⫹-activated K⫹ channels, SK3, in the interstitial cells of Cajal in
the gastrointestinal tract. Am J Physiol Cell Physiol 281: C1727–
C1733, 2001.
1169
1170
181.
182.
183.
184.
185.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
ubiquitin-proteasome pathway. J Biol Chem 280: 19419 –19425,
2005.
Gopel SO, Kanno T, Barg S, Rorsman P. Patch-clamp characterisation of somatostatin-secreting cells in intact mouse pancreatic islets. J Physiol 528: 497–507, 2000.
Goyal RK, Hirano I. The enteric nervous system. N Engl J Med
334: 1106 –1115, 1996.
Grahammer F, Herling AW, Lang HJ, Schmitt-Gräff A, Wittekindt OH, Nitschke R, Bleich M, Barhanin J, Warth R. The
cardiac K⫹ channel KCNQ1 is essential for gastric acid secretion.
Gastroenterology 120: 1363–1371, 2001.
Grahammer F, Warth R, Barhanin J, Bleich M, Hug MJ. The
small conductance K⫹ channel, KCNQ1. Expression, function, subunit composition in murine trachea. J Biol Chem 246: 42268 – 42275,
2001.
Grasset E, Gunter-Smith P, Schultz SG. Effects of Na-coupled
alanine transport on intracellular K activities and the K conductance of the basolateral membranes of Necturus small intestine. J
Membr Biol 71: 89 –94, 1983.
Gray JS, Adkison JL. The effect of inorganic ions on gastric
secretion in vitro. Am J Physiol 134: 27–31, 1941.
Gray MA, Greenwell JR, Garton AJ, Argent BE. Regulation of
maxi-K⫹ channels on pancreatic duct cells by cyclic AMP-dependent phosphorylation. J Membr Biol 115: 203–215, 1990.
Greger R, Heitzmann D, Hug MJ, Hoffmann EK, Bleich M. The
Na⫹-2Cl⫺-K⫹ cotransporter in the rectal gland of Squalus acanthias is activated by cell shrinkage. Pflügers Arch 438: 165–176,
1999.
Grishin A, Ford H, Wang J, Li H, Salvador-Recatala V, Levitan
ES, Zaks-Makhina E. Attenuation of apoptosis in enterocytes by
blockade of potassium channels. Am J Physiol Gastrointest Liver
Physiol 289: G815–G821, 2005.
Grissmer S, Nguyen AN, Cahalan MD. Calcium-activated potassium channels in resting and activated human T lymphocytes.
Expression levels, calcium dependence, ion selectivity, pharmacology. J Gen Physiol 102: 601– 630, 1993.
Grunnet M, Jespersen T, MacAulay N, Jorgensen NK, Schmitt
N, Pongs O, Olesen SP, Klaerke DA. KCNQ1 channels sense
small changes in cell volume. J Physiol 549: 419 – 427, 2003.
Grunnet M, Knaus HG, Solander C, Klaerke DA. Quantification
and distribution of Ca2⫹-activated maxi K⫹ channels in rabbit distal
colon. Am J Physiol Gastrointest Liver Physiol 277: G22–G30,
1999.
Grunnet M, Rasmussen HB, Hay-Schmidt A, Klaerke DA. The
voltage-gated potassium channel subunit, Kv1.3, is expressed in
epithelia. Biochim Biophys Acta 1616: 85–94, 2003.
Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks
NP. Two-pore-domain K⫹ channels are a novel target for the anesthetic gases xenon, nitrous oxide, cyclopropane. Mol Pharmacol
65: 443– 452, 2004.
Guan Y, Dong J, Tackett L, Meyer JW, Shull GE, Montrose
MH. NHE2 is the main apical NHE in mouse colonic crypts but an
alternative Na⫹-dependent acid extrusion mechanism is upregulated in NHE2-null mice. Am J Physiol Gastrointest Liver Physiol
291: G689 –G699, 2006.
Guba M, Kuhn M, Forssmann WG, Classen M, Gregor M,
Seidler U. Guanylin strongly stimulates rat duodenal. Gastroenterology 111: 1558 –1568, 1996.
Gubitosi-Klug RA, Mancuso DJ, Gross RW. The human Kv1.1
channel is palmitoylated, modulating voltage sensing: identification
of a palmitoylation consensus sequence. Proc Natl Acad Sci USA
102: 5964 –5968, 2005.
Gulbins E, Szabo I, Baltzer K, Lang F. Ceramide-induced inhibition of T lymphocyte voltage-gated potassium channel is mediated by tyrosine kinases. Proc Natl Acad Sci USA 94: 7661–7666,
1997.
Gunter-Smith PJ, Grasset E, Schultz SG. Sodium-coupled
amino acid and sugar transport by Necturus small intestine. An
equivalent electrical circuit analysis of a rheogenic co-transport
system. J Membr Biol 66: 25–39, 1982.
Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA,
Clapham DE, Covarriubias M, Desir GV, Furuichi K, Ganetzky
B, Garcia ML, Grissmer S, Jan LY, Karschin A, Kim D, KuperPhysiol Rev • VOL
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
schmidt S, Kurachi Y, Lazdunski M, Lesage F, Lester HA,
McKinnon D, Nichols CG, O’Kelly I, Robbins J, Robertson GA,
Rudy B, Sanguinetti M, Seino S, Stuehmer W, Tamkun MM,
Vandenberg CA, Wei A, Wulff H, Wymore RS. International
Union of Pharmacology. XLI. Compendium of voltage-gated ion
channels: potassium channels. Pharmacol Rev 55: 583–586, 2003.
Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon
D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stuhmer W, Wang X. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium
channels. Pharmacol Rev 57: 473–508, 2005.
Gyomorey K, Yeger H, Ackerley C, Garami E, Bear CE. Expression of the chloride channel ClC-2 in the murine small intestine
epithelium. Am J Physiol Cell Physiol 279: C1787–C1794, 2000.
Haas M, Forbush B. The Na-K-Cl cotransporter of secretory epithelia. Annu Rev Physiol 62: 515–534, 2000.
Halm DR, Halm ST. Secretagogue response of goblet cells and
columnar cells in human colonic crypts. Am J Physiol Cell Physiol
278: C212–C233, 2000.
Hamilton KL, Kiessling M. DCEBIO stimulates Cl⫺ secretion in
the mouse jejunum. Am J Physiol Cell Physiol 290: C152–C164,
2006.
Hamilton KL, Meads L, Butt AG. 1-EBIO stimulates Cl⫺ secretion by activating a basolateral K⫹ channel in the mouse jejunum.
Pflügers Arch 439: 158 –166, 1999.
Han J, Kang D, Kim D. Functional properties of four splice
variants of a human pancreatic tandem-pore K⫹ channel, TALK-1.
Am J Physiol Cell Physiol 285: C529 –C538, 2003.
Hart PJ, Overturf KE, Russell SN, Carl A, Hume JR, Sanders
KM, Horowitz B. Cloning and expression of a Kv1.2 class delayed
rectifier K⫹ channel from canine colonic smooth muscle. Proc Natl
Acad Sci USA 90: 9659 –9663, 1993.
Hatton WJ, Mason HS, Carl A, Doherty P, Latten MJ, Kenyon
JL, Sanders KM, Horowitz B. Functional and molecular expression of a voltage-dependent K(⫹) channel (Kv1.1) in interstitial
cells of Cajal. J Physiol 533: 315–327, 2001.
Hay-Schmidt A, Grunnet M, Abrahamse SL, Knaus HG, Klaerke DA. Localization of Ca2⫹ -activated big-conductance K⫹ channels in rabbit distal colon. Pflügers Arch 446: 61– 68, 2003.
Hayashi M, Komazaki S, Ishikawa T. An inwardly rectifying K⫹
channel in bovine parotid acinar cells: possible involvement of
Kir2.1. J Physiol 547: 255–269, 2003.
Hayashi M, Kunii C, Takahata T, Ishikawa T. ATP-dependent
regulation of SK4/IK1-like currents in rat submandibular acinar
cells: possible role of cAMP-dependent protein kinase. Am J
Physiol Cell Physiol 286: C635–C646, 2004.
Hayashi T, Young JA, Cook DI. The ACh-evoked Ca2⫹-activated
K⫹ current in mouse mandibular secretory cells. Single channel
studies. J Membr Biol 151: 19 –27, 1996.
He X, Tse CM, Donowitz M, Alper SL, Gabriel SE, Baum BJ.
Polarized distribution of key membrane transport proteins in the
rat submandibular gland. Pflügers Arch 433: 260 –268, 1997.
Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity
and regulation of renal potassium channels. Physiol Rev 85: 319 –
371, 2005.
Hede SE, Amstrup J, Christoffersen BC, Novak I. Purinoceptors evoke different electrophysiological responses in pancreatic
ducts. P2Y inhibits K(⫹) conductance, P2X stimulates cation conductance. J Biol Chem 274: 31784 –31791, 1999.
Hede SE, Amstrup J, Klaerke DA, Novak I. P2Y2 and P2Y4
receptors regulate pancreatic Ca2⫹-activated K⫹ channels differently. Pflügers Arch 450: 429 – 436, 2005.
Hediger MA, Coady MJ, Ikeda TS, Wright EM. Expression
cloning and cDNA sequencing of the Na⫹/glucose co-transporter.
Nature 330: 379 –381, 1987.
Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C,
Schweda F, El Wakil A, Lalli E, Guy N, Mengual R, Reichold
M, Tegtmeier I, Bendahhou S, Gomez-Sanchez CE, Isabel AM,
Wisden W, Weber A, Lesage F, Warth R, Barhanin J. Invalidation of TASK1 potassium channels disrupts adrenal gland zonation
and mineralocorticoid homeostasis. EMBO J 27: 179 –187, 2008.
Heitzmann D, Grahammer F, von Hahn T, Schmitt-Graff A,
Romeo E, Nitschke R, Gerlach U, Lang HJ, Verrey F, Barhanin
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
186.
DIRK HEITZMANN AND RICHARD WARTH
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
221.
222.
223.
224.
225.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
Physiol Rev • VOL
242. Ishibashi K, Yamazaki J, Okamura K, Teng Y, Kitamura K,
Abe K. Roles of CLCA and CFTR in electrolyte re-absorption from
rat saliva. J Dent Res 85: 1101–1105, 2006.
243. Ishiguro H, Steward M, Naruse S. Cystic fibrosis transmembrane
conductance regulator and SLC26 transporters in HCO⫺
3 secretion
by pancreatic duct cells. Sheng Li Xue Bao 59: 465– 476, 2007.
244. Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, Maylie J. A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA 94: 11651–11656, 1997.
245. Ishikawa T, Cook DI. Effects of K⫹ channel blockers on inwardly
and outwardly rectifying whole-cell K⫹ currents in sheep parotid
secretory cells. J Membr Biol 133: 29 – 41, 1993.
246. Ishikawa T, Murakami M. Tetraethylammonium-insensitive,
Ca2⫹-activated whole-cell K⫹ currents in rat submandibular acinar
cells. Pflügers Arch 429: 748 –750, 1995.
247. Ishikawa T, Murakami M, Seo Y. Basolateral K⫹ efflux is largely
independent of maxi-K⫹ channels in rat submandibular glands
during secretion. Pflügers Arch 428: 516 –525, 1994.
248. Ishikawa Y, Cho G, Yuan Z, Skowronski MT, Pan Y, Ishida H.
Water channels and zymogen granules in salivary glands. J Pharmacol Sci 100: 495–512, 2006.
249. Ishikawa Y, Skowronski MT, Inoue N, Ishida H. Alpha(1)adrenoceptor-induced trafficking of aquaporin-5 to the apical
plasma membrane of rat parotid cells. Biochem Biophys Res Commun 265: 94 –100, 1999.
250. Isomoto S, Kondo C, Yamada M, Matsumoto S, Higashiguchi
O, Horio Y, Matsuzawa Y, Kurachi Y. A novel sulfonylurea
receptor forms with BIR (Kir6.2) a smooth muscle type ATPsensitive K⫹ channel. J Biol Chem 271: 24321–24324, 1996.
251. Iversen HH, Wiklund NP, Olgart C, Gustafsson LE. Nerve
stimulation-induced nitric oxide release as a consequence of muscarinic M1 receptor activation. Eur J Pharmacol 331: 213–219,
1997.
252. Iwatsuki N, Petersen OH. Pancreatic acinar cells: localization of
acetylcholine receptors and the importance of chloride and calcium for acetylcholine-evoked depolarization. J Physiol 269: 723–
733, 1977.
253. Iwatsuki N, Petersen OH. Dissociation between stimulantevoked acinar membrane resistance change and amylase secretion
in the mouse parotid gland. J Physiol 314: 79 – 84, 1981.
254. Iwatsuki N, Petersen OH. Action of tetraethylammonium on
calcium-activated potassium channels in pig pancreatic acinar cells
studied by patch-clamp single-channel and whole cell current recording. J Membr Biol 86: 139 –144, 1985.
255. Iwatsuki N, Petersen OH. Inhibition of Ca2⫹ activated K⫹ channels in pig pancreatic acinar cells by Ba2⫹, Ca2⫹, quinine, quinidine.
Biochim Biophys Acta 819: 249 –257, 1985.
256. Izzo AA, Gaginella TS, Mascolo N, Borrelli F, Capasso F.
NG-nitro-L-arginine methyl ester reduces senna- and cascara-induced diarrhoea and fluid secretion in the rat. Eur J Pharmacol
301: 137–142, 1996.
257. Jena BP. Discovery of the Porosome: revealing the molecular
mechanism of secretion and membrane fusion in cells. J Cell Mol
Med 8: 1–21, 2004.
258. Jena BP. Cell secretion machinery: studies using the AFM. Ultramicroscopy 106: 663– 669, 2006.
259. Jensen BS, Strobaek D, Christophersen P, Jorgensen TD,
Hansen C, Silahtaroglu A, Olesen SP, Ahring PK. Characterization of the cloned human intermediate-conductance Ca2⫹-activated K⫹ channel. Am J Physiol Cell Physiol 275: C848 –C856, 1998.
260. Jespersen T, Membrez M, Nicolas CS, Pitard B, Staub O,
Olesen SP, Baro I, Abriel H. The KCNQ1 potassium channel is
down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like
family. Cardiovasc Res 74: 64 –74, 2007.
261. Ji B, Bi Y, Simeone D, Mortensen RM, Logsdon CD. Human
pancreatic acinar cells do not respond to cholecystokinin. Pharmacol Toxicol 91: 327–332, 2002.
262. Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R.
Crystal structure and mechanism of a calcium-gated potassium
channel. Nature 417: 515–522, 2002.
263. Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R. X-ray structure of a voltage-dependent K⫹ channel. Nature 423: 33– 41, 2003.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
226.
J, Warth R. Heteromeric KCNE2/KCNQ1 potassium channels in
the luminal membrane of gastric parietal cells. J Physiol 561:
547–557, 2004.
Heitzmann D, Koren V, Wagner M, Sterner C, Reichold M,
Tegtmeier I, Volk T, Warth R. KCNE beta subunits determine pH
sensitivity of KCNQ1 potassium channels. Cell Physiol Biochem 19:
21–32, 2007.
Heitzmann D, Warth R, Bleich M, Henger A, Nitschke R,
Greger R. Regulation of the Na⫹-2Cl⫺-K⫹ cotransporter in isolated
rat colon crypts. Pflügers Arch 439: 378 –384, 2000.
Helander HF. The cells of the gastric mucosa. Int Rev Cytol 70:
217–289, 1981.
Helander HF, Keeling DJ. Cell biology of gastric acid secretion.
Baillieres Clin Gastroenterol 7: 1–21, 1993.
Henke G, Maier G, Wallisch S, Boehmer C, Lang F. Regulation
of the voltage gated K⫹ channel Kv1.3 by the ubiquitin ligase
Nedd4 –2 and the serum and glucocorticoid inducible kinase SGK1.
J Cell Physiol 199: 194 –199, 2004.
Hermiston ML, Gordon JI. Organization of the crypt-villus axis
and evolution of its stem cell hierarchy during intestinal development. Am J Physiol Gastrointest Liver Physiol 268: G813–G822,
1995.
Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G,
Lazdunski M. TREK-1, a K⫹ channel involved in neuroprotection
and general anesthesia. EMBO J 23: 2684 –2695, 2004.
Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thummler S,
Peng XD, Noble F, Blondeau N, Widmann C, Borsotto M,
Gobbi G, Vaugeois JM, Debonnel G, Lazdunski M. Deletion of
the background potassium channel TREK-1 results in a depressionresistant phenotype. Nat Neurosci 9: 1134 –1141, 2006.
Heyer M, Muller-Berger S, Romero MF, Boron WF, Frömter
E. Stoichiometry of the rat kidney Na⫹-HCO⫺
3 cotransporter expressed in Xenopus laevis oocytes. Pflügers Arch 438: 322–329,
1999.
Hoffmann EK. Intracellular signalling involved in volume regulatory decrease. Cell Physiol Biochem 10: 273–288, 2000.
Hogan DL, Ainsworth MA, Isenberg JI. Review article: gastroduodenal bicarbonate secretion. Aliment Pharmacol Ther 8:
475– 488, 1994.
Hogan DL, Crombie DL, Isenberg JI, Svendsen P, Schaffalitzky de Muckadell OB, Ainsworth MA. CFTR mediates cAMPand Ca2⫹-activated duodenal epithelial HCO⫺
3 secretion. Am J
Physiol Gastrointest Liver Physiol 272: G872–G878, 1997.
Holmes JL, Van Itallie CM, Rasmussen JE, Anderson JM.
Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns 6: 581–588, 2006.
Homaidan FR, Broutman G. Regulation of ileal electrolyte transport by K⫹ channel activators. Eur J Pharmacol 271: 561–565, 1994.
Honore E. The neuronal background K(2P) channels: focus on
TREK1. Nat Rev Neurosci 8: 251–261, 2007.
Horger S, Schultheiss G, Diener M. Segment-specific effects of
epinephrine on ion transport in the colon of the rat. Am J Physiol
Gastrointest Liver Physiol 275: G1367–G1376, 1998.
Hou W, Schubert ML. Gastric secretion. Curr Opin Gastroenterol
22: 593–598, 2006.
Ihara T, Tsujikawa T, Fujiyama Y, Bamba T. Regulation of
PepT1 peptide transporter expression in the rat small intestine
under malnourished conditions. Digestion 61: 59 – 67, 2000.
Inagaki N, Tsuura Y, Namba N, Masuda K, Gonoi T, Horie M,
Seino Y, Mizuta M, Seino S. Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously
expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, heart. J Biol Chem 270: 5691–5694, 1995.
Inoue T, Okamoto K, Moriyama T, Takahashi T, Shimizu K,
Miyama A. Effect of Yersinia enterocolitica ST on cyclic
guanosine 3⬘,5⬘-monophosphate levels in mouse intestines and cultured cells. Microbiol Immunol 27: 159 –166, 1983.
Isbrandt D, Leicher T, Waldschutz R, Zhu X, Luhmann U,
Michel U, Sauter K, Pongs O. Gene structures and expression
profiles of three human KCND (Kv4) potassium channels mediating
A-type currents I(TO) and I(SA). Genomics 64: 144 –154, 2000.
1171
1172
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
284. Kim SJ, Greger R. Voltage-dependent, slowly activating K⫹ current (IKs) and its augmentation by carbachol in rat pancreatic acini.
Pflügers Arch 438: 604 – 611, 1999.
285. Kim SJ, Kerst G, Schreiber R, Pavenstadt H, Greger R, Hug
MJ, Bleich M. Inwardly rectifying K⫹ channels in the basolateral
membrane of rat pancreatic acini. Pflügers Arch 441: 331–340, 2000.
286. Kim SJ, Kim JK, Pavenstädt H, Greger R, Hug MJ, Bleich M.
Regulation of slowly activating potassium current [I(Ks)] by secretin in rat pancreatic acinar cells. J Physiol 535: 349 –358, 2001.
287. Kim Y, Bang H, Gnatenco C, Kim D. Synergistic interaction and
the role of C-terminus in the activation of TRAAK K⫹ channels by
pressure, free fatty acids and alkali. Pflügers Arch 442: 64 –72, 2001.
288. Kim Y, Bang H, Kim D. TASK-3, a new member of the tandem pore
K⫹ channel family. J Biol Chem 275: 9340 –9347, 2000.
289. Kirchhoff P, Dave MH, Remy C, Kosiek O, Busque SM, Dufner
M, Geibel JP, Verrey F, Wagner CA. An amino acid transporter
involved in gastric acid secretion. Pflügers Arch 451: 738 –748, 2006.
290. Kita T, Smith CE, Fok KF, Duffin KL, Moore WM, Karabatsos
PJ, Kachur JF, Hamra FK, Pidhorodeckyj NV, Forte LR, Currie MG. Characterization of human uroguanylin: a member of the
guanylin peptide family. Am J Physiol Renal Fluid Electrolyte
Physiol 266: F342–F348, 1994.
291. Klemm MF, Lang RJ. Distribution of Ca2⫹-activated K⫹ channel
(SK2 and SK3) immunoreactivity in intestinal smooth muscles of
the guinea-pig. Clin Exp Pharmacol Physiol 29: 18 –25, 2002.
292. Kleta R, Romeo E, Ristic Z, Ohura T, Stuart C, Arcos-Burgos
M, Dave MH, Wagner CA, Camargo SR, Inoue S, Matsuura N,
Helip-Wooley A, Bockenhauer D, Warth R, Bernardini I, Visser G, Eggermann T, Lee P, Chairoungdua A, Jutabha P, Babu
E, Nilwarangkoon S, Anzai N, Kanai Y, Verrey F, Gahl WA,
Koizumi A. Mutations in SLC6A19, encoding B(0)AT1, cause Hartnup disorder. Nat Genet 36: 999 –1002, 2004.
293. Koh SD, Ward SM, Dick GM, Epperson A, Bonner HP, Sanders
KM, Horowitz B, Kenyon JL. Contribution of delayed rectifier
potassium currents to the electrical activity of murine colonic
smooth muscle. J Physiol 515: 475– 487, 1999.
294. Komatsu H, Mieno H, Tamaki K, Inoue M, Kajiyama G,
Seyama I. Modulation of Ca2⫹-activated K⫹ channels by Mg2⫹ and
ATP in frog oxyntic cells. Pflügers Arch 431: 494 –503, 1996.
295. Kondo C, Isomoto S, Matsumoto S, Yamada M, Horio Y, Yamashita S, Takemura-Kameda K, Matsuzawa Y, Kurachi Y.
Cloning and functional expression of a novel isoform of ROMK
inwardly rectifying ATP-dependent K⫹ channel, ROMK6 (Kir1.1f).
FEBS Lett 399: 122–126, 1996.
296. Koo NY, Li J, Hwang SM, Choi SY, Lee SJ, Oh SB, Kim JS, Lee
JH, Park K. Molecular cloning and functional expression of a
sodium bicarbonate cotransporter from guinea-pig parotid glands.
Biochem Biophys Res Commun 342: 1114 –1122, 2006.
297. Kopelman H, Corey M, Gaskin K, Durie P, Weizman Z, Forstner G. Impaired chloride secretion, as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis
pancreas. Gastroenterology 95: 349 –355, 1988.
298. Kotera T, Hashimoto A, Ueda S, Okada Y. Whole-cell K⫹ current
activation in response to voltages and carbachol in gastric parietal
cells isolated from guinea pig. J Membr Biol 124: 43–52, 1991.
299. Kovac J, Moore B, Vanner S. Potassium currents regulating
secretion from Brunner’s glands in guinea pig duodenum. Am J
Physiol Gastrointest Liver Physiol 286: G377–G384, 2004.
300. Kovacs I, Pocsai K, Czifra G, Sarkadi L, Szucs G, Nemes Z,
Rusznak Z. TASK-3 immunoreactivity shows differential distribution in the human gastrointestinal tract. Virchows Arch 446: 402–
410, 2005.
301. Koyama K, Sasaki I, Naito H, Funayama Y, Fukushima K,
Unno M, Matsuno S, Hayashi H, Suzuki Y. Induction of epithelial Na⫹ channel in rat ileum after proctocolectomy. Am J Physiol
Gastrointest Liver Physiol 276: G975–G984, 1999.
302. Köttgen M, Hoefer A, Kim SJ, Beschorner U, Schreiber R, Hug
MJ, Greger R. Carbachol activates a K⫹ channel of very small
conductance in the basolateral membrane of rat pancreatic acinar
cells. Pflügers Arch 438: 597– 603, 1999.
303. Krane CM, Melvin JE, Nguyen HV, Richardson L, Towne JE,
Doetschman T, Menon AG. Salivary acinar cells from aquaporin
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
264. Jirakulsomchok D, Schneyer CA. Effects of sympathetic nerve
stimulation in the presence of specific adrenergic antagonists on
Na, K, Cl transport in perfused rat submandibular duct. J Auton
Nerv Syst 19: 255–259, 1987.
265. Jirakulsomchok D, Yu JH, Schneyer CA. Effects of substance P
on Na and K transport in perfused main submandibular duct of rat.
Proc Soc Exp Biol Med 177: 165–167, 1984.
266. Johansen PG, Anderson CM, Hadorn B. Cystic fibrosis of the
pancreas. A generalised disturbance of water and electrolyte movement in exocrine tissues. Lancet 1: 455– 460, 1968.
267. Johnson RP, O’Kelly IM, Fearon IM. System-specific O2-sensitivity of the tandem-pore-domain K⫹ channel TASK-1. Am J Physiol
Cell Physiol 286: C391–C397, 2004.
268. Joiner WJ, Basavappa S, Vidyasagar S, Nehrke K, Krishnan S,
Binder HJ, Boulpaep EL, Rajendran VM. Active K⫹ secretion
through multiple KCa-type channels and regulation by IKCa channels in rat proximal colon. Am J Physiol Gastrointest Liver
Physiol 285: G185–G196, 2003.
269. Joiner WJ, Khanna R, Schlichter LC, Kaczmarek LK. Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2⫹-activated
K⫹ channels. J Biol Chem 276: 37980 –37985, 2001.
270. Joiner WJ, Wang LY, Tang MD, Kaczmarek LK. hSK4, a member of a novel subfamily of calcium-activated potassium channels.
Proc Natl Acad Sci USA 94: 11013–11018, 1997.
271. Jurkat-Rott K, Lehmann-Horn F. Periodic paralysis mutation
MiRP2–R83H in controls: interpretations and general recommendation. Neurology 62: 1012–1015, 2004.
272. Kagawa S, Aoi M, Kubo Y, Kotani T, Takeuchi K. Stimulation
by capsaicin of duodenal HCO⫺
3 secretion via afferent neurons and
vanilloid receptors in rats: comparison with acid-induced HCO⫺
3
response. Dig Dis Sci 48: 1850 –1856, 2003.
273. Kalman K, Nguyen A, Tseng-Crank J, Dukes ID, Chandy G,
Hustad CM, Copeland NG, Jenkins NA, Mohrenweiser H,
Brandriff B, Cahalan M, Gutman GA, Chandy KG. Genomic
organization, chromosomal localization, tissue distribution, biophysical characterization of a novel mammalian Shaker-related
voltage-gated potassium channel, Kv1.7. J Biol Chem 273: 5851–
5857, 1998.
274. Kang D, Kim D. Single-channel properties and pH sensitivity of
two-pore domain K(⫹) channels of the TALK family. Biochem
Biophys Res Commun 315: 836 – 844, 2004.
275. Kang D, Mariash E, Kim D. Functional expression of TRESK-2, a
new member of the tandem-pore K⫹ channel family. J Biol Chem
279: 28063–28070, 2004.
276. Kaplan WD, Trout WE III. The behavior of four neurological
mutants of Drosophila. Genetics 61: 399 – 409, 1969.
277. Kawahara K, Hunter M, Giebisch G. Calcium-activated potassium channels in the luminal membrane of Amphiuma diluting
segment: voltage-dependent block by intracellular Na⫹ upon depolarisation. Pflügers Arch 416: 422– 427, 1990.
278. Keast JR. Mucosal innervation and control of water and ion
transport in the intestine. Rev Physiol Biochem Pharmacol 109:
1–59, 1987.
279. Kelly ML, Abu-Hamdah R, Jeremic A, Cho SJ, Ilie AE, Jena
BP. Patch clamped single pancreatic zymogen granules: direct
measurements of ion channel activities at the granule membrane.
Pancreatology 5: 443– 449, 2005.
280. Ketchum KA, Joiner WJ, Sellers AJ, Kaczmarek LK, Goldstein SA. A new family of outwardly rectifying potassium channel
proteins with two pore domains in tandem. Nature 376: 690 – 695,
1995.
281. Khanna R, Chang MC, Joiner WJ, Kaczmarek LK, Schlichter
LC. hSK4/hIK1, a calmodulin-binding KCa channel in human T
lymphocytes. Roles in proliferation and volume regulation. J Biol
Chem 274: 14838 –14849, 1999.
282. Kim D, Fujita A, Horio Y, Kurachi Y. Cloning and functional
expression of a novel cardiac two-pore background K⫹ channel
(cTBAK-1). Circ Res 82: 513–518, 1998.
283. Kim D, Gnatenco C. Task-5, a new member of the tandem-pore
K⫹ channel family. Biochem Biophys Res Commun 284: 923–930,
2001.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
304.
305.
306.
307.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
Physiol Rev • VOL
324. Lang F, Huber SM, Szabo I, Gulbins E. Plasma membrane ion
channels in suicidal cell death. Arch Biochem Biophys 462: 189 –
194, 2007.
325. Lang F, Lepple-Wienhues A, Paulmichl M, Szabo I, Siemen D,
Gulbins E. Ion channels, cell volume, apoptotic cell death. Cell
Physiol Biochem 8: 285–292, 1998.
326. Lapointe JY, Gagnon M, Poirier S, Bissonnette P. The presence of local osmotic gradients can account for the water flux
driven by the Na⫹-glucose cotransporter. J Physiol 542: 61– 62,
2002.
327. Lastraioli E, Guasti L, Crociani O, Polvani S, Hofmann G,
Witchel H, Bencini L, Calistri M, Messerini L, Scatizzi M,
Moretti R, Wanke E, Olivotto M, Mugnai G, Arcangeli A. herg1
gene and HERG1 protein are overexpressed in colorectal cancers
and regulate cell invasion of tumor cells. Cancer Res 64: 606 – 611,
2004.
328. Laukoetter MG, Bruewer M, Nusrat A. Regulation of the intestinal epithelial barrier by the apical junctional complex. Curr Opin
Gastroenterol 22: 85– 89, 2006.
329. Lauritzen I, Zanzouri M, Honore E, Duprat F, Ehrengruber
MU, Lazdunski M, Patel AJ. K⫹-dependent cerebellar granule
neuron apoptosis. Role of task leak K⫹ channels. J Biol Chem 278:
32068 –32076, 2003.
330. Lee E, Gerlach U, Uhm DY, Kim J. Inhibitory effect of somatostatin on secretin-induced augmentation of the slowly activating
K⫹ current (IKs) in the rat pancreatic acinar cell. Pflügers Arch 443:
405– 410, 2002.
331. Lee J, Simpson G, Scholes P. An ATPase from dog gastric
mucosa: changes of outer pH in suspensions of membrane vesicles
accompanying ATP hydrolysis. Biochem Biophys Res Commun 60:
825– 832, 1974.
332. Lee JE, Kim JH, Choi SJ, Han TH, Uhm DY, Kim SJ. Inhibitory
effects of PGE2 on K⫹ currents and Ca2⫹ oscillations in rat pancreatic acinar cells. Pflügers Arch 444: 619 – 626, 2002.
333. Lee JE, Park HS, Uhm DY, Kim SJ. Effects of KCNQ1 channel
blocker, 293B, on the acetylcholine-induced Cl⫺ secretion of rat
pancreatic acini. Pancreas 28: 435– 442, 2004.
334. Lee MP, Ravenel JD, Hu RJ, Lustig LR, Tomaselli G, Berger
RD, Brandenburg SA, Litzi TJ, Bunton TE, Limb C, Francis H,
Gorelikow M, Gu H, Washington K, Argani P, Goldenring JR,
Coffey RJ, Feinberg AP. Targeted disruption of the Kvlqt1 gene
causes deafness and gastric hyperplasia in mice. J Clin Invest 106:
1447–1455, 2000.
335. Lee YM, Kim BJ, Chun YS, So I, Choi H, Kim MS, Park JW.
NOX4 as an oxygen sensor to regulate TASK-1 activity. Cell Signal
18: 499 –507, 2006.
336. Leipziger J. Control of epithelial transport via luminal P2 receptors. Am J Physiol Renal Physiol 284: F419 –F432, 2003.
337. Leipziger J, Kerstan D, Nitschke R, Greger R. ATP increases
[Ca2⫹]i and ion secretion via a basolateral P2Y-receptor in rat distal
colonic mucosa. Pflügers Arch 434: 77– 83, 1997.
338. Lerche C, Bruhova I, Lerche H, Steinmeyer K, Wei A, StrutzSeebohm N, Busch AE, Lang F, Zhorov BS, Seebohm G. Chromanol 293B binding in KCNQ1 (Kv7.1) channels involves electrostatic interactions with a potassium ion in the selectivity filter. Mol
Pharmacol 2007.
339. Lerche C, Seebohm G, Wagner CI, Scherer CR, Dehmelt L,
Abitbol I, Gerlach U, Brendel J, Attali B, Busch AE. Molecular
impact of MinK on the enantiospecific block of I(Ks) by chromanols. Br J Pharmacol 131: 1503–1506, 2000.
340. Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M,
Romey G, Barhanin J. TWIK-1, a ubiquitous human weakly inward rectifying K⫹ channel with a novel structure. EMBO J 15:
1004 –1011, 1996.
341. Lesage F, Lauritzen I, Duprat F, Reyes R, Fink M, Heurteaux
C, Lazdunski M. The structure, function and distribution of the
mouse TWIK-1 K⫹ channel. FEBS Lett 402: 28 –32, 1997.
342. Lesage F, Lazdunski M. Potassium channels with two P domains.
Curr Top Membr Transp 46: 199 –222, 1999.
343. Lesage F, Lazdunski M. Molecular and functional properties of
two-pore-domain potassium channels. Am J Physiol Renal Physiol
279: F793–F801, 2000.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
308.
5-deficient mice have decreased membrane water permeability and
altered cell volume regulation. J Biol Chem 276: 23413–23420, 2001.
Krapivinsky G, Medina I, Eng L, Krapivinsky L, Yang Y,
Clapham DE. A novel inward rectifier K⫹ channel with unique
pore properties. Neuron 20: 995–1005, 1998.
Kubisch C, Schroeder BC, Friedrich T, Lütjohann B, ElAmraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel
potassium channel expressed in sensory outer hair cells, is mutated
in dominant deafness. Cell 96: 437– 446, 1999.
Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA.
International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels.
Pharmacol Rev 57: 509 –526, 2005.
Kuhn M, Fuchs M, Beck FX, Martin S, Jahne J, Klempnauer J,
Kaever V, Rechkemmer G, Forssmann WG. Endothelin-1 potently stimulates chloride secretion and inhibits Na(⫹)-glucose
absorption in human intestine in vitro. J Physiol 499: 391– 402,
1997.
Kunzelmann K. Ion channels and cancer. J Membr Biol 205:
159 –173, 2005.
Kunzelmann K, Bleich M, Warth R, Levy-Holzman R, Garty H,
Schreiber R. Expression and function of colonic epithelial KvLQT1 K⫹ channels. Clin Exp Pharmacol Physiol 28: 79 – 83, 2001.
Kunzelmann K, Gerlach L, Fröbe U, Greger R. Bicarbonate
permeability of epithelial chloride channels. Pflügers Arch 417:
616 – 621, 1991.
Kunzelmann K, Hübner M, Schreiber R, Levy-Holzman R,
Garty H, Bleich M, Warth R, Slavik M, von Hahn T, Greger R.
Cloning and function of the rat colonic epithelial K⫹ channel
KvLQT1. J Membr Biol 179: 155–164, 2001.
Kunzelmann K, Mall M. Electrolyte transport in the mammalian
colon: mechanisms and implications for disease. Physiol Rev 82:
245–289, 2002.
Kunzelmann K, Milenkovic VM, Spitzner M, Soria RB, Schreiber R. Calcium-dependent chloride conductance in epithelia: is
there a contribution by Bestrophin? Pflügers Arch 454: 878 – 889,
2007.
Kurachi Y, Ishii M. Cell signal control of the G protein-gated
potassium channel and its subcellular localization. J Physiol 554:
285–294, 2004.
Kuwahara A, Cooke HJ. Tachykinin-induced anion secretion in
guinea pig distal colon: role of neural and inflammatory mediators.
J Pharmacol Exp Ther 252: 1–7, 1990.
L’Hoste S, Poet M, Duranton C, Belfodil R, Barriere HE,
Rubera I, Tauc M, Poujeol C, Barhanin J, Poujeol P. Role of
TASK2 in the control of apoptotic volume decrease in proximal
kidney cells. J Biol Chem 282: 36692–36703, 2007.
Laforenza U, Cova E, Gastaldi G, Tritto S, Grazioli M, LaRusso NF, Splinter PL, D’Adamo P, Tosco M, Ventura U.
Aquaporin-8 is involved in water transport in isolated superficial
colonocytes from rat proximal colon. J Nutr 135: 2329 –2336, 2005.
Lam RS, Shaw AR, Duszyk M. Membrane cholesterol content
modulates activation of BK channels in colonic epithelia. Biochim
Biophys Acta 1667: 241–248, 2004.
Lambrecht NW, Yakubov I, Scott D, Sachs G. Identification of
the K efflux channel coupled to the gastric H,K ATPase during acid
secretion. Physiol Genomics 21: 81–91, 2005.
Lamprecht SA, Lipkin M. Migrating colonic crypt epithelial cells:
primary targets for transformation. Carcinogenesis 23: 1777–1780,
2002.
Lan M, Shi Y, Han Z, Hao Z, Pan Y, Liu N, Guo C, Hong L, Wang
J, Qiao T, Fan D. Expression of delayed rectifier potassium channels and their possible roles in proliferation of human gastric
cancer cells. Cancer Biol Ther 4: 1342–1347, 2005.
Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E,
Haussinger D. Functional significance of cell volume regulatory
mechanisms. Physiol Rev 78: 247–306, 1998.
Lang F, Foller M, Lang KS, Lang PA, Ritter M, Gulbins E,
Vereninov A, Huber SM. Ion channels in cell proliferation and
apoptotic cell death. J Membr Biol 205: 147–157, 2005.
1173
1174
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
364. Lopatin AN, Nichols CG. Internal Na⫹ and Mg2⫹ blockade of
DRK1 (Kv2.1) potassium channels expressed in Xenopus oocytes.
Inward rectification of a delayed rectifier. J Gen Physiol 103:
203–216, 1994.
365. Lotz MM, Wang H, Song JC, Pories SE, Matthews JB. K⫹
channel inhibition accelerates intestinal epithelial cell wound healing. Wound Repair Regen 12: 565–574, 2004.
366. Lu R, Alioua A, Kumar Y, Eghbali M, Stefani E, Toro L. MaxiK
channel partners: physiological impact. J Physiol 570: 65–72, 2006.
367. Lu T, Ye D, Wang X, Seubert JM, Graves JP, Bradbury JA,
Zeldin DC, Lee HC. Activation of KATP channels by endogenous
cytochrome P450 epoxygenase metabolites of arachidonic acid:
cardiac and vascular katp channels are activated by epoxyeicosatrienoic acids through different mechanisms. J Physiol 575: 627–
644, 2006.
368. Lundgren O. Enteric nerves and diarrhoea. Pharmacol Toxicol 90:
109 –120, 2002.
369. Lundgren O, Jodal M. The enteric nervous system and cholera
toxin-induced secretion. Comp Biochem Physiol A Physiol 118:
319 –327, 1997.
370. Luo X, Choi JY, Ko SB, Pushkin A, Kurtz I, Ahn W, Lee MG,
Muallem S. HCO⫺
3 salvage mechanisms in the submandibular
gland acinar and duct cells. J Biol Chem 276: 9808 –9816, 2001.
371. Lytle C, Forbush B. Regulatory phosphorylation of the secretory
Na-K-Cl cotransporter: modulation by cytoplasmic Cl. Am J
Physiol Cell Physiol 270: C437–C448, 1996.
372. Ma T, Song Y, Gillespie A, Carlson EJ, Epstein CJ, Verkman
AS. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J Biol Chem 274: 20071–20074, 1999.
373. Ma T, Verkman AS. Aquaporin water channels in gastrointestinal
physiology. J Physiol 517: 317–326, 1999.
374. MacDonald PE, Ha XF, Wang J, Smukler SR, Sun AM, Gaisano
HY, Salapatek AM, Backx PH, Wheeler MB. Members of the Kv1
and Kv2 voltage-dependent K⫹ channel families regulate insulin
secretion. Mol Endocrinol 15: 1423–1435, 2001.
375. MacDonald PE, Sewing S, Wang J, Joseph JW, Smukler SR,
Sakellaropoulos G, Wang J, Saleh MC, Chan CB, Tsushima
RG, Salapatek AM, Wheeler MB. Inhibition of Kv2.1 voltagedependent K⫹ channels in pancreatic beta-cells enhances glucosedependent insulin secretion. J Biol Chem 277: 44938 – 44945, 2002.
376. MacKinnon R. Determination of the subunit stoichiometry of a
voltage-activated potassium channel. Nature 350: 232–235, 1991.
377. MacLeod RJ, Hamilton JR. Ca2⫹/calmodulin kinase II and decreases in intracellular pH are required to activate K⫹ channels
after substantial swelling in villus epithelial cells. J Membr Biol
172: 59 – 66, 1999.
378. MacLeod RJ, Hamilton JR. Increases in intracellular pH and
Ca2⫹ are essential for K⫹ channel activation after modest “physiological” swelling in villus epithelial cells. J Membr Biol 172: 47–58,
1999.
379. MacLeod RJ, Lembessis P, Hamilton JR. Effect of osmotic
swelling on K⫹ conductance in jejunal crypt epithelial cells. Am J
Physiol Gastrointest Liver Physiol 262: G1021–G1026, 1992.
380. MacVinish LJ, Hickman ME, Mufti DAH, Durrington HJ,
Cuthbert AW. Importance of basolateral K⫹ conductance in maintaining Cl⫺ secretion in murine nasal and colonic epithelia.
J Physiol 510: 237–247, 1998.
381. Maingret F, Fosset M, Lesage F, Lazdunski M, Honore E.
TRAAK is a mammalian neuronal mechano-gated K⫹ channel.
J Biol Chem 274: 1381–1387, 1999.
382. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E.
Mechano- or acid stimulation, two interactive modes of activation
of the TREK-1 potassium channel. J Biol Chem 274: 26691–26696,
1999.
383. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E.
Lysophospholipids open the two-pore domain mechano-gated K⫹
channels TREK-1 and TRAAK. J Biol Chem 275: 10128 –10133, 2000.
384. Malik B, Price SR, Mitch WE, Yue Q, Eaton DC. Regulation of
epithelial sodium channels by the ubiquitin-proteasome proteolytic
pathway. Am J Physiol Renal Physiol 290: F1285–F1294, 2006.
385. Malinowska DH, Cuppoletti J, Sachs G. Cl⫺ requirement of acid
secretion in isolated gastric glands. Am J Physiol Gastrointest
Liver Physiol 245: G573–G581, 1983.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
344. Lesage F, Maingret F, Lazdunski M. Cloning and expression of
human TRAAK, a polyunsaturated fatty acids-activated and
mechano-sensitive K⫹ channel. FEBS Lett 471: 137–140, 2000.
345. Lesage F, Terrenoire C, Romey G, Lazdunski M. Human
TREK2, a 2P domain mechano-sensitive K⫹ channel with multiple
regulations by polyunsaturated fatty acids, lysophospholipids, Gs,
Gi, Gq protein-coupled receptors. J Biol Chem 275: 28398 –28405,
2000.
346. Levitan IB. Phosphorylation of ion channels. J Membr Biol 87:
177–190, 1985.
347. Li J, Koo NY, Cho IH, Kwon TH, Choi SY, Lee SJ, Oh SB, Kim
JS, Park K. Expression of the Na⫹-HCO⫺
3 cotransporter and its
role in pHi regulation in guinea pig salivary glands. Am J Physiol
Gastrointest Liver Physiol 291: G1031–G1040, 2006.
348. Liao T, Wang L, Halm ST, Lu L, Fyffe RE, Halm DR. The
K⫹channel KvLQT (Kcnq1) located in the basolateral membrane of
distal colonic epithelium is not essential for activating Cl⫺ secretion. Am J Physiol Cell Physiol 289: C564 –C575, 2005.
349. Lin DH, Sterling H, Wang Z, Babilonia E, Yang B, Dong K,
Hebert SC, Giebisch G, Wang WH. ROMK1 channel activity is
regulated by monoubiquitination. Proc Natl Acad Sci USA 102:
4306 – 4311, 2005.
350. Lin DH, Sterling H, Yang B, Hebert SC, Giebisch G, Wang WH.
Protein tyrosine kinase is expressed and regulates ROMK1 location
in the cortical collecting duct. Am J Physiol Renal Physiol 286:
F881–F892, 2004.
351. Linden AM, Aller MI, Leppa E, Vekovischeva O, Aitta-Aho T,
Veale EL, Mathie A, Rosenberg P, Wisden W, Korpi ER. The in
vivo contributions of TASK-1-containing channels to the actions of
inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, cannabinoid agonists. J Pharmacol Exp Ther 317:
615– 626, 2006.
352. Lipkin M. Growth and development of gastrointestinal cells. Annu
Rev Physiol 47: 175–197, 1985.
353. Liu X, Singh BB, Ambudkar IS. ATP-dependent activation of
K(Ca) and ROMK-type K(ATP) channels in human submandibular
gland ductal cells. J Biol Chem 274: 25121–25129, 1999.
354. Liu Y, McKenna E, Figueroa DJ, Blevins R, Austin CP, Bennett PB, Swanson R. The human inward rectifier K⫹ channel
subunit kir5.1 (KCNJ16) maps to chromosome 17q25 and is expressed in kidney and pancreas. Cytogenet Cell Genet 90: 60 – 63,
2000.
355. Logsdon NJ, Aiyar J. Murine intermediate conductance calciumactivated potassium channel (mKCa4, KCNN4) complete cds. GenBank AF072884, 1998.
356. Logsdon NJ, Kang J, Togo JA, Christian EP, Aiyar J. A novel
gene, hKCa4, encodes the calcium-activated potassium channel in
human T lymphocytes. J Biol Chem 272: 32723–32726, 1997.
357. Lohrmann E, Burhoff I, Nitschke RB, Lang HJ, Mania D,
Englert HC, Hropot M, Warth R, Rohm W, Bleich M, Greger R.
A new class of inhibitors of cAMP-mediated Cl⫺ secretion in rabbit
colon, acting by the reduction of cAMP-activated K⫹ conductance.
Pflügers Arch 429: 517–530, 1995.
358. Loktionov A. Cell exfoliation in the human colon: myth, reality
and implications for colorectal cancer screening. Int J Cancer 120:
2281–2289, 2007.
359. Lomax RB, McNicholas CM, Lombes M, Sandle GI. Aldosterone-induced apical Na⫹ and K⫹ conductances are located predominantly in surface cells in rat distal colon. Am J Physiol Gastrointest Liver Physiol 266: G71–G82, 1994.
360. Lomax RB, Warhurst G, Sandle GI. Characteristics of two basolateral potassium channel populations in human colonic crypts.
Gut 38: 243–247, 1996.
361. Long SB, Tao X, Campbell EB, MacKinnon R. Atomic structure
of a voltage-dependent K(⫹) channel in a lipid membrane-like
environment. Nature 450: 376 –382, 2007.
362. Loo DD, Zeuthen T, Chandy G, Wright EM. Cotransport of
water by the Na⫹/glucose cotransporter. Proc Natl Acad Sci USA
93: 13367–13370, 1996.
363. Lopatin AN, Makhina EN, Nichols CG. Potassium channel block
by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature 372: 366 –369, 1994.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
Physiol Rev • VOL
409.
410.
411.
412.
413.
414.
415.
416.
417.
418.
419.
420.
421.
422.
423.
424.
425.
426.
tivity to mammalian large conductance voltage- and Ca-activated K
(BK) channel alpha-subunits. Proc Natl Acad Sci USA 102: 17870 –
17876, 2005.
McCormack K, Connor JX, Zhou L, Ho LL, Ganetzky B, Chiu
SY, Messing A. Genetic analysis of the mammalian K⫹ channel
beta subunit Kvbeta 2 (Kcnab2). J Biol Chem 277: 13219 –13228,
2002.
McManaman JL, Reyland ME, Thrower EC. Secretion and fluid
transport mechanisms in the mammary gland: comparisons with
the exocrine pancreas and the salivary gland. J Mammary Gland
Biol Neoplasia 11: 249 –268, 2006.
McNicholas CM, Fraser G, Sandle GI. Properties and regulation
of basolateral K⫹ channels in rat duodenal crypts. J Physiol 477:
381–392, 1994.
Meadows HJ, Benham CD, Cairns W, Gloger I, Jennings C,
Medhurst AD, Murdock P, Chapman CG. Cloning, localisation
and functional expression of the human orthologue of the TREK-1
potassium channel. Pflügers Arch 439: 714 –722, 2000.
Medhurst AD, Rennie G, Chapman CG, Meadows H, Duckworth MD, Kelsell RE, Gloger II, Pangalos MN. Distribution
analysis of human two pore domain potassium channels in tissues
of the central nervous system and periphery. Brain Res 86: 101–
114, 2001.
Meinild A, Klaerke DA, Loo DD, Wright EM, Zeuthen T. The
human Na⫹-glucose cotransporter is a molecular water pump.
J Physiol 508: 15–21, 1998.
Melvin JE, Yule D, Shuttleworth T, Begenisich T. Regulation of
fluid and electrolyte secretion in salivary gland acinar cells. Annu
Rev Physiol 67: 445– 469, 2005.
Meneton P, Schultheis PJ, Greeb J, Nieman ML, Liu LH,
Clarke LL, Duffy JJ, Doetschman T, Lorenz JN, Shull GE.
Increased sensitivity to K⫹ deprivation in colonic H,K-ATPasedeficient mice. J Clin Invest 101: 536 –542, 1998.
Meuth SG, Aller MI, Munsch T, Schuhmacher T, Seidenbecher
T, Meuth P, Kleinschnitz C, Pape HC, Wiendl H, Wisden W,
Budde T. The contribution of TWIK-related acid-sensitive K⫹containing channels to the function of dorsal lateral geniculate
thalamocortical relay neurons. Mol Pharmacol 69: 1468 –1476, 2006.
Mieno H, Kajiyama G. Electrical characteristics of inward-rectifying K⫹ channels in isolated bullfrog oxyntic cells. Am J Physiol
Gastrointest Liver Physiol 261: G206 –G212, 1991.
Miki T, Suzuki M, Shibasaki T, Uemura H, Sato T, Yamaguchi
K, Koseki H, Iwanaga T, Nakaya H, Seino S. Mouse model of
Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat
Med 8: 466 – 472, 2002.
Miki T, Tashiro F, Iwanaga T, Nagashima K, Yoshitomi H,
Aihara H, Nitta Y, Gonoi T, Inagaki N, Miyazaki J, Seino S.
Abnormalities of pancreatic islets by targeted expression of a
dominant-negative KATP channel. Proc Natl Acad Sci USA 94:
11969 –11973, 1997.
Millar ID, Taylor HC, Cooper GJ, Kibble JD, Barhanin J,
Robson L. Adaptive downregulation of a quinidine-sensitive cation
conductance in renal principal cells of TWIK-1 knockout mice.
Pflügers Arch 453: 107–116, 2006.
Mintenig GM, Monaghan AS, Sepulveda FV. A large conductance K⫹-selective channel of guinea pig villus enterocytes is Ca2⫹
independent. Am J Physiol Gastrointest Liver Physiol 262: G369 –
G374, 1992.
Mogami H, Nakano K, Tepikin AV, Petersen OH. Ca2⫹ flow via
tunnels in polarized cells: recharging of apical Ca2⫹ stores by focal
Ca2⫹ entry through basal membrane patch. Cell 88: 49 –55, 1997.
Moore-Hoon ML, Turner RJ. Molecular and topological characterization of the rat parotid Na⫹-K⫹-2Cl⫺ cotransporter1. Biochim
Biophys Acta 1373: 261–269, 1998.
Morimoto K, Sugimoto Y, Katsuyama M, Oida H, Tsuboi K,
Kishi K, Kinoshita Y, Negishi M, Chiba T, Narumiya S,
Ichikawa A. Cellular localization of mRNAs for prostaglandin E
receptor subtypes in mouse gastrointestinal tract. Am J Physiol
Gastrointest Liver Physiol 272: G681–G687, 1997.
Morita T, Hanaoka K, Morales MM, Montrose-Rafizadeh C,
Guggino WB. Cloning and characterization of maxi K⫹ channel
␣-subunit in rabbit kidney. Am J Physiol Renal Physiol 273: F615–
F624, 1997.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
386. Malinowska DH, Kupert EY, Bahinski A, Sherry AM, Cuppoletti J. Cloning, functional expression, characterization of a PKAactivated gastric Cl⫺ channel. Am J Physiol Cell Physiol 268:
C191–C200, 1995.
387. Malinowska DH, Sachs G. Cellular mechanisms of acid secretion.
Clin Gastroenterol 13: 309 –326, 1984.
388. Malinowska DH, Sherry AM, Tewari KP, Cuppoletti J. Gastric
parietal cell secretory membrane contains PKA- and acid-activated
Kir2.1 K⫹ channels. Am J Physiol Cell Physiol 286: C495–C506,
2004.
389. Mall M, Bleich M, Schürlein M, Kühr J, Seydewitz HH, Brandis M, Greger R, Kunzelmann K. Cholinergic ion secretion in
human colon requires coactivation by cAMP. Am J Physiol Gastrointest Liver Physiol 275: G1274 –G1281, 1998.
390. Mall M, Gonska T, Thomas J, Hirtz S, Schreiber R, Kunzelmann K. Activation of ion secretion via proteinase-activated receptor-2 in human colon. Am J Physiol Gastrointest Liver Physiol
282: G200 –G210, 2002.
391. Mall M, Wissner A, Seydewitz HH, Kuehr J, Brandis M, Greger R, Kunzelmann K. Defective cholinergic Cl⫺ secretion and
detection of K⫹ secretion in rectal biopsies from cystic fibrosis
patients. Am J Physiol Gastrointest Liver Physiol 278: G617–G624,
2000.
392. Martinez JR. Cellular mechanisms underlying the production of
primary secretory fluid in salivary glands. Crit Rev Oral Biol Med 1:
67–78, 1990.
393. Martinsen TC, Bergh K, Waldum HL. Gastric juice: a barrier
against infectious diseases. Basic Clin Pharmacol Toxicol 96: 94 –
102, 2005.
394. Marty A, Tan YP, Trautmann A. Three types of calcium-dependent channel in rat lacrimal glands. J Physiol 357: 293–325, 1984.
395. Maruyama Y, Gallacher DV, Petersen OH. Voltage and Ca2⫹activated K⫹ channel in basolateral acinar cell membranes of mammalian salivary glands. Nature 302: 827– 829, 1983.
396. Maruyama Y, Petersen OH, Flanagan P, Pearson GT. Quantification of Ca2⫹-activated K⫹ channels under hormonal control in
pig pancreas acinar cells. Nature 305: 228 –232, 1983.
397. Masyuk AI, Marinelli RA, LaRusso NF. Water transport by
epithelia of the digestive tract. Gastroenterology 122: 545–562,
2002.
398. Mathialahan T, Maclennan KA, Sandle LN, Verbeke C, Sandle
GI. Enhanced large intestinal potassium permeability in end-stage
renal disease. J Pathol 206: 46 –51, 2005.
399. Matos JE, Robaye B, Boeynaems JM, Beauwens R, Leipziger
J. K⫹ secretion activated by luminal P2Y2 and P2Y4 receptors in
mouse colon. J Physiol 564: 269 –279, 2005.
400. Matos JE, Sausbier M, Beranek G, Sausbier U, Ruth P, Leipziger J. Role of cholinergic-activated K1.1 189: 251–258, 2007.
401. Matsuzaki T, Suzuki T, Koyama H, Tanaka S, Takata K. Aquaporin-5 (AQP5), a water channel protein, in the rat salivary and
lacrimal glands: immunolocalization and effect of secretory stimulation. Cell Tissue Res 295: 513–521, 1999.
402. Matsuzaki T, Tajika Y, Ablimit A, Aoki T, Hagiwara H, Takata
K. Aquaporins in the digestive system. Med Electron Microsc 37:
71– 80, 2004.
403. Matthews JC, Anderson KJ. Recent advances in amino acid
transporters and excitatory amino acid receptors. Curr Opin Clin
Nutr Metab Care 5: 77– 84, 2002.
404. Mauerer UR, Boulpaep EL, Segal AS. Regulation of an inwardly
rectifying ATP-sensitive K⫹ channel in the basolateral membrane
of renal proximal tubule. J Gen Physiol 111: 161–180, 1998.
405. Mayorga-Wark O, Dubinsky WP, Schultz SG. Reconstitution of
a KATP channel from basolateral membranes of Necturus enterocytes. Am J Physiol Cell Physiol 269: C464 –C471, 1995.
406. März A, Tegtmeier I, Reichold M, Sterner C, Heitzmann D,
Warth R. Expression profile of epithelial potassium channels along
the gastrointestinal tract (Abstract). Acta Physiol Scand 189 Suppl
653: P07, 2007.
407. McCabe RD, Smith PL. Effects of histamine and histamine receptor antagonists on ion transport in rabbit descending colon. Am J
Physiol Gastrointest Liver Physiol 247: G411–G418, 1984.
408. McCartney CE, McClafferty H, Huibant JM, Rowan EG, Shipston MJ, Rowe IC. A cysteine-rich motif confers hypoxia sensi-
1175
1176
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
448. Niemeyer MI, Cid LP, Sepulveda FV. K⫹ conductance activated
during regulatory volume decrease. The channels in Ehrlich cells
and their possible molecular counterpart. Comp Biochem Physiol
A Physiol 130: 565–575, 2001.
449. Niemeyer MI, Gonzalez-Nilo FD, Zuniga L, Gonzalez W, Cid
LP, Sepulveda FV. Neutralization of a single arginine residue
gates open a two-pore domain, alkali-activated K⫹ channel. Proc
Natl Acad Sci USA 104: 666 – 671, 2007.
450. Nobles M, Diener M, Rummel W. Segment-specific effects of the
heat-stable enterotoxin of E. coli on electrolyte transport in the rat
colon. Eur J Pharmacol 202: 201–211, 1991.
451. Nordgren B. The rate of secretion and electrolyte content of
normal gastric juice. Acta Physiol Scand Suppl 58: 1– 83, 1963.
452. Novak I. ␤-Adrenergic regulation of ion transport in pancreatic
ducts: patch-clamp study of isolated rat pancreatic ducts. Gastroenterology 115: 714 –721, 1998.
453. Novak I, Greger R. Electrophysiological study of transport systems in isolated perfused pancreatic ducts: properties of the basolateral membrane. Pflügers Arch 411: 58 – 68, 1988.
454. Novak I, Greger R. Effect of bicarbonate on potassium conductance of isolated perfused rat pancreatic ducts. Pflügers Arch 419:
76 – 83, 1991.
455. Nussberger J. Investigating mineralocorticoid hypertension.
J Hypertens Suppl 21: S25–S30, 2003.
456. O’Grady SM, Lee SY. Molecular diversity and function of voltagegated (Kv) potassium channels in epithelial cells. Int J Biochem
Cell Biol 37: 1578 –1594, 2005.
457. O’Malley KE, Farrell CB, O’Boyle KM, Baird AW. Cholinergic
activation of Cl⫺ secretion in rat colonic epithelia. Eur J Pharmacol 275: 83– 89, 1995.
458. Ohya S, Asakura K, Muraki K, Watanabe M, Imaizumi Y.
Molecular and functional characterization of ERG, KCNQ, KCNE
subtypes in rat stomach smooth muscle. Am J Physiol Gastrointest
Liver Physiol 282: G277–G287, 2002.
459. Okada Y, Shimizu T, Maeno E, Tanabe S, Wang X, Takahashi
N. Volume-sensitive chloride channels involved in apoptotic volume decrease and cell death. J Membr Biol 209: 21–29, 2006.
460. Okada Y, Ueda S. Electrical membrane responses to secretagogues in parietal cells of the rat gastric mucosa in culture.
J Physiol 354: 109 –119, 1984.
461. Okamoto CT, Forte JG. Vesicular trafficking machinery, the actin
cytoskeleton, H⫹-K⫹-ATPase recycling in the gastric parietal cell.
J Physiol 532: 287–296, 2001.
462. Oliver D, Lien CC, Soom M, Baukrowitz T, Jonas P, Fakler B.
Functional conversion between A-type and delayed rectifier K⫹
channels by membrane lipids. Science 304: 265–270, 2004.
463. Oshiro T, Takahashi H, Ohsaga A, Ebihara S, Sasaki H, Maruyama Y. Delayed expression of large conductance K⫹ channels
reshaping agonist-induced currents in mouse pancreatic acinar
cells. J Physiol 563: 379 –391, 2005.
464. Ottschytsch N, Raes A, Van Hoorick D, Snyders DJ. Obligatory
heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome. Proc Natl Acad
Sci USA 99: 7986 –7991, 2002.
465. Ousingsawat J, Spitzner M, Puntheeranurak S, Terracciano
L, Tornillo L, Bubendorf L, Kunzelmann K, Schreiber R. Expression of voltage-gated potassium channels in human and mouse
colonic carcinoma. Clin Cancer Res 13: 824 – 831, 2007.
466. Overturf KE, Russell SN, Carl A, Vogalis F, Hart PJ, Hume JR,
Sanders KM, Horowitz B. Cloning and characterization of a Kv1.5
delayed rectifier K⫹ channel from vascular and visceral smooth
muscles. Am J Physiol Cell Physiol 267: C1231–C1238, 1994.
467. Pacha J. Development of intestinal transport function in mammals. Physiol Rev 80: 1633–1667, 2000.
468. Pahl C, Novak I. Effect of vasoactive intestinal peptide, carbachol
and other agonists on the membrane voltage of pancreatic duct
cells. Pflügers Arch 424: 315–320, 1993.
469. Palacin M, Estevez R, Bertran J, Zorzano A. Molecular biology
of mammalian plasma membrane amino acid transporters. Physiol
Rev 78: 969 –1054, 1998.
470. Pan X, Terada T, Irie M, Saito H, Inui K. Diurnal rhythm of
H⫹-peptide cotransporter in rat small intestine. Am J Physiol Gastrointest Liver Physiol 283: G57–G64, 2002.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
427. Morris AP, Gallacher DV, Lee JA. A large conductance, voltageand calcium-activated K⫹ channel in the basolateral membrane of
rat enterocytes. FEBS Lett 206: 87–92, 1986.
428. Morton MJ, Abohamed A, Sivaprasadarao A, Hunter M. pH
sensing in the two-pore domain K⫹ channel, TASK2. Proc Natl
Acad Sci USA 102: 16102–16106, 2005.
429. Morton MJ, Chipperfield S, Abohamed A, Sivaprasadarao A,
Hunter M. Na⫹-induced inward rectification in the two-pore domain K⫹ channel, TASK-2. Am J Physiol Renal Physiol 288: F162–
F169, 2004.
430. Morton MJ, O’Connell AD, Sivaprasadarao A, Hunter M. Determinants of pH sensing in the two-pore domain K⫹ channels
TASK-1 and -2. Pflügers Arch 445: 577–583, 2003.
431. Mount DB, Romero MF. The SLC26 gene family of multifunctional anion exchangers. Pflügers Arch 447: 710 –721, 2004.
432. Mu D, Chen L, Zhang X, See LH, Koch CM, Yen C, Tong JJ,
Spiegel L, Nguyen KC, Servoss A, Peng Y, Pei L, Marks JR,
Lowe S, Hoey T, Jan LY, McCombie WR, Wigler MH, Powers S.
Genomic amplification and oncogenic properties of the KCNK9
potassium channel gene. Cancer Cell 3: 297–302, 2003.
433. Muallem S, Burnham C, Blissard D, Berglindh T, Sachs G.
Electrolyte transport across the basolateral membrane of the parietal cells. J Biol Chem 260: 6641– 6653, 1985.
434. Murakami M, Shachar-Hill B, Steward MC, Hill AE. The paracellular component of water flow in the rat submandibular salivary
gland. J Physiol 537: 899 –906, 2001.
435. Naftalin RJ, Pedley KC. Regional crypt function in rat large
intestine in relation to fluid absorption and growth of the pericryptal sheath. J Physiol 514: 211–227, 1999.
436. Naftalin RJ, Zammit PS, Pedley KC. Regional differences in rat
large intestinal crypt function in relation to dehydrating capacity in
vivo. J Physiol 514: 201–210, 1999.
437. Nakamoto T, Srivastava A, Romanenko VG, Ovitt CE, PerezCornejo P, Arreola J, Begenisich T, Melvin JE. Functional and
molecular characterization of the fluid secretion mechanism in
human parotid acinar cells. Am J Physiol Regul Integr Comp
Physiol 292: R2380 –R2390, 2007.
438. Nakamura N, Suzuki Y, Sakuta H, Ookata K, Kawahara K,
Hirose S. Inwardly rectifying K⫹ channel Kir7.1 is highly expressed in thyroid follicular cells, intestinal epithelial cells and
choroid plexus epithelial cells: implication for a functional coupling with Na⫹,K⫹-ATPase. Biochem J 342: 329 –336, 1999.
439. Nauntofte B. Regulation of electrolyte and fluid secretion in salivary acinar cells. Am J Physiol Gastrointest Liver Physiol 263:
G823–G837, 1992.
440. Nehrke K, Arreola J, Nguyen HV, Pilato J, Richardson L,
Okunade G, Baggs R, Shull GE, Melvin JE. Loss of hyperpolarization-activated Cl⫺ current in salivary acinar cells from Clcn2
knockout mice. J Biol Chem 277: 23604 –23611, 2002.
441. Nehrke K, Quinn CC, Begenisich T. Molecular identification of
Ca2⫹-activated K⫹ channels in parotid acinar cells. Am J Physiol
Cell Physiol 284: C535–C546, 2003.
442. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K,
Guicheney P. A novel mutation in the potassium channel gene
KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet 15: 186 –189, 1997.
443. Nguyen HV, Stuart-Tilley A, Alper SL, Melvin JE. Cl⫺/HCO⫺
3
exchange is acetazolamide sensitive and activated by a muscarinic
2⫹
receptor-induced [Ca ]i increase in salivary acinar cells. Am J
Physiol Gastrointest Liver Physiol 286: G312–G320, 2004.
444. Nichols CG. KATP channels as molecular sensors of cellular metabolism. Nature 440: 470 – 476, 2006.
445. Nie X, Arrighi I, Kaissling B, Pfaff I, Mann J, Barhanin J,
Vallon V. Expression and insights on function of potassium channel TWIK-1 in mouse kidney. Pflügers Arch 451: 479 – 488, 2005.
446. Nielsen MS, Warth R, Bleich M, Weyand B, Greger R. The
basolateral Ca2⫹-dependent K⫹ channel in rat colonic crypt cells.
Pflügers Arch 435: 267–272, 1998.
447. Niemeyer MI, Cid LP, Barros LF, Sepulveda FV. Modulation of
the two-pore domain acid-sensitive K⫹ channel TASK-2 (KCNK5)
by changes in cell volume. J Biol Chem 276: 43166 – 43174, 2001.
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
Physiol Rev • VOL
495. Petersen OH, Findlay I, Iwatsuki N, Singh J, Gallacher DV,
Fuller CM, Pearson GT, Dunne MJ, Morris AP. Human pancreatic acinar cells: studies of stimulus-secretion coupling. Gastroenterology 89: 109 –117, 1985.
496. Petersen OH, Gallacher DV. Electrophysiology of pancreatic and
salivary acinar cells. Annu Rev Physiol 50: 65– 80, 1988.
497. Pfeifer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fassler R.
Intestinal secretory defects and dwarfism in mice lacking cGMPdependent protein kinase II. Science 274: 2082–2086, 1996.
498. Piccini M, Vitelli F, Seri M, Galietta LJ, Moran O, Bulfone A,
Banfi S, Pober B, Renieri A. KCNE1-like gene is deleted in
AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs. Genomics 60: 251–257,
1999.
499. Plant LD, Kemp PJ, Peers C, Henderson Z, Pearson HA. Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1. Stroke 33: 2324 –2328, 2002.
500. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou
S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E,
Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn
A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G,
Fu YH, Ptacek LJ. Mutations in Kir21 cause the developmental
and episodic electrical phenotypes of Andersen’s syndrome. Cell
105: 511–519, 2001.
501. Pothoulakis C, Castagliuolo I, LaMont JT. Nerves and instestinal mast cells modulate responses to enterotoxins. News Physiol
Sci 13: 58 – 63, 1998.
502. Poulsen JH, Fischer H, Illek B, Machen TE. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA 91: 5340 –
5344, 1994.
503. Puntheeranurak S, Schreiber R, Spitzner M, Ousingsawat J,
Krishnamra N, Kunzelmann K. Control of ion transport in mouse
proximal and distal colon by prolactin. Cell Physiol Biochem 19:
77– 88, 2007.
504. Putney JW Jr. Identification of cellular activation mechanisms
associated with salivary secretion. Annu Rev Physiol 48: 75– 88,
1986.
505. Rahner C, Mitic LL, Anderson JM. Heterogeneity in expression
and subcellular localization of claudins 2, 3, 4, 5 in the rat liver,
pancreas, gut. Gastroenterology 120: 411– 422, 2001.
506. Rajan S, Plant LD, Rabin ML, Butler MH, Goldstein SA.
Sumoylation silences the plasma membrane leak K⫹ channel K2P1.
Cell 121: 37– 47, 2005.
507. Rajan S, Preisig-Muller R, Wischmeyer E, Nehring R, Hanley
PJ, Renigunta V, Musset B, Schlichthorl G, Derst C, Karschin
A, Daut J. Interaction with 14 –3-3 proteins promotes functional
expression of the potassium channels TASK-1 and TASK-3.
J Physiol 545: 13–26, 2002.
508. Rajan S, Wischmeyer E, Karschin C, Preisig-Muller R, Grzeschik KH, Daut J, Karschin A, Derst C. THIK-1 and THIK-2, a
novel subfamily of tandem pore domain K⫹ channels. J Biol Chem
276: 7302–7311, 2000.
509. Rajan S, Wischmeyer E, Xin LG, Preisig-Muller R, Daut J,
Karschin A, Derst C. TASK-3, a novel tandem pore domain acidsensitive K⫹ channel. An extracellular histiding as pH sensor.
J Biol Chem 275: 16650 –16657, 2000.
510. Ramadan T, Camargo SM, Summa V, Hunziker P, Chesnov S,
Pos KM, Verrey F. Basolateral aromatic amino acid transporter
TAT1 (Slc16a10) functions as an efflux pathway. J Cell Physiol 206:
771–779, 2006.
511. Ramu Y, Xu Y, Lu Z. Enzymatic activation of voltage-gated potassium channels. Nature 442: 696 – 699, 2006.
512. Rao JN, Platoshyn O, Li L, Guo X, Golovina VA, Yuan JX,
Wang JY. Activation of K⫹ channels and increased migration of
differentiated intestinal epithelial cells after wounding. Am J
Physiol Cell Physiol 282: C885–C898, 2002.
513. Rapedius M, Haider S, Browne KF, Shang L, Sansom MS,
Baukrowitz T, Tucker SJ. Structural and functional analysis of
the putative pH sensor in the Kir1.1 (ROMK) potassium channel.
EMBO Rep 7: 611– 616, 2006.
514. Reenstra WW, Forte JG. Characterization of K⫹ and Cl⫺ conductances in apical membrane vesicles from stimulated rabbit oxyntic
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
471. Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan LY. Cloning of genomic and complementary DNA from Shaker, a putative
potassium channel gene from Drosophila. Science 237: 749 –753,
1987.
472. Pardo LA. Voltage-gated potassium channels in cell proliferation.
Physiology 19: 285–292, 2004.
473. Pardo LA, Contreras-Jurado C, Zientkowska M, Alves F, Stuhmer W. Role of voltage-gated potassium channels in cancer. J
Membr Biol 205: 115–124, 2005.
474. Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A,
Beckh S, Stuhmer W. Oncogenic potential of EAG K(⫹) channels.
EMBO J 18: 5540 –5547, 1999.
475. Park K, Case RM, Brown PD. Identification and regulation of K⫹
and Cl⫺ channels in human parotid acinar cells. Arch Oral Biol 46:
801– 810, 2001.
476. Park K, Hurley PT, Roussa E, Cooper GJ, Smith CP, Thevenod F, Steward MC, Case RM. Expression of a sodium bicarbonate cotransporter in human parotid salivary glands. Arch Oral
Biol 47: 1–9, 2002.
477. Park KS, Mohapatra DP, Misonou H, Trimmer JS. Graded
regulation of the Kv2.1 potassium channel by variable phosphorylation. Science 313: 976 –979, 2006.
478. Park MK, Lomax RB, Tepikin AV, Petersen OH. Local uncaging
of caged Ca2⫹ reveals distribution of Ca2⫹-activated Cl⫺ channels
in pancreatic acinar cells. Proc Natl Acad Sci USA 98: 10948 –10953,
2001.
479. Partiseti M, Collura V, Agnel M, Culouscou JM, Graham D.
Cloning and characterization of a novel human inwardly rectifying
potassium channel predominantly expressed in small intestine.
FEBS Lett 434: 171–176, 1998.
480. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY,
Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley
MA, Lowell BB. Glucose sensing by POMC neurons regulates
glucose homeostasis and is impaired in obesity. Nature 449: 228 –
232, 2007.
481. Patel AJ, Honore E. Molecular physiology of oxygen-sensitive
potassium channels. Eur Respir J 18: 221–227, 2001.
482. Patel AJ, Honore E. Properties and modulation of mammalian 2P
domain K⫹ channels. Trends Neurosci 24: 339 –346, 2001.
483. Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M.
Inhalational anesthetics activate two-pore-domain background K⫹
channels. Nat Neurosci 2: 422– 426, 1999.
484. Patel AJ, Lazdunski M. The 2P-domain K⫹ channels: role in
apoptosis and tumorigenesis. Pflügers Arch 448: 261–273, 2004.
485. Patel AJ, Lazdunski M, Honore E. Kv2.1/Kv9.3, an ATP-dependent delayed-rectifier K⫹ channel in pulmonary artery myocytes.
Ann NY Acad Sci 868: 438 – 441, 1999.
486. Paulais M, Cragoe EJ Jr, Turner RJ. Ion transport mechanisms
in rat parotid intralobular striated ducts. Am J Physiol Cell Physiol
266: C1594 –C1602, 1994.
487. Paulais M, Lachheb S, Teulon J. A Na⫹- and Cl⫺-activated K⫹
channel in the thick ascending limb of mouse kidney. J Gen Physiol
127: 205–215, 2006.
488. Paulais M, Turner RJ. ␤-Adrenergic upregulation of the Na⫹-K⫹2Cl⫺ cotransporter in parotid acinar cells. J Clin Invest 89: 1142–
1147, 1992.
489. Peers C, Kemp PJ. Ion channel regulation by chronic hypoxia in
models of acute oxygen sensing. Cell Calcium 36: 341–348, 2004.
490. Pena-Munzenmayer G, Catalan M, Cornejo I, Figueroa CD,
Melvin JE, Niemeyer MI, Cid LP, Sepulveda FV. Basolateral
localization of native ClC-2 chloride channels in absorptive intestinal epithelial cells and basolateral sorting encoded by a CBS-2
domain di-leucine motif. J Cell Sci 118: 4243– 4252, 2005.
491. Peretz A, Schottelndreier H, Aharon-Shamgar LB, Attali B.
Modulation of homomeric and heteromeric KCNQ1 channels by
external acidification. J Physiol 545: 751–766, 2002.
492. Petersen OH. Calcium-activated potassium channels and fluid
secretion by exocrine glands. Am J Physiol Gastrointest Liver
Physiol 251: G1–G13, 1986.
493. Petersen OH. Ca2⫹ signalling and Ca2⫹-activated ion channels in
exocrine acinar cells. Cell Calcium 38: 171–200, 2005.
494. Petersen OH, Findlay I. Electrophysiology of the pancreas.
Physiol Rev 67: 1054 –1116, 1987.
1177
1178
515.
516.
517.
518.
520.
521.
522.
523.
524.
525.
526.
527.
528.
529.
530.
531.
532.
533.
534.
cells. Am J Physiol Gastrointest Liver Physiol 259: G850 –G858,
1990.
Remy C, Kirchhoff P, Hafner P, Busque S, Mueller M, Geibel
J, Wagner C. Stimulatory pathways of the calcium-sensing receptor on acid secretion in freshly isolated human gastric glands. Cell
Physiol Biochem 19: 33– 42, 2007.
Renigunta V, Yuan H, Zuzarte M, Rinne S, Koch A, Wischmeyer E, Schlichthorl G, Gao Y, Karschin A, Jacob R, Schwappach B, Daut J, Preisig-Muller R. The retention factor p11 confers an endoplasmic reticulum-localization signal to the potassium
channel TASK-1. Traffic 7: 168 –181, 2006.
Reubi JC, Waser B, Gugger M, Friess H, Kleeff J, Kayed H,
Buchler MW, Laissue JA. Distribution of CCK1 and CCK2 receptors in normal and diseased human pancreatic tissue. Gastroenterology 125: 98 –106, 2003.
Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N,
Lazdunski M. Cloning and expression of a novel pH-sensitive two
pore domain K⫹ channel from human kidney. J Biol Chem 273:
30863–30869, 1998.
Rhodes KJ, Carroll KI, Sung MA, Doliveira LC, Monaghan
MM, Burke SL, Strassle BW, Buchwalder L, Menegola M, Cao
J, An WF, Trimmer JS. KChIPs and Kv4 alpha subunits as integral
components of A-type potassium channels in mammalian brain.
J Neurosci 24: 7903–7915, 2004.
Rijke RP, Plaisier HM, Langendoen NJ. Epithelial cell kinetics
in the descending colon of the rat. Virchows Arch B Cell Pathol Incl
Mol Pathol 30: 85–94, 1979.
Robertson MA, Foskett JK. Na⫹ transport pathways in secretory
acinar cells: membrane cross talk mediated by [Cl⫺]i. Am J Physiol
Cell Physiol 267: C146 –C156, 1994.
Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young
JB, Geibel JP, Lerner DJ, Abbott GW. The KCNE2 potassium
channel ancillary subunit is essential for gastric acid secretion.
J Biol Chem 281: 23740 –23747, 2006.
Romanenko V, Nakamoto T, Srivastava A, Melvin JE, Begenisich T. Molecular identification and physiological roles of parotid acinar cell maxi-K channels. J Biol Chem 281: 27964 –27972,
2006.
Romanenko VG, Nakamoto T, Srivastava A, Begenisich T,
Melvin JE. Regulation of membrane potential and fluid secretion
by Ca2⫹-activated K⫹ channels in mouse submandibular glands.
J Physiol 581: 801– 817, 2007.
Romero MF, Fulton CM, Boron WF. The SLC4 family of HCO⫺
3
transporters. Pflügers Arch 447: 495–509, 2004.
Romey G, Attali B, Chouabe C, Abitbol I, Guillemare E, Barhanin J, Lazdunski M. Molecular mechanism and functional significance of the minK control of the KvLQT channel activity. J Biol
Chem 272: 16713–16716, 1997.
Rosati B, Marchetti P, Crociani O, Lecchi M, Lupi R, Arcangeli A, Olivotto M, Wanke E. Glucose- and arginine-induced
insulin secretion by human pancreatic beta-cells: the role of HERG
K(⫹) channels in firing and release. FASEB J 14: 2601–2610, 2000.
Roussa E. H⫹ and HCO⫺
3 transporters in human salivary ducts. An
immunohistochemical study. Histochem J 33: 337–344, 2001.
Roussa E, Alper SL, Thevenod F. Immunolocalization of anion
exchanger AE2, Na⫹/H⫹ exchangers NHE1 and NHE4, vacuolar
type H⫹-ATPase in rat pancreas. J Histochem Cytochem 49: 463–
474, 2001.
Roussa E, Romero MF, Schmitt BM, Boron WF, Alper SL,
Thevenod F. Immunolocalization of anion exchanger AE2 and
Na⫹-HCO⫺
3 cotransporter in rat parotid and submandibular glands.
Am J Physiol Gastrointest Liver Physiol 277: G1288 –G1296, 1999.
Sachs G, Chang HH, Rabon E, Schackman R, Lewin M, Saccomani G. A nonelectrogenic H⫹ pump in plasma membranes of hog
stomach. J Biol Chem 251: 7690 –7698, 1976.
Sakai H, Okada Y, Morii M, Takeguchi N. Anion and cation
channels in the basolateral membrane of rabbit parietal cells.
Pflügers Arch 414: 185–192, 1989.
Sakurai-Yamashita Y, Yamashita K, Kanematsu T, Taniyama
K. Localization of the 5-HT(4) receptor in the human and the
guinea pig colon. Eur J Pharmacol 383: 281–285, 1999.
Salinas M, Reyes R, Lesage F, Fosset M, Heurteaux C, Romey
G, Lazdunski M. Cloning of a new mouse two-P domain channel
Physiol Rev • VOL
535.
536.
537.
538.
539.
540.
541.
542.
543.
544.
545.
546.
547.
548.
549.
550.
551.
552.
553.
554.
555.
subunit and a human homologue with a unique pore structure.
J Biol Chem 274: 11751–11760, 1999.
Sand P, Anger A, Rydqvist B. Hypotonic stress activates an
intermediate conductance K⫹ channel in human colonic crypt cells.
Acta Physiol Scand 182: 361–368, 2004.
Sandle G, Perry M, Mathialahan T, Linley J, Robinson P,
Hunter M, Maclennan K. Altered cryptal expression of luminal
potassium (BK) channels in ulcerative colitis. J Pathol 212: 66 –73,
2007.
Sandle GI, Butterfield I. Potassium secretion in rat distal colon
during dietary potassium loading: role of pH regulated apical potassium channels. Gut 44: 40 – 46, 1999.
Sandle GI, McNicholas CM, Lomax RB. Potassium channels in
colonic crypts. Lancet 343: 23–25, 1994.
Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS,
Atkinson DL, Keating MT. Coassembly of KvLQT1 and minK
(IsK) proteins to form cardiac IKs potassium channel. Nature 384:
80 – 83, 1996.
Sano Y, Mochizuki S, Miyake A, Kitada C, Inamura K, Yokoi
H, Nozawa K, Matsushime H, Furuichi K. Molecular cloning and
characterization of Kv6.3, a novel modulatory subunit for voltagegated K(⫹) channel Kv21. FEBS Lett 512: 230 –234, 2002.
Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H,
Sausbier U, Sailer CA, Feil R, Hofmann F, Korth M, Shipston
MJ, Knaus HG, Wolfer DP, Pedroarena CM, Storm JF, Ruth P.
Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2⫹activated K⫹ channel deficiency. Proc Natl Acad Sci USA 101:
9474 –9478, 2004.
Sausbier M, Matos JE, Sausbier U, Beranek G, Arntz C, Neuhuber W, Ruth P, Leipziger J. Distal colonic K⫹ secretion occurs
via BK channels. J Am Soc Nephrol 17: 1275–1282, 2006.
Schirgi-Degen A, Beubler E. Involvement of K⫹ channel modulation in the proabsorptive effect of nitric oxide in the rat jejunum
in vivo. Eur J Pharmacol 316: 257–262, 1996.
Schmalz F, Kinsella J, Koh SD, Vogalis F, Schneider A, Flynn
ER, Kenyon JL, Horowitz B. Molecular identification of a component of delayed rectifier current in gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol 274: G901–G911,
1998.
Schmid A, Schulz I. Characterization of single potassium channels in mouse pancreatic acinar cells. J Physiol 484: 661– 676, 1995.
Schmitz H, Fromm M, Bode H, Scholz P, Riecken EO, Schulzke JD. Tumor necrosis factor-alpha induces Cl⫺ and K⫹ secretion
in human distal colon driven by prostaglandin E2. Am J Physiol
Gastrointest Liver Physiol 271: G669 –G674, 1996.
Schneyer LH. Parasympathetic control of Na-K transport in perfused submaxillary duct of the rat. Am J Physiol Renal Fluid
Electrolyte Physiol 233: F22–F28, 1977.
Schneyer LH, Young JA, Schneyer CA. Salivary secretion of
electrolytes. Physiol Rev 52: 720 –777, 1972.
Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ. A constitutively open potassium channel
formed by KCNQ1 and KCNE3. Nature 403: 196 –199, 2000.
Schubert ML. Gastric secretion. Curr Opin Gastroenterol 21:
636 – 643, 2005.
Schulte U, Hahn H, Konrad M, Jeck N, Derst C, Wild K,
Weidemann S, Ruppersberg JP, Fakler B, Ludwig J. pH gating
of ROMK [K(ir)1.1] channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome. Proc Natl Acad Sci USA 96:
15298 –15303, 1999.
Schultheiss G, Ribeiro R, Schafer KH, Diener M. Activation of
apical K⫹ conductances by muscarinic receptor stimulation in rat
distal colon: fast and slow components. J Membr Biol 195: 183–196,
2003.
Schultheiss G, Siefjediers A, Diener M. Muscarinic receptor
stimulation activates a Ca(2⫹)-dependent Cl(⫺) conductance in
rat distal colon. J Membr Biol 204: 117–127, 2005.
Schultheiß G, Diener M. Regulation of apical and basolateral K⫹
conductance in the rat colon. Br J Pharmacol 122: 87–94, 1997.
Schultz SG. Homocellular regulatory mechanisms in sodiumtransporting epithelia: avoidance of extinction by “flush-through”.
Am J Physiol Renal Fluid Electrolyte Physiol 241: F579 –F590,
1981.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
519.
DIRK HEITZMANN AND RICHARD WARTH
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
Physiol Rev • VOL
578.
579.
580.
581.
582.
583.
584.
585.
586.
587.
588.
589.
590.
591.
592.
593.
594.
595.
596.
predominant apical membrane Cl⫺/HCO⫺
3 exchanger in the upper
villous epithelium of the murine duodenum. Am J Physiol Gastrointest Liver Physiol 292: G1079 –G1088, 2007.
Singer-Lahat D, Sheinin A, Chikvashvili D, Tsuk S, Greitzer
D, Friedrich R, Feinshreiber L, Ashery U, Benveniste M, Levitan ES, Lotan I. K⫹ channel facilitation of exocytosis by dynamic
interaction with syntaxin. J Neurosci 27: 1651–1658, 2007.
Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis
R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV, McHarg
ML, Gagnon D, Rosales TO, Peiffer A, Anderson VE, Leppert
M. A novel potassium channel gene, KCNQ2, is mutated in an
inherited epilepsy of newborns. Nature Genet 18: 25–29, 1998.
Slawik M, Zdebik A, Hug MJ, Kerstan D, Leipziger J, Greger
R. Whole-cell conductive properties of rat pancreatic acini.
Pflügers Arch 432: 112–120, 1996.
Smart SL, Lopantsev V, Zhang CL, Robbins CA, Wang H, Chiu
SY, Schwartzkroin PA, Messing A, Tempel BL. Deletion of the
K(V)1.1 potassium channel causes epilepsy in mice. Neuron 20:
809 – 819, 1998.
Smith JJ, Welsh MJ. cAMP stimulates bicarbonate secretion
across normal, but not cystic fibrosis airway epithelia. J Clin Invest
89: 1148 –1153, 1992.
Smith PL, McCabe RD. Potassium secretion by rabbit descending
colon: effects of adrenergic stimuli. Am J Physiol Gastrointest
Liver Physiol 250: G432–G439, 1986.
Sorensen CE, Amstrup J, Rasmussen HN, Ankorina-Stark I,
Novak I. Rat pancreas secretes particulate ecto-nucleotidase
CD39. J Physiol 551: 881– 892, 2003.
Sorensen CE, Novak I. Visualization of ATP release in pancreatic
acini in response to cholinergic stimulus. Use of fluorescent probes
and confocal microscopy. J Biol Chem 276: 32925–32932, 2001.
Spitzner M, Ousingsawat J, Scheidt K, Kunzelmann K, Schreiber R. Voltage-gated K⫹ channels support proliferation of colonic
carcinoma cells. FASEB J 21: 35– 44, 2007.
Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover
A, Schild L, Rotin D. Regulation of stability and function of the
epithelial Na⫹ channel (ENaC) by ubiquitination. EMBO J 16:
6325– 6336, 1997.
Steward MC, Ishiguro H, Case RM. Mechanisms of bicarbonate
secretion in the pancreatic duct. Annu Rev Physiol 67: 377– 409,
2005.
Strabel D, Diener M. The effect of neuropeptide Y on sodium,
chloride and potassium transport across the rat distal colon. Br J
Pharmacol 115: 1071–1079, 1995.
Streb H, Irvine RF, Berridge MJ, Schulz I. Release of Ca2⫹ from
a nonmitochondrial intracellular store in pancreatic acinar cells by
inositol-1,4,5-trisphosphate. Nature 306: 67– 69, 1983.
Stuhmer W, Alves F, Hartung F, Zientkowska M, Pardo LA.
Potassium channels as tumour markers. FEBS Lett 580: 2850 –2852,
2006.
Stummann TC, Poulsen JH, Hay-Schmidt A, Grunnet M, Klaerke DA, Rasmussen HB, Olesen SP, Jorgensen NK. Pharmacological investigation of the role of ion channels in salivary secretion. Pflügers Arch 446: 78 – 87, 2003.
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D,
Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP,
Walker JR, Hogenesch JB. A gene atlas of the mouse and human
protein-encoding transcriptomes. Proc Natl Acad Sci USA 101:
6062– 6067, 2004.
Su K, Kyaw H, Fan P, Zeng Z, Shell BK, Carter KC, Li Y.
Isolation, characterization, mapping of two human potassium channels. Biochem Biophys Res Commun 241: 675– 681, 1997.
Sugamoto S, Kawauch S, Furukawa O, Mimaki TH, Takeuchi
K. Role of endogenous nitric oxide and prostaglandin in duodenal
bicarbonate response induced by mucosal acidification in rats. Dig
Dis Sci 46: 1208 –1216, 2001.
Sugimoto T, Tanabe Y, Shigemoto R, Iwai M, Takumi T, Ohkubo H, Nakanishi S. Immunohistochemical study of a rat membrane protein which induces a selective potassium permeation: its
localization in the apical membrane portion of epithelial cells. J
Membr Biol 113: 39 – 47, 1990.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
556. Schultz SG, Dubinsky WP. Sodium absorption, volume control
and potassium channels: in tribute to a great biologist. J Membr
Biol 184: 255–261, 2001.
557. Schumacher MA, Rivard AF, Bachinger HP, Adelman JP.
Structure of the gating domain of a Ca2⫹-activated K⫹ channel
complexed with Ca2⫹/calmodulin. Nature 410: 1120 –1124, 2001.
558. Schwab A, Wojnowski L, Gabriel K, Oberleithner H. Oscillating activity of a Ca(2⫹)-sensitive K⫹ channel. A prerequisite for
migration of transformed Madin-Darby canine kidney focus cells.
J Clin Invest 93: 1631–1636, 1994.
559. Schweinfest CW, Spyropoulos DD, Henderson KW, Kim JH,
Chapman JM, Barone S, Worrell RT, Wang Z, Soleimani M.
slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, distinct up-regulation of ion transporters in the colon. J Biol Chem 281: 37962–37971, 2006.
560. Seidler U, Blumenstein I, Kretz A, Viellard-Baron D, Rossmann H, Colledge WH, Evans M, Ratcliff R, Gregor M. A
functional CFTR protein is required for mouse intestinal cAMP-,
cGMP- and Ca2⫹-dependent. J Physiol 505: 411– 423, 1997.
561. Sellin JH, De Soignie R. Regulation of Na-Cl absorption in rabbit
proximal colon in vitro. Am J Physiol Gastrointest Liver Physiol
252: G45–G51, 1987.
562. Sellin JH, Desoignie R. Differing mechanisms of stimulation of
Na⫹ absorption in rabbit proximal colon. Am J Physiol Gastrointest Liver Physiol 272: G435–G445, 1997.
563. Sellin JH, Dubinsky WP. Apical nonspecific cation conductances
in rabbit cecum. Am J Physiol Gastrointest Liver Physiol 266:
G475–G484, 1994.
564. Sellin JH, Hall A, Cragoe EJJ, Dubinsky WP. Characterization
of an apical sodium conductance in rabbit cecum. Am J Physiol
Gastrointest Liver Physiol 264: G13–G21, 1993.
565. Sellin JH, Oyarzabal H, Cragoe EJ. Electrogenic sodium absorption in rabbit cecum in vitro. J Clin Invest 81: 1275–1283, 1988.
566. Sepulveda FV, Fargon F, McNaughton PA. K⫹ and Cl⫺ currents
in enterocytes isolated from guinea-pig small intestinal villi.
J Physiol 434: 351–367, 1991.
567. Sesti F, Goldstein SA. Single-channel characteristics of wild-type
IKs channels and channels formed with two minK mutants that
cause long QT syndrome. J Gen Physiol 112: 651– 663, 1998.
568. Shamgar L, Ma L, Schmitt N, Haitin Y, Peretz A, Wiener R,
Hirsch J, Pongs O, Attali B. Calmodulin is essential for cardiac
IKS channel gating and assembly: impaired function in long-QT
mutations. Circ Res 98: 1055–1063, 2006.
569. Shao XD, Wu KC, Hao ZM, Hong L, Zhang J, Fan DM. The
potent inhibitory effects of cisapride, a specific blocker for human
ether-a-go-go-related gene (HERG) channel, on gastric cancer cells.
Cancer Biol Ther 4: 295–301, 2005.
570. Shcheynikov N, Kim KH, Kim KM, Dorwart MR, Ko SB, Goto
H, Naruse S, Thomas PJ, Muallem S. Dynamic control of cystic
fibrosis transmembrane conductance regulator Cl⫺/HCO⫺
3 selectivity by external Cl⫺. J Biol Chem 279: 21857–21865, 2004.
571. Sheppard DN, Valverde MA, Giraldez F, Sepulveda FV. Potassium currents of isolated Necturus enterocytes: a whole-cell patchclamp study. J Physiol 433: 663– 676, 1991.
572. Shin VY, Liu ES, Koo MW, Luo JC, So WH, Cho CH. Nicotine
suppresses gastric wound repair via the inhibition of polyamine
and K⫹ channel expression. Eur J Pharmacol 444: 115–121, 2002.
573. Shuck ME, Piser TM, Bock JH, Slightom JL, Lee KS, Bienkowski MJ. Cloning and characterization of two K⫹ inward rectifier (Kir) 1.1 potassium channel homologs from human kidney
(Kir12 and Kir13). J Biol Chem 272: 586 –593, 1997.
574. Shull GE, Lingrel JB. Molecular cloning of the rat stomach
(H⫹⫹K⫹)-ATPase. J Biol Chem 261: 16788 –16791, 1986.
575. Sidani SM, Kirchhoff P, Socrates T, Stelter L, Ferreira E,
Caputo C, Roberts KE, Bell RL, Egan ME, Geibel JP. Delta
F508 mutation results in impaired gastric acid secretion. J Biol
Chem 282: 6068 – 6074, 2006.
576. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K⫹ channel, ROMK. Nature Genet 14: 152–156, 1996.
577. Simpson JE, Schweinfest CW, Shull GE, Gawenis LR, Walker
NM, Boyle KT, Soleimani M, Clarke LL. PAT-1 (Slc26a6) is the
1179
1180
DIRK HEITZMANN AND RICHARD WARTH
Physiol Rev • VOL
618.
619.
620.
621.
622.
623.
624.
625.
626.
627.
628.
629.
630.
631.
632.
633.
634.
635.
636.
637.
638.
linemic hypoglycemia of infancy. Hum Mol Genet 5: 1809 –1812,
1996.
Thompson-Vest N, Shimizu Y, Hunne B, Furness JB. The distribution of intermediate-conductance, calcium-activated, potassium (IK) channels in epithelial cells. J Anat 208: 219 –229, 2006.
Thorens B, Sarkar HK, Kaback HR, Lodish HF. Cloning and
functional expression in bacteria of a novel glucose transporter
present in liver, intestine, kidney, beta-pancreatic islet cells. Cell
55: 281–290, 1988.
Thorn P, Petersen OH. A voltage-sensitive transient potassium
current in mouse pancreatic acinar cells. Pflügers Arch 428: 288 –
295, 1994.
Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J.
KCNE2 confers background current characteristics to the cardiac
KCNQ1 potassium channel. EMBO J 19: 6326 – 6330, 2000.
Toro B, Cox N, Wilson RJ, Garrido-Sanabria E, Stefani E,
Toro L, Zarei MM. KCNMB1 regulates surface expression of a
voltage and Ca2⫹-activated K⫹ channel via endocytic trafficking
signals. Neuroscience 142: 661– 669, 2006.
Traber PG. Epithelial cell growth and differentiation. V. Transcriptional regulation, development, neoplasia of the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 273: G979 –G981,
1997.
Traynor TR, O’Grady SM. Regulation of colonic ion transport by
GRP. I. GRP stimulates transepithelial K and Na secretion. Am J
Physiol Cell Physiol 270: C848 –C858, 1996.
Traynor TR, O’Grady SM. Regulation of colonic ion transport by
GRP. II. GRP modulates the epithelial response to PGE2. Am J
Physiol Cell Physiol 270: C859 –C865, 1996.
Tsubouchi S. Kinetic analysis of epithelial cell migration in the
mouse descending colon. Am J Anat 161: 239 –246, 1981.
Tsuchiya K, Wang W, Giebisch G, Welling PA. ATP is a coupling
modulator of parallel Na,K-ATPase-K-channel activity in the renal
proximal tubule. Proc Natl Acad Sci USA 89: 6418 – 6422, 1992.
Tuo B, Riederer B, Wang Z, Colledge WH, Soleimani M, Seidler U. Involvement of the anion exchanger SLC26A6 in prostaglandin E2- but not forskolin-stimulated duodenal. Gastroenterology 130: 349 –358, 2006.
Turnberg LA. Potassium transport in the human small bowel. Gut
12: 811– 818, 1971.
Turner RJ, Sugiya H. Understanding salivary fluid and protein
secretion. Oral Dis 8: 3–11, 2002.
Turvill JL, Farthing MJ. Water and electrolyte absorption and
secretion in the small intestine. Curr Opin Gastroenterol 15: 108 –
112, 1999.
Tyson J, Tranebjaerg L, Bellman S, Wren C, Taylor JF, Bathen J, Aslaksen B, Sorland SJ, Lund O, Malcolm S, Pembrey
M, Bhattacharya S, Bitner-Glindzicz M. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the
delayed rectifier potassium channel can cause Jervell and LangeNielsen syndrome. Hum Mol Genet 6: 2179 –2185, 1997.
Uebele VN, Lagrutta A, Wade T, Figueroa DJ, Liu Y, McKenna
E, Austin CP, Bennett PB, Swanson R. Cloning and functional
expression of two families of beta-subunits of the large conductance calcium-activated K⫹ channel. J Biol Chem 275: 23211–23218,
2000.
Ueda S, Loo DD, Sachs G. Regulation of K⫹ channels in the
basolateral membrane of Necturus oxyntic cells. J Membr Biol 97:
31– 41, 1987.
Unsold B, Kerst G, Brousos H, Hubner M, Schreiber R,
Nitschke R, Greger R, Bleich M. KCNE1 reverses the response of
the human K⫹ channel KCNQ1 to cytosolic pH changes and alters
its pharmacology and sensitivity to temperature. Pflügers Arch 441:
368 –378, 2000.
Urushidani T, Forte JG. Signal transduction and activation of
acid secretion in the parietal cell. J Membr Biol 159: 99 –111, 1997.
Vallon V, Grahammer F, Richter K, Bleich M, Lang F, Barhanin J, Völkl H, Warth R. Role of KCNE1-dependent K⫹ fluxes in
mouse proximal tubule. J Am Soc Nephrol 12: 2003–2011, 2001.
Vallon V, Grahammer F, Volkl H, Sandu CD, Richter K, Rexhepaj R, Gerlach U, Rong Q, Pfeifer K, Lang F. KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl
Acad Sci USA 102: 17864 –17869, 2005.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
597. Supplisson S, Loo DD, Sachs G. Diversity of K⫹ channels in the
basolateral membrane of resting Necturus oxyntic cells. J Membr
Biol 123: 209 –221, 1991.
598. Surprenant A. Control of the gastrointestinal tract by enteric
neurons. Annu Rev Physiol 56: 117–140, 1994.
599. Suzuki K, Petersen OH. Patch-clamp study of single-channel and
whole-cell K⫹ currents in guinea pig pancreatic acinar cells. Am J
Physiol Gastrointest Liver Physiol 255: G275–G285, 1988.
600. Suzuki M, Fujikura K, Inagaki N, Seino S, Takata K. Localization of the ATP-sensitive K⫹ channel subunit Kir6.2 in mouse
pancreas. Diabetes 46: 1440 –1444, 1997.
601. Swartz KJ. Towards a structural view of gating in potassium
channels. Nat Rev Neurosci 5: 905–916, 2004.
602. Takahata T, Hayashi M, Ishikawa T. SK4/IK1-like channels mediate tetraethylammonium insensitive, Ca2⫹-activated K⫹ currents
in bovine parotid acinar cells. Am J Physiol Cell Physiol 284:
C127–C144, 2002.
603. Takimoto K, Yang EK, Conforti L. Palmitoylation of KChIP
splicing variants is required for efficient cell surface expression of
Kv4.3 channels. J Biol Chem 277: 26904 –26911, 2002.
604. Takumi T, Ohkubo H, Nakanishi S. Cloning of a membrane
protein that induces a slow voltage-gated potassium current. Science 242: 1042–1045, 1988.
605. Talley EM, Bayliss DA. Modulation of TASK-1 (Kcnk3) and
TASK-3 (Kcnk9) potassium channels. Volatile anesthetics and neurotransmitter share a molecular site of action. J Biol Chem 277:
17733–17742, 2002.
606. Tamargo J, Caballero R, Gomez R, Valenzuela C, Delpon E.
Pharmacology of cardiac potassium channels. Cardiovasc Res 62:
9 –33, 2004.
607. Tamarina NA, Wang Y, Mariotto L, Kuznetsov A, Bond C,
Adelman J, Philipson LH. Small-conductance calcium-activated
K⫹ channels are expressed in pancreatic islets and regulate glucose
responses. Diabetes 52: 2000 –2006, 2003.
608. Tanaka H, Miake J, Notsu T, Sonyama K, Sasaki N, Iitsuka K,
Kato M, Taniguchi S, Igawa O, Yoshida A, Shigemasa C,
Hoshikawa Y, Kurata Y, Kuniyasu A, Nakayama H, Inagaki N,
Nanba E, Shiota G, Morisaki T, Ninomiya H, Kitakaze M,
Hisatome I. Proteasomal degradation of Kir6.2 channel protein
and its inhibition by a Na⫹ channel blocker aprindine. Biochem
Biophys Res Commun 331: 1001–1006, 2005.
609. Tandler B, Pinkstaff CA, Phillips CJ. Interlobular excretory
ducts of mammalian salivary glands: structural and histochemical
review. Anat Rec A Discov Mol Cell Evol Biol 288: 498 –526, 2006.
610. Tang NL, Chow CC, Ko GT, Tai MH, Kwok R, Yao XQ, Cockram CS. No mutation in the KCNE3 potassium channel gene in
Chinese thyrotoxic hypokalaemic periodic paralysis patients. Clin
Endocrinol 61: 109 –112, 2004.
611. Tatsuta H, Ueda S, Morishima S, Okada Y. Voltage- and timedependent K⫹ channel currents in the basolateral membrane of
villus enterocytes isolated from guinea pig small intestine. J Gen
Physiol 103: 429 – 446, 1994.
612. Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE,
Bond CT, Adelman JP, Nelson MT. Altered expression of smallconductance Ca2⫹-activated K⫹ (SK3) channels modulates arterial
tone and blood pressure. Circ Res 93: 124 –131, 2003.
613. Thaysen JH, Thorn NA, Schwartz IL. Excretion of sodium,
potassium, chloride and carbon dioxide in human parotid saliva.
Am J Physiol 178: 155–159, 1954.
614. Thevenod F. Ion channels in secretory granules of the pancreas
and their role in exocytosis and release of secretory proteins. Am J
Physiol Cell Physiol 283: C651–C672, 2002.
615. Thevenod F, Hildebrandt JP, Striessnig J, de Jonge HR,
Schulz I. Chloride and potassium conductances of mouse pancreatic zymogen granules are inversely regulated by a ⬃80-kDa mdr1a
gene product. J Biol Chem 271: 3300 –3305, 1996.
616. Thiery E, Gosset P, Damotte D, Delezoide AL, Saint-Sauveur
N, Vayssettes C, Creau N. Developmentally regulated expression
of the murine ortholog of the potassium channel KIR4.2 (KCNJ15).
Mech Dev 95: 313–316, 2000.
617. Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet
inward rectifier Kir6.2 also leads to familial persistent hyperinsu-
POTASSIUM CHANNELS IN GASTROINTESTINAL EPITHELIA
Physiol Rev • VOL
660. Warth R, Barhanin J. The multifaceted phenotype of the knockout mouse for the KCNE1 potassium channel gene. Am J Physiol
Regul Integr Comp Physiol 282: R639 –R648, 2002.
661. Warth R, Barriere H, Meneton P, Block M, Thomas J, Tauc M,
Heitzmann D, Romeo E, Verrey F, Mengual R, Guy N, Bendahhou S, Lesage F, Poujeol P, Barhanin J. Proximal renal tubular
acidosis in TASK2 K⫹ channel deficient mice reveals a mechanism
for stabilizing bicarbonate transport. Proc Natl Acad Sci USA 101:
8215– 8220, 2004.
662. Warth R, Bleich M. K⫹ channels and colonic function. Rev Physiol
Biochem Pharmacol 140: 1– 62, 2000.
663. Warth R, Garcia Alzamora M, Kim K, Zdebik A, Nitschke R,
Bleich M, Gerlach U, Barhanin J, Kim J. The role of KCNQ1/
KCNE1 K⫹ channels in intestine and pancreas: lessons from the
KCNE1 knockout mouse. Pflügers Arch 443: 822– 828, 2002.
664. Warth R, Greger R. The ion conductances of CFPAC-1 cells. Cell
Physiol Biochem 3: 2–16, 1993.
665. Warth R, Hamm K, Bleich M, Kunzelmann K, von Hahn T,
Schreiber R, Ullrich E, Mengel M, Trautmann N, Kindle P,
Schwab A, Greger R. Molecular and functional characterisation of
the small Ca2⫹-regulated K⫹ channel (rSK4) of colonic crypts.
Pflügers Arch 438: 437– 444, 1999.
666. Warth R, Riedemann N, Bleich M, Van Driessche W, Busch AE,
Greger R. The cAMP-regulated and 293B inhibited K⫹ conductance of rat colonic crypt base cells. Pflügers Arch 432: 81– 88,
1996.
667. Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D, Mock AF, Evidente VG, Fee DB, Muller U,
Durr A, Brice A, Papazian DM, Pulst SM. Mutations in voltagegated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 38: 447– 451,
2006.
668. Wei A, Solaro C, Lingle C, Salkoff L. Calcium sensitivity of
BK-type KCa channels determined by a separable domain. Neuron
13: 671– 681, 1994.
669. Weyand B, Warth R, Bleich M, Greger R. Hypertonic cell shrinkage reduces the K⫹ conductance in rat colonic crypt cells. Pflügers
Arch 436: 227–232, 1998.
670. Wilson KT, Vaandrager AB, De Vente J, Musch MW, de Jonge
HR, Chang EB. Production and localization of cGMP and PGE2 in
nitroprusside-stimulated rat colonic ion transport. Am J Physiol
Cell Physiol 270: C832–C840, 1996.
671. Wolosin JM, Forte JG. Stimulation of oxyntic cell triggers K⫹ and
Cl⫺ conductances in apical H⫹-K⫹-ATPase membrane. Am J
Physiol Cell Physiol 246: C537–C545, 1984.
672. Wonderlin WF, Strobl JS. Potassium channels, proliferation and
G1 progression. J Membr Biol 154: 91–107, 1996.
673. Wu CF, Ganetzky B, Haugland FN, Liu AX. Potassium currents
in Drosophila: different components affected by mutations of two
genes. Science 220: 1076 –1078, 1983.
674. Wu WK, Li GR, Wong HP, Hui MK, Tai EK, Lam EK, Shin VY,
Ye YN, Li P, Yang YH, Luo JC, Cho CH. Involvement of Kv1.1 and
Nav1.5. in proliferation of gastric epithelial cells. J Cell Physiol 207:
437– 444, 2006.
675. Wyatt CN, Mustard KJ, Pearson SA, Dallas ML, Atkinson L,
Kumar P, Peers C, Hardie DG, Evans AM. AMP-activated protein kinase mediates carotid body excitation by hypoxia. J Biol
Chem 282: 8092– 8098, 2007.
676. Xia XM, Fakler B, Rivard A, Wayman G, Johnson-Pais T, Keen
JE, Ishii T, Hirschberg B, Bond CT, Lutsenko S, Maylie J,
Adelman JP. Mechanism of calcium gating in small-conductance
calcium- activated potassium channels. Nature 395: 503–507, 1998.
677. Xu J, Barone S, Petrovic S, Wang Z, Seidler U, Riederer B,
Ramaswamy K, Dudeja PK, Shull GE, Soleimani M. Identification of an apical Cl⫺/HCO⫺
3 exchanger in gastric surface mucous
and duodenal villus cells. Am J Physiol Gastrointest Liver Physiol
285: G1225–G1234, 2003.
678. Xu J, Koni PA, Wang P, Li G, Kaczmarek L, Wu Y, Li Y, Flavell
RA, Desir GV. The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight. Hum Mol Genet 12:
551–559, 2003.
679. Xu JC, Lytle C, Zhu TT, Payne JA, Benz EJ, Forbush B.
Molecular cloning and functional expression of the bumetanide-
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
639. Vandenberg CA. Inward rectification of a potassium channel in
cardiac ventricular cells depends on internal magnesium ions. Proc
Natl Acad Sci USA 84: 2560 –2564, 1987.
640. Vandorpe DH, Shmukler BE, Jiang L, Lim B, Maylie J, Adelman JP, de Franceschi L, Cappellini MD, Brugnara C, Alper
SL. cDNA cloning and functional characterization of the mouse
Ca2⫹-gated K⫹ channel, mIK1. Roles in regulatory volume decrease
and erythroid differentiation. J Biol Chem 273: 21542–21553, 1998.
641. Varas R, Wyatt CN, Buckler KJ. Modulation of TASK-like background potassium channels in rat arterial chemoreceptor cells by
intracellular ATP and other nucleotides. J Physiol 583: 521–536,
2007.
642. Vaughn J, Wolford JK, Prochazka M, Permana PA. Genomic
structure and expression of human KCNJ9 (Kir3.3/GIRK3). Biochem Biophys Res Commun 274: 302–309, 2000.
643. Vega-Saenz de Miera EC. Modification of Kv2.1 K⫹ currents by
the silent Kv10 subunits. Brain Res 123: 91–103, 2004.
644. Von Hahn T, Thiele I, Zingaro L, Hamm K, Garcia Alzamora M,
Köttgen M, Bleich M, Warth R. Characterisation of the rat SK4/
IK1 K⫹ channel. Cell Physiol Biochem 11: 219 –230, 2001.
645. Walker NM, Flagella M, Gawenis LR, Shull GE, Clarke LL. An
alternate pathway of cAMP-stimulated Cl⫺ secretion across the
NKCC1-null murine duodenum. Gastroenterology 123: 531–541,
2002.
646. Walters JR. New advances in the molecular and cellular biology of
the small intestine. Curr Opin Gastroenterol 18: 161–167, 2002.
647. Wang BJ, Cui ZJ. How does cholecystokinin stimulate exocrine
pancreatic secretion? From birds, rodents, to humans. Am J
Physiol Regul Integr Comp Physiol 292: R666 –R678, 2007.
648. Wang J, Wang H, Han H, Zhang Y, Yang B, Nattel S, Wang Z.
Phospholipid metabolite 1-palmitoyl-lysophosphatidylcholine enhances human ether-a-go-go-related gene (HERG) K⫹ channel function. Circulation 104: 2645–2648, 2001.
649. Wang KS, Ma T, Filiz F, Verkman AS, Bastidas JA. Colon water
transport in transgenic mice lacking aquaporin-4 water channels.
Am J Physiol Gastrointest Liver Physiol 279: G463–G470, 2000.
650. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM,
VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T,
Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM,
Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
Nature Genet 12: 17–23, 1996.
651. Wang W, Cassola A, Giebisch G. Arachidonic acid inhibits the
secretory K⫹ channel of cortical collecting duct of rat kidney. Am J
Physiol Renal Fluid Electrolyte Physiol 262: F554 –F559, 1992.
652. Wang W, Lu M. Effect of arachidonic acid on activity of the apical
K⫹ channel in the thick ascending limb of the rat kidney. J Gen
Physiol 106: 727–743, 1995.
653. Wang Y, Soyombo AA, Shcheynikov N, Zeng W, Dorwart M,
Marino CR, Thomas PJ, Muallem S. Slc26a6 regulates CFTR
activity in vivo to determine pancreatic duct HCO⫺
3 secretion:
relevance to cystic fibrosis. EMBO J 25: 5049 –5057, 2006.
654. Wang YZ, Cooke HJ, Su HC, Fertel R. Histamine augments
colonic secretion in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol 258: G432–G439, 1990.
655. Wang Z, Petrovic S, Mann E, Soleimani M. Identification of an
apical Cl⫺/HCO⫺
3 exchanger in the small intestine. Am J Physiol
Gastrointest Liver Physiol 282: G573–G579, 2002.
656. Wang Z, Wang T, Petrovic S, Tuo B, Riederer B, Barone S,
Lorenz JN, Seidler U, Aronson PS, Soleimani M. Renal and
intestinal transport defects in Slc26a6-null mice. Am J Physiol Cell
Physiol 288: C957–C965, 2005.
657. Warhurst G, Barbezat GO, Higgs NB, Reyl-Desmars F, Lewin
MJ, Coy DHXRI, Grigor MR. Expression of somatostatin receptor genes and their role in inhibiting Cl⫺ secretion in HT-29cl. 19A
colonocytes. Am J Physiol Gastrointest Liver Physiol 269: G729 –
G736, 1995.
658. Warmke JW, Ganetzky B. A family of potassium channel genes
related to eag in Drosophila and mammals. Proc Natl Acad Sci USA
91: 3438 –3442, 1994.
659. Warth R. Potassium channels in epithelial transport. Pflügers Arch
446: 505–513, 2003.
1181
1182
680.
681.
682.
683.
684.
686.
687.
688.
689.
sensitive Na-K-Cl cotransporter. Proc Natl Acad Sci USA 91: 2201–
2205, 1994.
Xu X, Diaz J, Zhao H, Muallem S. Characterization, localization
and axial distribution of Ca2⫹ signalling receptors in the rat submandibular salivary gland ducts. J Physiol 491: 647– 662, 1996.
Yamazaki J, Okamura K, Ishibashi K, Kitamura K. Characterization of CLCA protein expressed in ductal cells of rat salivary
glands. Biochim Biophys Acta 1715: 132–144, 2005.
Yan L, Figueroa DJ, Austin CP, Liu Y, Bugianesi RM, Slaughter RS, Kaczorowski GJ, Kohler MG. Expression of voltagegated potassium channels in human and rhesus pancreatic islets.
Diabetes 53: 597– 607, 2004.
Yang B, Song Y, Zhao D, Verkman AS. Phenotype analysis of
aquaporin-8 null mice. Am J Physiol Cell Physiol 288: C1161–
C1170, 2005.
Yang WP, Levesque PC, Little WA, Conder ML, Shalaby FY,
Blanar MA. KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Proc Natl Acad Sci USA 94:
4017– 4021, 1997.
Yang Y, Sigworth FJ. Single-channel properties of IKs potassium
channels. J Gen Physiol 112: 665– 678, 1998.
Yao X, Forte JG. Cell biology of acid secretion by the parietal cell.
Annu Rev Physiol 65: 103–131, 2003.
Yasuo M, Fujimoto K, Tanabe T, Yaegashi H, Tsushima K,
Takasuna K, Koike T, Yamaya M, Nikaido T. Relationship between calcium-activated chloride channel 1 and MUC5AC in goblet
cell hyperplasia induced by interleukin-13 in human bronchial epithelial cells. Respiration 73: 347–359, 2006.
Yatani A, Mattera R, Codina J, Graf R, Okabe K, Padrell E,
Iyengar R, Brown AM, Birnbaumer L. The G protein-gated atrial
K⫹ channel is stimulated by three distinct Gi alpha-subunits. Nature 336: 680 – 682, 1988.
Yoshimoto Y, Fukuyama Y, Horio Y, Inanobe A, Gotoh M,
Kurachi Y. Somatostatin induces hyperpolarization in pancreatic
islet alpha cells by activating a G protein-gated K⫹ channel. FEBS
Lett 444: 265–269, 1999.
Physiol Rev • VOL
690. Yost CS. Update on tandem pore (2P) domain K⫹ channels. Curr
Drug Targets 4: 347–351, 2003.
691. Yuan A, Dourado M, Butler A, Walton N, Wei A, Salkoff L.
SLO-2, a K⫹ channel with an unusual Cl⫺ dependence. Nat Neurosci 3: 771–779, 2000.
692. Yuan A, Santi CM, Wei A, Wang ZW, Pollak K, Nonet M,
Kaczmarek L, Crowder CM, Salkoff L. The sodium-activated
potassium channel is encoded by a member of the Slo gene family.
Neuron 37: 765–773, 2003.
693. Zdebik A, Hug MJ, Greger R. Chloride channels in the luminal
membrane of rat pancreatic acini. Pflügers Arch 434: 188 –194,
1997.
694. Zdebik AA, Cuffe JE, Bertog M, Korbmacher C, Jentsch TJ.
Additional disruption of the ClC-2 Cl⫺ channel does not exacerbate
the cystic fibrosis phenotype of cystic fibrosis transmembrane
conductance regulator mouse models. J Biol Chem 279: 22276 –
22283, 2004.
695. Zeng W, Lee MG, Yan M, Diaz J, Benjamin I, Marino CR,
Kopito R, Freedman S, Cotton C, Muallem S, Thomas P.
Immuno and functional characterization of CFTR in submandibular
and pancreatic acinar and duct cells. Am J Physiol Cell Physiol
273: C442–C455, 1997.
696. Zhang RG, Westbrook ML, Westbrook EM, Scott DL, Otwinowski Z, Maulik PR, Reed RA, Shipley GG. The 2.4 A crystal
structure of cholera toxin B subunit pentamer: choleragenoid. J
Mol Biol 251: 550 –562, 1995.
697. Zhao H, Muallem S. Na⫹, K⫹, Cl⫺ transport in resting pancreatic
acinar cells. J Gen Physiol 106: 1225–1242, 1995.
698. Zhu XR, Wulf A, Schwarz M, Isbrandt D, Pongs O. Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K⫹ current. Receptors Channels 6: 387–
400, 1999.
699. Zhu Y, Golden CM, Ye J, Wang XY, Akbarali HI, Huizinga JD.
ERG K⫹ currents regulate pacemaker activity in ICC. Am J Physiol
Gastrointest Liver Physiol 285: G1249 –G1258, 2003.
88 • JULY 2008 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
685.
DIRK HEITZMANN AND RICHARD WARTH