Physiol Rev 85: 1205–1253, 2005;
doi:10.1152/physrev.00002.2005.
Molecular Physiology of Cardiac Repolarization
JEANNE M. NERBONNE AND ROBERT S. KASS
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis,
Missouri; and Department of Pharmacology, College of Physicians and Surgeons,
Columbia University, New York, New York
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I. Introduction
II. Myocardial Action Potentials and Voltage-Gated Inward Sodium and Calcium Currents
A. Voltage-gated Na⫹(Nav) currents
B. Voltage-gated Ca2⫹ (Cav) currents
III. Myocardial Action Potentials and Repolarizing Voltage-Gated Potassium Currents
A. Transient outward Kv currents
B. Delayed rectifier Kv currents
C. Regional differences in Kv current expression and properties
IV. Other Myocardial Potassium Currents Contributing to Repolarization
V. Molecular Components of Myocardial Nav and Cav Channels
A. Nav channel pore-forming ␣-subunits
B. Nav channel accessory subunits and other interacting proteins
C. Cav channel pore-forming ␣-subunits
D. Cav channel accessory subunits and other interacting proteins
VI. Molecular Components of Myocardial Kv Channels
A. Kv channel pore-forming ␣-subunits
B. Kv channel accessory subunits
C. Molecular correlates of cardiac transient outward Kv channels
D. Molecular correlates of cardiac delayed rectifier Kv channels
VII. Molecular Components of Other Cardiac Potassium Channels
A. Inwardly rectifying cardiac K⫹ (Kir) channel pore-forming ␣-subunits
B. Two-pore domain K⫹ (K2P) channel pore-forming ␣-subunits
VIII. Myocardial Potassium Channels and the Actin Cytoskeleton
IX. Summary and Conclusions
Nerbonne, Jeanne M., and Robert S. Kass. Molecular Physiology of Cardiac Repolarization. Physiol Rev 85:
1205–1253, 2005; doi:10.1152/physrev.00002.2005.—The heart is a rhythmic electromechanical pump, the functioning of
which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until
the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward
(Na⫹ and Ca2⫹) and outward (K⫹) current carrying ion channels. In different regions of the heart, action potential
waveforms are distinct, owing to differences in Na⫹, Ca2⫹, and K⫹ channel expression, and these differences contribute
to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel
functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the
generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms
that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the
Na⫹, Ca2⫹, and K⫹ currents that generate cardiac action potentials, and molecular cloning has revealed a large number
of pore forming (␣) and accessory (␤, ␦, and ␥) subunits thought to contribute to the formation of these channels.
Considerable progress has been made in defining the functional roles of the various channels and in identifying the
␣-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits
and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function
as components of macromolecular complexes, comprising the ␣-subunits, one or more accessory subunit, and a variety
of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the
actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as
well as between cardiac structure and electrical functioning. Important areas of future research will be the identification
of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms
involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.
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JEANNE M. NERBONNE AND ROBERT S. KASS
I. INTRODUCTION
FIG. 1. Electrical activity in the myocardium. Top: schematic of a human
heart with illustration of typical action
potential waveforms recorded in different regions. Bottom: schematic of a surface electrocardiogram; three sequential
beats are displayed.
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The normal mechanical (pump) functioning of the
mammalian heart depends on proper electrical functioning (56, 173), reflected in the sequential activation of cells
in specialized, “pacemaker” regions of the heart and the
propagation of activity through the ventricles (Fig. 1).
Myocardial electrical activity is attributed to the generation of action potentials in individual cardiac cells, and
the normal coordinated electrical functioning of the
whole heart is readily detected in surface electrocardiograms (Fig. 1). The propagation of activity and the coordination of the electromechanical functioning of the ventricles also depend on electrical coupling between cells,
mediated by gap junctions (251, 435). The generation of
myocardial action potentials reflects the sequential activation and inactivation of ion channels that conduct depolarizing, inward (Na⫹ and Ca2⫹), and repolarizing, outward (K⫹), currents (24, 375). The waveforms of action
potentials in different regions of the heart are distinct
(Fig. 1), owing to differences in the expression and/or the
properties of the underlying ion channels (24, 374). These
differences contribute to the normal unidirectional propagation of excitation through the myocardium and to the
generation of normal cardiac rhythms (23, 24, 259, 374,
375). Changes in the properties or the functional expression of myocardial ion channels, resulting from inherited
mutations in the genes encoding these channels (23, 36,
51, 102, 204, 243, 253) or from myocardial disease (34, 49,
67, 184, 365, 496, 501–503, 510), can lead to changes in
action potential waveforms, synchronization, and/or
propagation, thereby predisposing the heart to potentially
life-threatening arrhythmias (13, 14, 16, 24, 127, 259, 436).
There is, therefore, considerable interest in delineating
the molecular, cellular, and systemic mechanisms contributing to the generation and maintenance of normal
cardiac rhythms, as well as in understanding how these
mechanisms are altered in the diseased myocardium.
Myocardial electrical activity is initiated in the pacemaker cells in the sinoatrial (SA) node and then propagated through the atria to the atrioventricular (AV) node
(Fig. 1). Following a brief pause in the AV node, excitation
spreads in the conducting Purkinje fibers to the apex of
the heart and into the working, ventricular myocardium
(Fig. 1). In cells in each of these specialized regions,
excitation results in action potential generation, followed
by relaxation and a period of refractoriness until the next
impulse is generated and propagated. The observed heterogeneity in action potential waveforms in different cell
types (Fig. 1) reflects differences in ion channel expression levels, and modeling studies suggest that small
changes in the time- and/or voltage-dependent properties
of cardiac sarcolemmal ion channels can have rather
profound effects on action potential durations, as well as
impact refractoriness and rhythmicity (105, 127, 311, 312).
In ventricular and atrial myocytes and in Purkinje fibers
(Fig. 1), the upstroke of the action potential (phase 0) is
rapid, resulting from the activation of voltage-gated Na⫹
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
play a role in automaticity (57, 394). As with cardiac Nav
channels, however, the properties of the L- and T-type
cardiac Cav channels characterized electrophysiologically in different cell types and in different species (Table
1) are quite similar, suggesting that the molecular correlates of the underlying L- and T-type (Cav) channels are
also similar throughout the myocardium (see sect. VC).
The driving force for K⫹ efflux is high during the
plateau phase of the action potential in ventricular and
atrial myocardium and, as the Cav channels inactivate, the
outward K⫹ currents predominate, resulting in (phase 3)
repolarization, bringing the membrane voltage back to the
resting potential (Fig. 2). In contrast to Nav and Cav
currents, however, there are multiple types of voltagegated K⫹ (Kv) currents, as well as non-voltage-gated,
inwardly rectifying K⫹ (Kir) currents (Table 1), that contribute to myocardial action potential repolarization. The
greatest functional diversity is among Kv channels (Table
1). At least two types of transient outward currents, Ito,f
and Ito,s, and several components of delayed rectification,
including IKr [IK(rapid)], IKs [IK(slow)], and IKur [IK(ultrarapid)],
for example, have been distinguished (Table 1). The timeand voltage-dependent properties of the various Kv currents identified in myocytes isolated from different species and/or from different regions of the heart in the same
species, however, are remarkably similar, suggesting that
the same (or very similar) molecular entities contribute to
the generation of each of the various types of Kv channels
(Table 1) in different cells/species. The relative Kv channel expression levels vary in cardiac cells in different
regions (i.e., atria, ventricles) of the heart, and this hetero-
FIG. 2. Action potential waveforms and
underlying ionic currents in adult human and
ventricular (left) and atrial (right) myocytes.
The time- and voltage-dependent properties
of the voltage-gated inward Na⫹ (Nav) and
Ca2⫹ (Cav) currents expressed in human
atrial and ventricular myocytes are similar.
In contrast, there are multiple types of K⫹
currents, particularly Kv currents, contributing to atrial and ventricular action potential
repolarization. The properties of the various
Kv currents are distinct, and in contrast to
the inward currents, there are multiple Kv
currents expressed in individual myocytes
throughout the myocardium.
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(Nav) channels (172) (Fig. 2). In pacemaker cells in the SA
node (SAN) and AV node (AVN), however, phase 0 is
markedly slower than in atria/ventricles (Fig. 1), suggesting that Nav channels do not play a prominent role in
depolarization. Nevertheless, Nav currents have been described in subsets of rabbit and guinea pig AVN cells (361,
579), as well as in rabbit SAN cells (173). The properties
of the Nav currents expressed in cardiac cells from different species, as well as in different cell types in the
same species (Table 1), are similar, an observation that
might be interpreted as suggesting that the molecular
correlates of the underlying channels are the same (see
sect. VA).
Phase 0 of the action potential in Purkinje fibers and
in atrial and ventricular myocytes is followed by a transient repolarization (phase 1), reflecting Nav channel inactivation and the activation of the fast transient voltagegated outward K⫹ current (Ito,f) (Fig. 2). This transient
repolarization or “notch,” which can be quite prominent in
Purkinje and ventricular cells (Fig. 1), influences the
height and duration of the action potential plateau (phase
2). Membrane depolarization also activates voltage-gated
Ca2⫹ (Cav) currents, and the influx of Ca2⫹ through Ltype Cav channels during the phase 2 plateau is the main
trigger for excitation-contraction coupling in the working
myocardium (57, 154). In SAN and AVN cells, activation of
(L-type) Cav channels also contributes to action potential
generation, particularly in cells expressing low levels of
functional Nav channels (57). In some cardiac cells/species, another class of Cav channels, the T-type Cav channels (Table 1), has been distinguished and suggested to
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TABLE
JEANNE M. NERBONNE AND ROBERT S. KASS
1.
Cardiac currents contributing to action potential repolarization
Channel Type
Current Name
Activation
Inactivation
Recovery
Species
Tissue
Nav
INa
Very fast
Fast
Fast
Cat, dog, ferret, human, mouse, rat
A, P, V, SAN†, AVN‡
ICa(L)
ICa(T)
Fast
Fast
Moderate*
Fast
Fast
Slow
Cat, dog, ferret, human, mouse, rat
Cat, dog, guinea pig, rat
A, P, V, SAN, AVN
A, P, SAN, AVN
Ito, t
Ito,s
Fast
Fast
Fast
Moderate
Fast
Slow
Cat, dog, ferret, human, mouse, rat
Ferret, human, mouse, rat, rabbit
A, P, V
V (A, AVN, SAN)‡
IKr
IKs
Moderate
Very slow
Fast
No
Slow
Cat, dog, guinea pig, human, mouse, rabbit, rat
Dog, guinea pig, human, rabbit
A, P, V, SAN, AVN
A, P, V, SAN
IKur
IK,slow1
IKp
Very fast
Very fast
Fast
Very slow
Slow
No
Slow
Slow
Dog, human
Mouse
Guinea pig
A
A, V
V
IK,slow2
Fast
Very slow
Slow
Mouse
A, V
IK
Iss
Slow
Slow
Slow
No
Slow
Rat
Dog, human, mouse, rabbit, rat
V
A, V, AVN
Cat, dog, ferret, human, mouse, rabbit, rat
A, P, V
Cav
Kv (Ito)
Kv (Ik)
IKl
A, atrial; P, Purkinje; V, ventricular; SAN, sinoatrial node; AVN, atrioventricular node. The dashed boxes are placed around currents given
different names in different species that likely are encoded by the same channel’s subunit genes. * Inactivation is Ca2⫹ and voltage dependent.
† Observed in some, but not all, AVN and SAN cells. ‡ Only in nonventricular cells in rabbit.
geneity contributes importantly to the observed regional
differences in action potential waveforms (24, 127, 373,
374). Changes in the properties or the functional expression of Kv channels, as occurs in a variety of myocardial
diseases (34, 49, 67, 365, 496, 503, 510), can, therefore,
have dramatic effects on action potential waveforms,
propagation, and rhythmicity.
A large number of pore-forming (␣) subunits, encoding Nav, Cav, Kv, and Kir channels, and a variety of
channel accessory (␤, ␦, and ␥) subunits have been identified (Tables 2– 6), and considerable progress has been
made in defining the expression patterns of these subunits
in the heart and the roles of the individual subunits in the
generation of functional cardiac (Nav, Cav, Kv, and Kir)
channels (Tables 2– 6). These studies have demonstrated
that distinct molecular entities underlie the various cardiac ion channels/currents that have been distinguished
electrophysiologically and shown to contribute to myocardial action potential repolarization. It also has now
been shown that mutations in the genes encoding the
subunits involved in the generation of functional cardiac
Nav, Kv, Cav, and Kir channels underlie several inherited
cardiac arrhythmias (23, 36, 51, 102, 204, 253, 479, 481).
Although inherited rhythm disorders are rare, these mutations belong to an ever-increasing number of “channelopathies,” i.e., diseases linked to genes encoding ion
channels (35, 123, 204, 220, 234, 243, 267, 309, 359, 403,
442, 459). Based on the rapid progression of this field
(249) and the growing molecular complexity of ion channels, it seems certain that the number of genes encoding
ion channels or ion channel regulatory molecules linked
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to inherited and acquired disorders of the cardiovascular
(and other) system will continue to increase, perhaps
dramatically, in the future. The densities and the functional properties of myocardial Nav, Cav, Kv, and Kir
currents also change in a number of acquired myocardial
disease states (34, 49, 67, 365, 496, 503, 510), and these
changes can lead to the generation of potentially lifethreatening cardiac arrhythmias. At present, therefore,
there is considerable interest in understanding the detailed molecular mechanisms controlling the properties
and the functional cell surface expression of the various
ion channels controlling myocardial action potential repolarization, as well as the impact of genetic and epigenetic factors, including cardiac and noncardiac disease,
on the functioning of these channels.
II. MYOCARDIAL ACTION POTENTIALS AND
VOLTAGE-GATED INWARD SODIUM AND
CALCIUM CURRENTS
A. Voltage-Gated Naⴙ(Nav) Currents
Voltage-gated cardiac Na⫹ (Nav) channels open rapidly on membrane depolarization (Fig. 2) and underlie the
rapidly rising phases of the action potentials recorded in
mammalian ventricular and atrial myocytes and in cardiac
Purkinje fibers (93, 375). Although not evident in all cells,
Nav channels with similar properties are also expressed
in subsets of mammalian SAN and AVN cells, and differences in functional Nav channel expression likely contrib-
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Kir
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
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membrane depolarizations. Although the persistent Nav
channel (“window”) current is small, this current could, in
principle, contribute to determining action potential durations (438, 439). In this context, it is interesting to note
that it has been reported that the expression level of the
persistent Nav current component varies in different regions of the ventricles (438), differences that could contribute to the observed regional heterogeneities in ventricular action potential durations (24, 374). The concept
that small inward (Na⫹) currents could profoundly affect
action potential waveforms and excitability in the myocardium was suggested more than 50 years ago in the
pioneering studies of Silvio Weidman (542). The impact of
alterations in the “persistent” Nav channel window current on cardiac rhythms has now been definitively demonstrated with the identification of mutations in the gene,
SCN5A, encoding the TTX-insensitive cardiac Nav channels (see sect. VA) in patients with an inherited form of
long QT syndrome, LQT3 (52). A number of SCN5A mutations in different affected individuals/families have been
identified (Fig. 3A) and linked to Brugada syndrome and
to conduction defects, in addition to LQT3 (23, 36, 51, 60,
93, 102, 105, 204, 253, 422, 519, 525, 540). Interestingly,
mutations in noncardiac Nav channel genes have also
been linked to familial paroxysmal dysfunction in the
skeletal and nervous systems (123, 204, 220, 359).
B. Voltage-Gated Ca2ⴙ (Cav) Currents
In contrast to skeletal muscle, it has long been recognized that Ca2⫹ entry from the extracellular space is
required for excitation-contraction coupling in the mammalian myocardium (56, 57, 154, 173). The pathway for
plasmalemmal Ca2⫹ entry was first revealed in voltageclamp recordings from multicellular (frog) atrial preparations and was termed the “slow inward” current pathway
(416 – 418, 429). Subsequent studies revealed that this
“slow inward” current is carried by Ca2⫹ through a membrane conductance distinct from the voltage-dependent
(Nav channel) pathway for Na⫹ movement (45, 332, 386,
416 – 418, 429). Further studies detailed the time- and
voltage-dependent properties of voltage-gated cardiac
Ca2⫹ (Cav) currents, first, in multicellular preparations
and later, in isolated single cardiac cells (45, 57, 172,
416 – 418).
Although the presence of two functionally distinct
types of Cav currents in single (starfish egg) cells was first
reported in 1975 (201), it was not until the late 1980s that
the import and the generality of these observations became clear. Two types of Cav currents/channels, for example, were clearly distinguished in (chick and rat) sensory neurons, based primarily on differences in the
thresholds for channel activation (85, 86). These channels
were termed high voltage-activated (HVA) and low volt-
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ute to action potential heterogeneity in pacemaker cells
(262, 361, 579, 582). Although the properties of the Nav
channels expressed in different cardiac cells are similar,
the biophysical and pharmacological properties of these
channels are distinct from Nav channels expressed in
other excitable cells, such as neurons and skeletal muscle
(93, 573). Cardiac Nav channels, for example, are remarkably insensitive to the Nav channel toxin tetrodotoxin
(TTX), which binds with high (nM) affinity to neuronal
and skeletal muscle Nav channels and blocks Na⫹ influx
(93, 573). This observation was probably the first indication that the molecular identities of the Nav channels in
cardiac myocytes, neurons, and skeletal muscle were distinct, and as detailed in section VA, this has now been
demonstrated.
On membrane depolarization, cardiac Nav channels
activate and inactivate rapidly (172, 174). The threshold
for Nav channel activation is quite negative (approximately ⫺55 mV), and the activation of these channels is
steeply voltage dependent. Importantly, inactivation is
also voltage dependent, and cardiac Nav channels can
undergo voltage-dependent inactivation without ever
opening (174). Nevertheless, persistent openings of cardiac Nav channels are occasionally observed, even at
depolarized membrane potentials (437, 591). At potentials
corresponding to the action potential plateau in ventricular myocytes, present estimates are that ⬃99% of the Nav
channels are in an inactivated, nonconducting state (423,
525). There is, therefore, a finite, albeit small (⬃1%),
probability of Nav channels being open at potentials corresponding to the action potential plateau (525). A slow
component of Nav channel inactivation has indeed been
described in normal human ventricular myocytes (323).
This current is modulated by lysolipids (501) and appears
to be upregulated in failing myocardium (501–503). Importantly, the inward (Na⫹) current through open Nav
channels during the action potential plateau (phase 2) will
counter the effects of the increased K⫹ efflux, thereby
slowing or delaying repolarization and increasing action
potential durations (23, 102). It follows, therefore, that
changes in Nav channel open probability at voltages corresponding to the plateau (i.e., phase 2) could markedly
affect action potential waveforms, particularly in ventricular cells.
The probability of Nav channel opening at depolarized potentials (i.e., during phase 2) is determined by the
overlap of the curves describing the voltage dependences
of channel activation and inactivation (30). At the molecular level, the fact that some channels are open over this
voltage “window” implies that there is a finite probability
that inactivation is reversible, i.e., that inactivated channels can reopen at depolarized potentials. Consistent with
these predictions, electrophysiological studies reveal the
presence of a sustained component of inward Nav current, i.e., a “persistent” Nav current, during prolonged
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age-activated (LVA) Cav channels. Cardiac HVA and LVA
Cav channels were first described in isolated canine atrial
cells (44). LVA Cav channels, also referred to as T-type
Ca2⫹ channels (394), activate at relatively hyperpolarized
membrane potentials, i.e., approximately ⫺50 mV, and
these channels activate and inactivate rapidly (85, 86,
382). HVA Cav channels, in contrast, open on depolarization to membrane potentials positive to approximately
⫺20 mV, and these channels inactivate over a time course
of several tens of milliseconds to seconds, depending on
the preparation and the charge carrying ion (85, 326).
Under physiological conditions, with Ca2⫹ as the charge
carrier, HVA channels in most cells inactivate in ⬍100 ms
at depolarized voltages (44, 326).
The detailed kinetic, pharmacological, and voltagedependent properties of HVA Cav channels in different
cell types are distinct, suggesting that HVA Cav channels
are heterogeneous, particularly compared with LVA Cav
channels. Consistent with this view, multiple types of
HVA channels have now been identified in different cell
types, and these are referred to as L, N, P, Q, or R
channels (276, 382, 394). Although all HVA Cav channels
exhibit relatively large single-channel conductances
(13–25 pS) and have similar permeation properties, the
detailed biophysical properties and the pharmacological
sensitivities of the various types of HVA Cav channels are
distinct. In the mammalian heart, L-type HVA Cav currents appear to be ubiquitously expressed (44, 49, 326). In
addition, the properties and the densities of L-type Cav
channel currents in cells isolated from different regions of
the myocardium, as well as in cardiac cells from different
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species, are quite similar, suggesting that the molecular
compositions of the underlying channels and the molecular mechanisms controlling the functional expression of
these channels are the same. Importantly, however, the
time- and voltage-dependent properties of cardiac L-type
HVA currents are distinct from the L-type HVA Cav currents expressed in skeletal muscle and in neurons (44,
326, 340), suggesting that, similar to the Nav channels,
distinct molecular entities underlie the L-type HVA Cav
channels in different tissues (see sect. VC).
The opening of cardiac L-type Cav channels in response to membrane depolarization is delayed relative to
the Nav channels (Fig. 2), and these channels, therefore,
contribute little to phase 0 depolarization in Purkinje,
atrial and ventricular cells. Rather, the opening of HVA
L-type Cav channels and the Ca2⫹ entry through these
channels underlies the action potential plateau (phase 2),
which is particularly prominent in ventricular and Purkinje cells (Fig. 2). In addition, Ca2⫹ influx through the
L-type HVA Cav channels triggers Ca2⫹ release from intracellular Ca2⫹ stores and underlies excitation-contraction coupling in the working (ventricular) myocardium
(56, 57, 154, 173). L-type HVA Cav channels are also
expressed in SAN and AVN cells, where they play a role in
action potential generation, as well as in regulating automaticity (49, 72, 262, 340, 361, 579). Cardiac L-type HVA
Cav channels undergo rapid voltage- and Ca2⫹-dependent
inactivation (166, 281, 326), processes that will also influence action potential waveforms (Fig. 2) by affecting the
duration of the plateau (phase 2) and the time course of
action potential repolarization.
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FIG. 3. Pore-forming (␣) subunits of
cardiac Nav (A) and Kv (B and C) channels linked to inherited arrhythmias. A:
membrane topology of the four domains
(I–IV) of SCN5A is illustrated with mutations linked to LQT3 and Brugada syndromes and to conduction disorders.
Schematics illustrating the transmembrane topologies of KCNH2 (B) and
KCNQ1 (C) subunits with the mutations
linked to LQT2 and LQT1, respectively,
depicted by the open and closed circles.
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that contribute to shaping action potential waveforms and
to regulating normal cardiac rhythms. Additional studies,
focused on further characterization of the properties of
LVA Cav channels in SAN and AVN cells and determination of the functional roles of these channels in regulating
pacemaking, will be needed to explore these possibilities
directly.
III. MYOCARDIAL ACTION POTENTIALS AND
REPOLARIZING VOLTAGE-GATED
POTASSIUM CURRENTS
Voltage-gated K⫹ (Kv) channels are the primary determinants of action potential repolarization in the mammalian myocardium, and compared with cardiac Nav and
Cav channels, there is considerable electrophysiological
and functional cardiac Kv channel diversity (42, 373, 375).
Based primarily on differences in time- and voltage-dependent properties and pharmacological sensitivities (42,
373, 375), two broad classes of repolarizing cardiac Kv
currents have been distinguished (42): transient outward
K⫹ currents (Ito) and delayed, outwardly rectifying K⫹
currents (IK) (Table 1). The transient currents (Ito) activate and inactivate rapidly on membrane depolarizations
to potentials positive to approximately ⫺30 mV and underlie the early phase (phase 1) of repolarization in ventricular and atrial cells (Fig. 2). Cardiac delayed rectifiers
(IK) activate at similar membrane potentials and with
variable kinetics, and these currents determine the latter
phase (phase 3) of repolarization back to the diastolic
potential (Fig. 2). Multiple types of myocardial Ito and IK
channels with distinct time- and voltage-dependent properties (Table 1), however, have been identified, and differences in the densities and the biophysical properties of
these channels contribute to variations in the waveforms
of action potentials recorded in different cardiac cell
types (Fig. 1), as well as in different species (24, 374, 375,
436). The detailed pharmacological, time- and voltagedependent properties of each of the various repolarizing
Kv currents characterized in different cardiac cell types
and species are quite similar, thereby allowing Kv channels to be classified based on these biophysical properties
(Table 1). The observed similarities in Kv channel properties also suggest that the molecular correlates of the
underlying Kv channels are also similar (42, 373), and
considerable experimental evidence has now been provided to support this hypothesis (see sect. VI).
A. Transient Outward Kv Currents
Although cardiac transient outward currents were
first described in (sheep) Purkinje fibers and thought to
reflect Cl⫺ conductances (143, 175), subsequent work
demonstrated the presence of two transient outward cur-
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In addition to the ubiquitously expressed HVA L-type
cardiac Cav currents, LVA or T-type Cav channel currents
have also been identified in voltage-clamp recordings
from adult atrial myocytes and conducting tissues in several different species (44, 200, 340, 394). Although not
evident in normal adult ventricular myocytes (394), T type
Cav currents have also been recorded in neonatal rat and
rabbit ventricular myocytes (547, 548). In addition, it has
been demonstrated that T-type Cav currents are expressed in ventricular myocytes in several animal models
of ventricular hypertrophy (328, 383), findings consistent
with the view that substantial remodeling occurs in the
hypertrophied myocardium, reflecting a reversion to a
fetal/neonatal pattern of gene expression (486). It is certainly possible that similar remodeling occurs in the hypertrophied human heart (49). Nevertheless, it is important to note that, to date, T-type LVA Cav channels have
not been detected in normal or diseased human myocardial cells (49, 394).
In addition to marked differences in biophysical
properties, the physiological role(s) of cardiac T-type LVA
Cav channels appears to be quite different from the L-type
HVA Cav channels. As noted previously, for example,
Ca2⫹ entry through L-type channels in cardiac cells results in Ca2⫹-induced Ca2⫹ release from intracellular
(Ca2⫹) stores and is the main trigger for excitation-contraction coupling (57, 154). Although Ca2⫹ entry through
T-type channels also triggers Ca2⫹ release from intracellular stores, the coupling is less efficient (589), and it
seems unlikely that T channels contribute importantly to
excitation-contraction coupling. This may simply reflect
the fact that LVA channel densities are low and that,
owing to rapid inactivation, very little Ca2⫹ actually enters cells on depolarization. Alternatively, these functional differences may reflect the fact that HVA and LVA
cardiac Cav channels are differentially localized, i.e., Ltype, but not T-type, Cav channels are highly localized in
the t tubules near the storage sites for intracellular Ca2⫹
sequestration/release (394, 589). Further experiments will
be necessary to determine the mechanistic basis for the
distinct functional roles of L- and T-type Ca2⫹ channels in
regulating excitation-contraction coupling.
The finding that T-type LVA Cav currents activate at
relatively hyperpolarized potentials and that these channels are expressed preferentially in pacemaker and conducting cells in the heart suggests the interesting possibility that there is a role for LVA channels in pacemaking
(200). Although some experimental support for this hypothesis has been provided, rigorous testing is complicated by the paucity of highly selective LVA Cav channel
blockers (394). In addition, it has been reported that
(rabbit) SAN cells express rapidly activating Na⫹-dependent inward currents that are blocked by Ca2⫹ channel
blockers (582). These observations suggest that pacemaker cells may express additional novel inward currents
1211
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JEANNE M. NERBONNE AND ROBERT S. KASS
Physiol Rev • VOL
different cells/species (15). These observations suggest
that there may well be subtle, albeit potentially important,
molecular heterogeneity among Ito,f and Ito,s channels in
different cell types and/or in different species (see
sect. VIC).
Although originally identified in Purkinje fibers, Ito,f
is a prominent repolarizing current in atrial and ventricular myocytes in most species (26, 58, 65, 69, 75, 79, 160,
178, 264, 294, 297, 500, 530, 545, 546, 578), including
humans. Nevertheless, there are exceptions. In guinea pig
ventricular cells, for example, Ito,f has not been detected
except when extracellular Ca2⫹ is removed (224). In addition, Ito,f is not detected in rabbit atrial or ventricular
cells (156, 160, 183, 530). Nevertheless, there are transient
Kv currents in rabbit myocytes (typically referred to as It),
which inactivate slowly and recover from (steady-state)
inactivation very slowly (160, 530). The properties of
these currents, therefore, more closely resemble mouse
ventricular Ito,s than Ito,f (562). Similar to the mouse,
however, two distinct transient outward Kv currents have
been described in the ventricles of other mammals (77,
178, 294, 500), including humans (225, 264, 545, 546), and
the properties of these currents are quite similar to those
of mouse ventricular Ito,f and Ito,s (79, 196, 562), permitting their classification as such (Table 1). In ferret, the
rates of inactivation and recovery (from steady-state inactivation) of the transient Kv currents in myocytes isolated from the left ventricular (LV) endocardium are significantly slower than the currents in cells from the epicardial surface of the LV, suggesting the presence of two
distinct transient Kv currents that are differentially expressed (77). Examination of the reported biophysical
properties (77) suggests that the endocardial and epicardial LV currents can be classified as Ito,s and Ito,f, respectively (Table 1). The distinct transient Kv currents in the
epicardial, midmyocardial, and endocardial layers of canine (294, 500) and human (264, 545, 546) ventricles can
also be appropriately referred to as Ito,f or Ito,s (Table 1).
Transient Kv currents that can be classified as Ito,f
(Table 1) have also been shown to be expressed in (rabbit) SAN cells, although, similar to Nav currents, Ito,f
densities vary markedly among (SAN) cells (213, 283). Ito,f
densities are higher, for example, in the larger cells isolated from the periphery, compared with the smaller cells
in the center, of the SAN (213, 283). In addition, when
expressed, Ito,f appears to play a role in shaping action
potential waveforms and in regulating automaticity in
SAN cells (72, 213, 283). Cells isolated from the (rabbit)
AVN also express Ito,f (349, 361, 371), and detailed kinetic
analysis of the currents reveals the presence of two components with distinct rates of inactivation and recovery
(349). It is unclear whether these findings reflect differences in the kinetic properties of a single type of Ito,f
channel or if two distinct types of Ito channels are expressed in (rabbit) AVN cells. Similar to the (rabbit) SAN,
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rents with distinct properties and referred to as Ito1 and
Ito2 (112). Pharmacological studies revealed that Ito1 is
blocked by 4-aminopyridine (4-AP) and unaffected by
changes in extracellular Ca2⫹, whereas Ito2 is not blocked
by 4-AP and is Ca2⫹ dependent (257, 256). In further
studies, it was shown that the Ca2⫹-dependent Ito2 in
Purkinje fibers and ventricular cells is a Cl⫺ (not a K⫹)
current (593, 594). In contrast, the Ca2⫹-independent
component, Ito1, was shown to be K⫹ selective (594), and
transient outward K⫹ currents, referred to variably by
different laboratories as Ito, Ito1, or It (42, 83, 436), have
now been described in many cardiac cell types and in
most species. Comparison of the detailed biophysical
properties of the transient outward K⫹ currents described
in various cell types/species, however, suggested there
might actually be two types of transient outward K⫹
currents (42), and electrophysiological and pharmacological studies have now provided considerable support for
this hypothesis. In adult mouse ventricular myocytes, for
example, two transient K⫹ currents, termed Ito,fast (Ito,f)
and Ito,slow (Ito,s), have been distinguished (562). On membrane depolarization, mouse ventricular Ito,f channels activate and inactivate rapidly, and on membrane repolarization, these (Ito,f) channels recover rapidly from steadystate inactivation (562). In the adult mouse, Ito,f channels
contribute importantly to the rapid repolarization of action potentials (194, 562) that is likely necessary to maintain the very high resting heart rates (⬃700 beats/min) in
these animals. In humans and other larger mammals, Ito,f
underlies the early phase (phase 1) of repolarization in
ventricular and atrial cells (Fig. 2) and likely also contributes to determining the plateau (phase 2).
Similar to Ito,f, mouse ventricular Ito,s channels activate and inactivate rapidly (562). In contrast to Ito,f, however, Ito,s channels recover very slowly (time constants of
seconds) from (steady-state) inactivation and are functionally distinct from Ito,f channels (196, 562). In addition,
Ito,f is readily distinguished from other Kv currents, including Ito,s, (562), using the spider K⫹ channel toxins
Heteropoda toxin-2 or -3 (449). The distinct properties of
Ito,f and Ito,s suggested that these currents reflect the
functioning of two molecularly distinct Kv channels, and
considerable evidence has now been provided to support
this hypothesis (see sect. VIC). Detailed comparisons of
the properties of the transient outward K⫹ currents expressed in other species, whether termed Ito, Ito1, or It,
suggest that, in each case, these currents could also be
classified as Ito,s or Ito,f, based on the kinetics of current
inactivation and recovery from steady-state inactivation,
as well as by the differential sensitivities of the channels
to the Heteropoda toxins. Although the properties of the
transient K⫹ currents in different cell types and species
are similar and are amenable to classification as either Ito,f
or Ito,s (Table 1), there are differences in the detailed
biophysical properties of the (Ito,f and Ito,s) currents in
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
B. Delayed Rectifier Kv Currents
Myocardial delayed rectifier Kv currents, IK, also first
described in (sheep) Purkinje fibers (379), have been
characterized in atrial and ventricular myocytes, as well
as in pacemaker cells, isolated from a variety of different
species, and, in most cases, multiple components of IK are
coexpressed (Table 1). In guinea pig ventricular and atrial
myocytes, for example, two prominent components of IK,
IKr (IK,rapid) and IKs (IK,slow), were first distinguished,
based on marked differences in time- and voltage-dependent properties (216, 445, 446). Both IKr and IKs are also
coexpressed in guinea pig AVN cells (579). Although IKr
activates rapidly, inactivates very rapidly, and displays
marked inward rectification, no inward rectification is
evident for the slowly activating IKs (445, 446). These
channels can also be distinguished at the microscopic
level, as well as by their unique pharmacological profiles
(37, 524). Similar to guinea pig, IKr and IKs are also reportedly coexpressed in human atrial and ventricular myocytes (290, 514, 532, 533), as well as in canine (296, 297,
513, 522, 578) and rabbit (440, 518) ventricles and in
canine Purkinje fibers (513) and, in each case, are prominent repolarizing currents. In adult rodent ventricles, in
contrast, IKr and IKs densities are very low (104) or the
currents are undetectable (562).
The unique time- and voltage-dependent properties
of IKr and IKs suggest that these currents play prominent
roles in action potential repolarization, particularly in
ventricular myocytes and Purkinje fibers. Nevertheless, in
some cardiac cells, only IKr or IKs appears to be expressed. In isolated human (225), feline (171), and rat
(404) ventricular myocytes and in rat atrial (404), mouse
SAN (108), rabbit AVN and SAN (218, 233, 467) cells, for
example, only IKr is detected. It has also been reported,
however, that both IKr and IKs are coexpressed in rabbit
SAN cells (284). In this study, the measured densities of
IKr and IKs (in rabbit SAN cells) were quite variable,
Physiol Rev • VOL
although, in general, IKr and IKs densities are highest in
the larger cells found at the periphery of the node (284).
It may be that the densities of IKr and/or IKs in some cells
are too low to be resolved reliably or, alternatively, that
the properties of IKs and IKr in each of these cell types are
distinct from guinea pig ventricular and atrial IKs and IKr.
The apparent absence of IKr and IKs in some cells, as well
as the observation that IKr and IKs expression is heterogeneous and variable, might also reflect the fact that
functional cardiac Kv channel expression is labile and
might well be affected by the isolation methods, which
typically involve the use of enzymes (578). Detailed studies focused on current characterizations in intact preparations, as well as on examining the effects of specific
enzymes and cell isolation methods on Kv current densities and properties, will be needed to explore these various possibilities further.
Although IKr and IKs are not prominent repolarizing
Kv currents in rodent atria or ventricles, there are other
components of delayed rectification with time- and voltage-dependent properties distinct from IKs and IKr (Table
1) in myocytes from these (and other) species. In rat
ventricular myocytes, for example, there are multiple delayed rectifier Kv currents that are coexpressed, and these
are referred to as IK, IKlate, and Iss (26, 210, 561). In adult
mouse ventricular myocytes, three distinct delayed rectifier Kv currents have also been separated and characterized (168, 196, 263, 291, 303, 560, 562, 586, 587), and these
are referred to as IK,slow1, IK,slow2, and Iss (Table 1). Multiple components of delayed rectification have also been
described in rodent atrial myocytes (68, 69, 74, 75, 497). In
both rat and mouse, it has been demonstrated that all the
various delayed rectifier Kv current components contribute, together with Ito,f channels, to (ventricular and atrial)
action potential repolarization (291, 303, 560, 586, 587).
It is interesting to note that a steady-state, noninactivating K⫹ current, which resembles Iss in rodent atria
and ventricles, has also been described in human atrial
myocytes (58).
In rat (74, 75), canine (577), and human (531–533)
atrial myocytes, a novel, very rapidly activating, and
largely noninactivating, outward Kv current, now typically referred to as IKultrarapid or IKur (479), has been
described (Table 1). In most species, IKur is not detected
in ventricular cells, and it seems likely that the expression
and the properties of IKur, together with Ito,f, contribute to
determining the more rapid repolarization evident in
atrial, compared with ventricular, myocytes (Fig. 2). Importantly, as in most other species, IKur is not expressed
in human ventricular myocytes or in Purkinje fibers, suggesting that IKur channels might represent a therapeutic
target for the treatment of atrial arrhythmias without
complicating effects on impulse propagation, ventricular
functioning, or cardiac output (444). The potential of this
pharmacological strategy, however, will have to be deter-
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there is considerable heterogeneity in Ito densities among
(rabbit) AVN cells (349). In contrast to SAN cells (213,
283), however, the differences in Ito,f densities are not
correlated with cell size in AVN cells (349). Interestingly,
and similar to findings in guinea pig atrial and ventricular
cells, Ito,f is not detected in guinea pig AVN cells (579). It
is presently unclear, however, whether currents with
properties similar to ventricular Ito,s are expressed in
conducting tissues in guinea pig heart. Owing to the
marked differences in inactivation and recovery kinetics
of Ito,f and Ito,s channels, however, the differential expression of these two channel types would be expected to
have profound functional effects on the regulation of
rhythmicity in the normal heart, effects that will be augmented in the diseased myocardium.
1213
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JEANNE M. NERBONNE AND ROBERT S. KASS
C. Regional Differences in Kv Current Expression
and Properties
Although the properties of Ito,f in different cardiac
cells are similar (Table 1), there are marked regional
differences in current densities. In humans (160, 367, 527,
542, 543) and in rats (26, 74, 75), for example, Ito,f densities are significantly higher in atrial, compared with ventricular, myocytes. Similarly, in the rabbit, Ito,s densities
are higher in atrial myocytes and Purkinje fibers than in
ventricular cells (75, 514). In the mouse, however, Ito,f
density is significantly higher in ventricular (79, 562), than
in atrial (69), myocytes. The density of Ito,f is also quite
variable in sheep Purkinje fibers (520) and in different
regions of the ventricles in canine (294, 297, 522), cat
(178), ferret (77), human (367, 545, 546), mouse (79, 196,
562), and rat (107, 545) hearts. In canine (522) and mouse
(79, 196, 562) heart, for example, Ito,f density is higher in
the right ventricle (RV), compared with the left ventricle
(LV), and Ito,f densities are lower in the base of the LV
than in the LV apex (79). In addition, in canine and in
human heart, Ito,f density varies throughout the thickness
of the ventricular walls, being severalfold higher in the
epicardial and midmyocardial, than in the endocardial,
layers (297, 546). In large mammals, the regional and
cellular heterogeneities in Ito,f densities are directly reflected in the differences in action potential waveforms in
Purkinje, ventricular, and atrial cells (75, 107, 366, 520,
551). Within the ventricles, for example, the differences in
Ito,f densities are revealed by the presence and the appearance and depth of the “notch” in the initial phase
(phase 1) of action potential repolarization (24, 364, 374;
see Fig. 2).
There are also marked regional differences in the
expression/distribution of Ito,s in adult rat, mouse, human,
and canine ventricles (77, 79, 196, 366, 367, 551, 562). In
mouse RV and LV, for example, Ito,s is undetectable,
whereas cells in the interventricular septum express only
Physiol Rev • VOL
Ito,s or both Ito,f and Ito,s (79, 196, 562). Even when expressed, however, Ito,f density is significantly lower in
septum, compared with ventricular (or atrial), cells (79,
562). The densities of the delayed rectifier Kv currents,
IK,slow1, IK,slow2, and Iss, in contrast, are similar throughout
adult mouse ventricles (79, 196, 562). The main determinant of action potential heterogeneity in the mouse,
therefore, appears to be the differential expression of
Ito,f (79, 196).
In larger mammals, including humans, the differential expression of Ito,f is also a primary determinant of
action potential heterogeneity (24, 374). In human heart,
however, it is clear that differences in the expression
levels of the various delayed rectifier Kv currents, as well
as the persistent component of the Nav current (see sect.
IIA), also play important roles in regulating action potential heterogeneity (24, 374). In canine heart, for example,
IKs density is higher in cells in the RV, compared with the
LV, whereas IKr densities are similar in both chambers
(24, 522). IKs density is also higher in canine LV epicardial
and endocardial cells than in M cells (24, 296). In guinea
pig heart, IKr and IKs densities are approximately twofold
higher in atrial, than in ventricular, myocytes (37, 216,
442, 524). There are also regional differences in functional
IKr and IKs expression within the ventricles (80, 316). In
cells isolated from the (guinea pig) LV free wall, for
example, IKr density is higher in subepicardial, than in
either midmyocardial or subendocardial, myocytes (316).
At the base of the LV, however, the densities of both IKr
and IKs are significantly lower in endocardial, than in
either epicardial or midmyocardial, cells (80). These differences clearly contribute to the marked differences in
action potential waveforms and frequency-dependent
properties in cells through the thickness of the ventricular
wall (24). In addition to having a major impact on action
potential repolarization, it is now very clear that differences in functional IKr and IKs densities are also expected
to influence the maintenance of normal cardiac rhythms
and the susceptibility to rhythm disturbances (24).
IV. OTHER MYOCARDIAL POTASSIUM
CURRENTS CONTRIBUTING
TO REPOLARIZATION
In addition to the depolarization-activated Kv currents, non-voltage-gated inwardly rectifying K⫹ (Kir) currents, through IK1 channels, also contribute to myocardial
action potential repolarization, particularly in ventricular
cells (232, 306, 377, 380). There are also other types of Kir
channels that are expressed and are important in the
normal functioning of the heart, although these do not
seem to play important roles in action potential repolarization under normal physiological conditions (306, 377).
One example of a functionally important class of myocar-
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mined by the atrial specificity/selectivity of the drugs that
are developed. In contrast to rat, canine, and human, Kv
currents have been described in guinea pig (576) and
mouse (168, 291, 587) ventricular myocytes that have
biophysical properties very similar to human (rat or canine) atrial IKur. Indeed, the properties of the rapidly
activating, IKur-like, current in guinea pig ventricular myocytes, referred to as IKp (576), and the micromolar 4-APsensitive component of mouse ventricular IK,slow, referred
to as IK,slow1 (69, 291, 302, 587), are indistinguishable from
human (canine and rat) atrial IKur. These currents should,
therefore, probably be renamed IKur (Table 1) to reflect
the similarities in properties, as well as molecular identities of the channels underlying IKp and IK,slow1 and IKur
(see sect. VID).
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
Physiol Rev • VOL
Mg2⫹ (506), Ca2⫹ (335), and polyamines (164, 307, 308).
Removal/depletion of intracellular polyamines, Mg2⫹
and/or Ca2⫹, eliminates the steep inward rectification of
(cardiac) IK1 channels and converts to a linear currentvoltage relation (164, 307, 308, 335, 506).
The expression of IK1 is clearly reflected in the negative slope region (between approximately ⫺50 and ⫺10
mV) of the (total steady-state) myocyte conductance-voltage relation, which is prominent in ventricular myocytes,
but is small or undetectable in atrial cells (183). The fact
that the strongly inwardly rectifying IK1 channels conduct
at negative membrane potentials suggests that these channels will play a role in establishing the resting membrane
potentials of Purkinje fibers, as well as of atrial and
ventricular myocytes. Direct experimental support for
this hypothesis was provided with the demonstration that
ventricular membrane potentials are depolarized in the
presence of Ba2⫹ (377), which blocks IK1 channels. In
addition, action potentials are prolonged, and phase 3
repolarization
is slowed in the presence of extracellular
2⫹
Ba (306), suggesting that IK1 channels also contribute to
repolarization, particularly in the ventricular myocardium. The voltage-dependent properties of IK1 channels
(306, 377), however, are such that the conductance is low
at potentials positive to approximately ⫺40 mV. Nevertheless, because the driving force on K⫹ is markedly
increased at depolarized potentials, these channels
should contribute outward K⫹ current during the phase 2
plateau and during phase 3 repolarization (Fig. 2). In
contrast to atrial, ventricular, and Purkinje cells, IK1 density is low or undetectable in SAN and AVN cells (244, 381,
468). These observations, as well as the fact that pacemaker currents are expressed and functional in SAN and
AVN cells, likely explain the findings that resting membrane potentials in these (SAN/AVN) cells are depolarized
(significantly) and that the rising phases of the action
potentials in these cells are less steep, relative to resting
membrane potentials/action potentials in atrial and ventricular cells (Fig. 1).
Similar to the Kv channels, IK1 densities and the
detailed biophysical properties of the currents do vary in
different myocardial cell types. In human heart, for example, IK1 density is more than twofold higher in ventricular,
than in atrial, cells (514). In guinea pig, the properties of
the atrial and ventricular IK1 currents are also distinct in
that ventricular IK1 inactivates during maintained depolarizations, whereas atrial IK1 does not (133, 223). In
addition, changes in extracellular K⫹ modulate the magnitude of ventricular IK1, but have little effect on atrial IK1
(223). At the microscopic level, (guinea pig) atrial and
ventricular IK1 channels are also distinct. Mean channel
open times of ventricular IK1 channels, for example, are
approximately five times longer than those of atrial IK1
channels, whereas the single atrial and ventricular IK1
channel conductances are indistinguishable (223). Taken
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dial Kir channels is the IKATP channels, which are inhibited by intracellular ATP, activated by nucleotide diphosphates, and thought to provide a link between cellular
metabolism and membrane potential (232, 380). In the
ventricular myocardium, the opening of IKATP channels is
thought to be important under conditions of metabolic
stress, as occurs during ischemia or hypoxia, and to result
in shortening action potential durations and minimizing
K⫹ efflux (165, 232). The opening of IKATP channels has
also been suggested to contribute to the cardioprotection
resulting from ischemic preconditioning (141, 188). Although IKATP channels appear to be distributed uniformly in the RV and LV and through the thickness of
the ventricular wall, these channels are expressed at
much higher density than other sarcolemmal K⫹ channels, suggesting that action potentials could be shortened markedly when only very small numbers of IKATP
channels are activated (463).
Another important cardiac Kir channel type is the
IK(ACh) channels, which are gated through a G proteincoupled mechanism mediated by muscarinic acetylcholine receptor activation (275, 564). Physiologically, IK(ACh)
channels are activated by the binding of G protein ␤␥subunits in response to the acetylcholine released on
vagal stimulation (414). Although IK(ACh) channels are
expressed in AVN, SAN, atrial, and Purkinje cells, and are
activated by acetylcholine released on vagal stimulation,
these channels are not thought to contribute appreciably
to action potential repolarization under normal physiological conditions. Consistent with this hypothesis, targeted
deletion of one of the Kir subunits (Table 6) encoding
IK(ACh) channels, Kir3.4, does not measurably affect resting heart rates (552). Interestingly, however, atrial fibrillation is not evident in Kir3.4 null mice exposed to the
acetylcholine receptor agonist carbachol, suggesting that
activation of IK(ACh) channels is involved in the cholinergic induction of atrial fibrillation (269).
As the “inward rectifier” terminology implies, Kir
channels
carry inward K⫹ currents better than outward
⫹
K currents (306, 377). Nevertheless, it is the outward K⫹
currents through these channels that are important physiologically because myocardial membrane potentials
never reach values more negative than the K⫹ reversal
potential (approximately ⫺90 mV). As a result, there is
never an opportunity for the inward movement of K⫹
currents through Kir (or any other K⫹ selective) channels.
At the macroscopic level, IK1 channels have been characterized in human (206, 514), guinea pig (133, 514), and
rabbit (183, 381, 468) atrial and ventricular myocytes and
in rabbit SAN cells (381). The properties of the IK1 channels in each of these preparations are similar in that all
are K⫹ selective, blocked by extracellular Ba2⫹ and intracellular Cs⫹ and strongly inwardly rectifying (183, 206,
223, 514). The strong inward rectification evident in cardiac IK1 channels is attributed to block by intracellular
1215
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JEANNE M. NERBONNE AND ROBERT S. KASS
together, these observations suggested the interesting
possibility that distinct molecular entities underlie ventricular and atrial IK1 channels, and experimental support
for this hypothesis has now been provided (133).
V. MOLECULAR COMPONENTS OF
MYOCARDIAL NAV AND CAV CHANNELS
A. Nav Channel Pore-Forming ␣-Subunits
TABLE
2.
Diversity of voltage-gated Na⫹ (Nav) channel ␣- and ␤-subunits
Subfamily
Nav␣1
Protein
Gene
Human
Mouse
Cardiac Current
2C1.3
INa (TTX)†??
Nav1.1
SCN1A
2q24
Nav1.2
SCN2A
2q23
Nav1.3
SCN3A
2q24
2C1.3
INa (TTX)†??
Nav1.4
SCN4A
17q21
11E1
INa (TTX)??
Nav1.5
SCN5A
3p21
9F3
INa (TTX-resistant)*
Nav1.6
SCN8A
2q13
15F2
INa (TTX)†??
Nav1.7
SCN9A
2q24
Nav1.8
SCN10A
3p22
9F3
9F3
Nav1.9
SCN11A
3p21
Nav␣X
Nav2.1
SCN6A
2q21-23
Nav␤
␤1
SCN1B
19p11
␤2
SCN2B
11q24
␤3
SCN3B
11q26
␤4
SCN4B
11q24
SCN7A
7A3
??
INa (TTX-resistant)*
9F3
INa (TTX-resistant)*
Boxes denote cardiac expression. * Major cardiac (TTX-resistant) Nav current in atria, ventricles, Purkinje fibers, and nodal cells. † TTXsensitive, neuronal-like, Nav current.
Physiol Rev • VOL
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Voltage-gated Na⫹ (Nav) channel pore-forming (␣)
subunits (Fig. 3A) belong to the “S4” superfamily of voltage-gated ion channel genes (93, 172, 174, 573). Nav ␣-subunits have four homologous domains (I to IV), each of
which contains six transmembrane-spanning regions (S1S6), and these four domains come together to form the
Na⫹-selective pore. Structure-function studies have revealed many of the important features of voltage-dependent Nav channel gating (91, 93). The cytoplasmic linker
between domains III and IV, for example, has been shown
to play a pivotal role in voltage-dependent Nav channel
inactivation (392), and a critical isoleucine, phenylalanine, methionine (IFM) motif within this linker (91, 444)
has been identified as an important molecular component
of the inactivation gate (516, 517, 544). Voltage-dependent
inactivation of Nav channels is attributed to the rapid
block of the inner mouth of the channel pore by the
cytoplasmic linker between domains III and IV that occurs within milliseconds of membrane depolarization
(483). Consistent with the functional electrophysiological
data, solution NMR analysis of this cytoplasmic linker
peptide revealed a rigid helical structure positioned to
block the pore (427).
Although there are a number of homologous Nav
␣-subunits (Table 2), Nav1.5 (SCN5A) is the prominent
Nav ␣-subunit expressed in the mammalian myocardium,
and this subunit encodes the rapidly activating and inactivating, tetrodotoxin (TTX)-insensitive Nav channels that
underlie rapid (phase 0) depolarization in atrial and ventricular myocytes and in Purkinje fibers (Fig. 1). Nevertheless, several studies have demonstrated that mRNAs
encoding other Nav ␣-subunits, notably Nav1.1, Nav1.3
(120, 426, 471), and Nav1.4 (590), which are typically
considered the Nav ␣-subunits encoding brain and skeletal muscle Nav channels, respectively, are also expressed
in the myocardium. In contrast to the Nav channels
formed by Nav1.5, however, Nav1.1-, Nav1.3- and Nav1.4encoded Nav channels are blocked by nanomolar concentrations of TTX (120, 426, 471, 590). In addition, although
cardiac Nav currents are generally considered relatively
TTX insensitive (174, 573), application of nanomolar concentrations of TTX has been reported to shorten canine
Purkinje fiber action potential durations (113). These findings suggest a possible role for TTX-sensitive Nav channels in the generation of the persistent component of
cardiac Nav currents, at least in canine Purkinje fibers.
Nevertheless, there have been very few reports documenting the presence of TTX-sensitive inward Nav current components in cardiac cells, raising some concern
about the functional significance of the expression data,
in spite of the fact that the (message) expression levels of
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
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SCN5A, linked to the LQT3 syndrome (Fig. 3A), disrupt
Nav channel inactivation (52, 346). These “gain of function” mutations lead to an increase in the amplitude of the
sustained component of the Na⫹ current (Fig. 4B) and to
action potential prolongation (Fig. 4A). The enhanced
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Nav1.1, Nav1.3, and Nav1.4 in the myocardium appear to
be quite high (120, 426, 471, 590).
It has also been reported that there are several Nav1
␣-subunit proteins in addition to Nav1.5 in adult (mouse)
myocardium (314). These include Nav1.1, Nav1.3, and
Nav1.6 (314). The immunolocalization data also suggest
that the Nav1.1, Nav1.3, and Nav1.6 ␣-subunits are localized in the t tubules in adult mouse ventricles (314),
whereas Nav1.5 appears to be localized preferentially to
intercalated disks in mouse, as well as in rabbit and rat,
hearts (270, 315, 400). The subcellular localization of
Nav1.5-encoded myocardial Nav channels at the intercalated disks has been interpreted as suggesting that these
(Nav) channels play a major role in regulating conduction
(270). Although the functional role(s) of t-tubular Nav
channels in cardiac functioning has not been established,
voltage-clamp studies have clearly demonstrated that
TTX-sensitive Nav currents can be measured in whole cell
recordings from adult mouse ventricular myocytes
treated with ␤-scorpion toxin, which shifts the voltage
dependence of activation of brain Nav channels, but does
not affect cardiac (i.e., SCN5A-encoded) Nav channels
(314). These observations have been interpreted as suggesting a distinct role for the neuronal Nav channels
localized to the t tubules, i.e., linking depolarization of the
sarcolemmal membrane with the t tubules, thereby coupling depolarization with excitation-contraction coupling
(314). This hypothesis has important functional implications and certainly warrants further direct experimental
testing.
Immunohistochemical studies have also provided evidence suggesting that Nav1.1 and Nav1.3, but not Nav1.5,
are expressed in rat and mouse SAN (314). These findings
suggest a substantive molecular difference between the
SAN and the remainder of the myocardium in terms of
Nav channel expression. Given the primary role of the
SAN in regulating heart rate, it would seem certain that
modulating the (TTX-sensitive) Na⫹ current in the SAN
should impact heart rate. Nevertheless, exposure to TTX
reportedly has no effect on heart rate in the mouse (314).
In mice in which one copy of the SCN5A gene has been
disrupted, however, conduction defects, as well as ventricular dysfunction, are evident (389), suggesting that
SCN5A encodes most, if not all, of the cardiac Nav current. It seems reasonable to suggest, therefore, that additional studies focused on exploring the functioning of
Nav1.1-, Nav1.3- and Nav1.6-encoded channels in the
heart are warranted.
During the plateau phase of the action potential in
human ventricular myocytes, ⬃99% of the Nav channels
are in an inactivated, nonconducting state with the inactivation gate occluding the inner mouth of the conducting
pore through specific interactions with sites on either the
S6 segment (345) or the S4-S5 loop (346) of domain IV.
Mutations in the linker between domains III and IV in
1217
FIG. 4. Simulated human ventricular action potentials reveal the
impact of gain of function (LQT3) and loss of function (Brugada) mutations in SCN5A. Steady-state action potential waveforms (A and C)
and inward Nav1.5 currents (B and D) were simulated (103, 105). Control action potential and current waveforms simulated for wild-type
SCN5A-encoded Nav1.5 currents are depicted by the solid black lines in
A–D. The corresponding voltage and current waveforms resulting from
LQT3 and Brugada mutations in SCN5A (Fig. 3A) are represented by the
dashed purple (LQT3) and red (Brugada) lines in A–D. “Gain of function”
LQT3 mutations in SCN5A, resulting in an increase in the persistent
component of the Nav current (B), lead to marked action potential
prolongation (A). “Loss of function” Brugada mutations in SCN5A, in
contrast, result in reduced Nav current (D) and changes in the action
potential upstroke velocity (C). The impact of the loss of function
Brugada mutations are more readily illustrated in the insets of C and D,
in which the voltage (C) and current (D) deflections are displayed on an
expanded time scale.
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JEANNE M. NERBONNE AND ROBERT S. KASS
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the COOH terminus of Nav1.5 and other components of
the channel protein complex and that these interactions
stabilize channels in the inactivated state (114). In addition, biochemical studies provide strong support for a
model in which there is a direct physical interaction between the III-IV linker of Nav1.5 and the proximal, structured portion of the COOH terminus (358). Taken together, these findings suggest the formation of a molecular complex between these domains that is pivotal for
channel inactivation and further that mutations in either
the III-IV linker or the COOH-terminal tail disrupt this
interaction and destabilize inactivation. In addition, the
homology with calmodulin suggests that there may be
structural similarities in the control of Nav and Cav channel gating, a hypothesis that clearly warrants direct experimental testing.
Analyses of additional mutations in SCN5A linked to
LQT3, Brugada, and conduction system defects have provided further molecular insights into Nav channel functioning and arrhythmia mechanisms. One of the welldescribed LQT3 mutations, I1768V, for example, does not
result in increased channel bursting, but rather, accelerates the rate of recovery of Nav channels from inactivation at diastolic membrane potentials (106). Computational analysis predicted that this mutation would have a
substantial effect under nonequilibrium conditions, e.g.,
during action potential repolarization (106). Subsequent
experiments confirmed this prediction, revealing a novel
mechanism by which mutation-altered Nav channel gating
can prolong cardiac action potentials (7). Interestingly, it
has also been demonstrated that a common polymorphism (that results in an S/Y switch) at residue 1102 in
SCN5A is associated with elevated arrhythmia risk in
African Americans (481). Expression studies revealed
that this variant results in very subtle changes in Nav1.5
channel activation and inactivation. Modeling studies suggest, however, that these changes are not likely to alter
cellular electrical activity in carriers unless they are
treated with drugs that block (cardiac) Kv channels (481).
Additional polymorphisms in SCN5A have also been identified that affect, at least in heterologous expression systems, the trafficking of functional cell surface Nav channels (318, 570). In principle, the presence of these polymorphisms could, like the S1102Y polymorphism (481),
impact arrhythmia susceptibility in the context of other
factors (e.g., disease or drugs) that affect membrane excitability, action potential durations, and rhythmicity
(318). Mutations in SCN5A and changes in Nav1.5-channel
gating have also been linked to sudden infant death syndrome (538). In addition, mutations in two of the neuronal
Nav channel ␣-subunits, SCN1A and SCN2A, are associated with epilepsies (204, 220, 249, 359). It will be interesting to determine if the molecular mechanisms linking
these mutations, as well as the mutations in the skeletal
muscle Nav channel SCN4A, to disorders in membrane
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inward current can be measured during sustained depolarizations and appears to reflect a change in (Nav channel) gating that results in channel “bursting” (52). As
illustrated in Figure 4A, the increase in late inward Na⫹
current (due to Nav channel bursting) prolongs “modeled” cardiac action potentials (103, 105). Interestingly,
action potential prolongation is also evident in genetically
modified mice expressing human LQT3-associated mutant
SCN5A Nav channels (384). In mice heterozygous for an
SCN5A deletion at residues (KPQ) 1505–1507, a modification linked to LQT3, premature ventricular beats and
pacing-induced ventricular tachycardia are also evident
(384). Mutations in SCN5A are also linked to another
(rare) inherited rhythm disorder, the Brugada syndrome
(23, 41) and, similar to LQT3 mutations, a number of
Brugada mutations in SCN5A have been identified (Fig.
4A). In contrast to long QT3, however, Brugada syndrome
mutations are “loss of function” mutations in Nav1.5 and
result in reduced Nav current (Fig. 4D) and lead to slowing of the action potential upstroke (Fig. 4C). Reductions
in Nav current can also influence action potential amplitudes (Fig. 4C), as well as phase 1 repolarization. In
addition, owing to intrinsic electrical heterogeneity of the
heart (Fig. 1), the impact of Brugada and LQT3 mutations
in SCN5A would be expected to be variable in different
regions/cell types, an effect which may contribute further
to arrhythmogenesis.
Other identified SCN5A mutations, linked to both the
LQT3 and Brugada syndromes, are found in several other
regions of SCN5A, most notably in the COOH terminus
(Fig. 3A), that also lead to altered channel inactivation
(60, 105, 358, 422, 519, 540). These findings should probably have been expected, given that structure-function
studies suggest that multiple domains in Nav ␣-subunits
contribute to the regulation of channel gating (8, 48, 91,
105, 114, 174, 248, 254, 299, 357, 358, 521). A role for the
COOH-terminal tail of Nav1.5 in the regulation of channel
inactivation, for example, has been demonstrated (36, 51,
248, 251, 521). In addition, point mutations in the COOH
terminus affect the kinetics and the voltage dependence
of channel inactivation and recovery from inactivation
and promote sustained channel activity (8, 48, 254, 299,
357). Single-channel studies have also demonstrated that
the proximal portion of the COOH terminus has pronounced effects on repetitive channel openings during
prolonged depolarization (114). Modeling studies of the
COOH terminus of Nav1.5, assuming homology with the
NH2 terminus of calmodulin, predict that the proximal
region (of the COOH terminus) adopts an ␣-helical structure, a prediction verified in circular dichroism studies on
a purified COOH-terminal protein (114). The distal region
of the COOH-terminal tail, in contrast, is largely unstructured and does not appear to affect channel gating measurably (114). These observations suggest that interactions occur between the structured (proximal) region of
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
excitability are similar to those evident for SCN5A in the
LQT3 and Brugada syndromes.
B. Nav Channel Accessory Subunits and Other
Interacting Proteins
(20). Expression studies suggest that SCN2b plays a role
in controlling the Ca2⫹ permeability of Nav channels
(450). The targeted deletion of SCN2b (in Nav␤2 ⫺/⫺
mice) markedly affects neuronal Nav channel expression
and properties and has profound neurological consequences (95). No cardiac phenotype, however, has been
described in Nav␤2 ⫺/⫺ mice (95), suggesting that Nav␤1
or Nav␤3 more likely contributes to the formation of the
SCN5A-encoded cardiac Nav channels. Consistent with
this hypothesis, heterologous coexpression of Nav␤1,
which markedly affects Nav1.4-encoded skeletal muscle
Nav channels (319), alters the inactivation kinetics and
the densities of Nav1.5-encoded (cardiac) Nav channels
(20, 134, 155). Heterologous coexpression of SCN3b with
SCN5A also reportedly increases the cell surface density
and modifies the inactivation kinetics of Nav1.5-encoded
currents (155).
In addition to modifying the cell surface expression
and the kinetic properties of Nav channels, Nav ␤-subunits also appear to be multifunctional cell adhesion molecules of the IgG superfamily (228) that target channels to
the plasma membrane and mediate channel interactions
with a variety of signaling molecules. It has been demonstrated, for example, that Nav ␤-subunits interact with
cell adhesion molecules (252, 413), components of the
extracellular matrix (413, 481, 559), and mediate the re-
FIG. 5. Molecular assembly of cardiac Cav (Nav), Kv, and Kir channels.
Top: the four domains (I–IV) of individual
Cav (and Nav) ␣-subunits contribute to
the formation of individual Cav (Nav)
channels, whereas four Kv (or Kir) ␣-subunits combine to form tetrameric Kv (or
Kir) channels. Bottom: schematic illustrating functional cardiac Nav, Cav, and
Kv channels, composed of the pore-forming ␣-subunits and a variety of channel
accessory subunits.
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Although molecular and functional studies of cardiac
Nav channels have focused primarily on the pore-forming
Nav1.5 ␣-subunit, it is now quite clear that functional Nav
channels in cardiac (and other) cells reflect the assembly
of multimeric protein complexes comprising accessory
subunits, as well as a variety of other auxiliary, interacting
and regulatory proteins. All available evidence suggests,
for example, that functional Nav channels in cardiac (and
other) cells are multisubunit proteins consisting of a central pore-forming Nav ␣-subunit (Fig. 5) and one to two
auxiliary Nav ␤-subunits (229). In brain, the functional
stoichiometry appears to be one Nav ␣- to two Nav ␤-subunits (229); the ␣/␤-subunit composition of cardiac Nav
changes is probably similar. Three different Nav ␤-subunit
genes, SCN1b (230, 320), SCN2b (231, 241), and SCN3b
(354) encoding Nav␤1, Nav␤2 and Nav␤3 proteins, respectively, have been identified, and it appears that all
three Nav ␤-subunits are expressed in heart (Table 2). The
functional role(s) of the Nav ␤-subunits in the generation
of cardiac Nav currents, however, is not well understood
1219
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JEANNE M. NERBONNE AND ROBERT S. KASS
in mediating Nav channel gating in the normal and in the
diseased myocardium.
An important functional role for the actin cytoskeleton in the regulation of Nav channel gating was directly
revealed with the demonstration that mice heterozygous
for a targeted deletion of ankyrin B, ankyrin B ⫹/⫺, have
abnormal cardiac electrical activity attributed to altered
Nav channel gating and cell surface expression levels
(40). Single-channel studies on ankyrin B ⫹/⫺ ventricular
cells revealed increased channel bursting, consistent with
a LQT channel phenotype (94). These observations were
interpreted as suggesting that mutations in ankyrin, which
would lead to Nav channel dysfunction, might well be
important in familial LQT syndromes or other inherited
cardiac rhythm disturbances (50). Consistent with this
hypothesis, molecular genetic studies subsequently revealed a loss-of-function mutation in ankyrin B (E1425G)
that is causally linked to variant 4 of familial long QT
syndrome, LQT4 (351). In addition to providing fundamentally important new insights into the molecular defect
underlying LQT4 (351), these findings demonstrate a
novel, physiologically important, mechanism for regulating Nav functioning involving interactions between channel proteins and the cytoskeleton that are coordinated by
the adaptor protein ankyrin B. It is possible that the
ankyrin B mutations interfere directly with Nav␤1-Nav␣1
interactions, or perhaps indirectly, through other regulatory and/or signaling molecules. In this context, it is also
interesting to note that the cell surface expression of the
Na⫹-K⫹-ATPase, the Na⫹/Ca2⫹ exchanger, and inositol
1,4,5-trisphosphate (IP3) receptors, each of which also
interacts with ankyrin B, are all affected in ankyrin B ⫹/⫺
ventricular myocytes (351). It seems certain that the
FIG. 6. Schematic illustrating the
complexity of protein-protein interactions that likely are involved in regulating/modulating the expression, distribution, and functioning of myocardial ion
channels. The ␣- and ␤-subunits of Nav
channels interact with the actin cytoskeleton through syntrophin-dystrophin and
ankyrin B and with the extracellular matrix through the sarcoglycan complex.
Interactions between Kv channel ␣
(and/or ␤) subunits and the actin cytoskeleton are mediated by the actin
binding proteins filamin and ␣-actinin
and through PDZ domain-containing
scaffolding proteins.
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cruitment of the actin-binding protein ankyrin to the
plasma membrane at points of cell-cell contact (321). The
ankyrins are (cytosolic) cytoskeletal proteins that have
been suggested to function in regulating the trafficking of
a variety of plasma membrane proteins (53, 54, 350). It has
been demonstrated directly that the intracellular COOH
terminus of Nav␤1 mediates the interaction with ankyrin
and that Nav␤1 and ankyrin B associate in transfected
cells and in rat brain membranes (135, 322). Interestingly,
the intracellular COOH-terminal domain of Nav␤1 has
also been shown to be required for interaction with Nav1,
specifically Nav1.2, ␣-subunits (347). Taken together,
these observations suggest an important functional role
for the cytosolic COOH-terminal domain of Nav␤1 in the
regulation of Nav channel trafficking and/or Nav channel
localization, perhaps through ankyrin B (Fig. 6) and/or
interactions with other components of the actin cytoskeleton (135).
It has long been recognized that the proper functioning of myocardial Nav channels requires an intact actin
cytoskeleton (324, 504). Disruption of actin polymerization on treatment with cytochalasin D, for example, results in marked (⬃20%) reductions in peak Nav current
densities in isolated rat and rabbit ventricular myocytes
(504). Single-channel recordings from excised membrane
patches from cytochalasin D-treated cells, however, revealed that, in addition to reduced open probability, channel “bursting” is increased (504). The latter effect is attributed to a change in Nav channel gating and is functionally similar to the alterations in channel activity seen
with some long QT3 mutations (52, 60, 105, 346, 358, 419,
519, 540). These results suggest the interesting possibility
that multiple pathways (mechanisms) may be important
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
Physiol Rev • VOL
syntrophin and, therefore, to Nav1.5 channels (Fig. 6).
Nitric oxide synthase (NOS), for example, which is also
part of the dystrophin-proteoglycan complex (189), and
thought to play a role in myocardial ischemia (466), appears to bind directly to syntrophin, as well as to caveolin-3 (115, 207, 265), the muscle-specific caveolin in plasmalemmal caveoli. Nearly all of the endothelial NOS activity can be coimmunoprecipitated from cardiac muscle
using an anti-caveolin-3 antibody (161, 162). The caveolins are also important regulators of NOS activity (161,
415), and it is of interest to note that overexpression of
caveolin-3 results in cardiomyopathy and the downregulation of NOS and other components of the dystrophindystroglycan complex (27). Given that it has also been
demonstrated that caveolin-3 binds directly to the cytoplasmic tail of ␤-dystroglycan (477), these observations
suggest additional links between cardiac Nav channels,
the actin cytoskeleton, and the extracellular matrix (Fig.
6). Caveolin-3 is thought to play a direct role in regulating
the interaction of caveoli with the sarcolemmal membrane and, therefore, to function to facilitate the transfer
of (Nav or other) channels to the cell surface membrane
from the intracellular compartment (161). It seems reasonable to suggest here that alterations in the interactions
between any of the individual components of the proposed functional Nav channel complex (Fig. 6), through
acquired or inherited disease, could have profound effects
on the properties and/or the functional cell surface expression of Nav channels, effects that in turn will impact
the generation of normal cardiac rhythms and the likelihood that rhythm disturbances will occur.
In cardiac myocytes, functional cell surface Nav
channel expression is also regulated directly by ␤-adrenergic receptor occupancy and the activation of the stimulatory G protein (Gs) pathway (310, 334). In addition, it
has now been demonstrated that Gs␣ functions through
binding to caveolin-3, increasing the presentation of
caveoli to the sarcolemmal membrane which could lead
to increased cell surface expression of Nav channels
(569). It has also been reported that caveolin-3 expression
is increased and that nitric oxide signaling is augmented
in a (canine) pacing-induced model of heart failure (203).
The relationship between these biochemical changes and
the observed structural and electrical changes evident in
this model and the relevance of this model and these
changes to human heart failure remain to be established.
As for heterologously expressed Nav channels, there may
well also be additional regulatory molecules, including
growth factors (295, 555) and membrane lipid-anchoring
proteins (460), that play a role in regulating the properties
and the functional cell surface density of cardiac Nav
channels. Clearly, this possibility warrants direct experimental testing.
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ankyrin B-mediated interactions between each of these
molecules and the actin cytoskeleton are important for
the normal functioning of each of these ion transport
proteins, as well as the intracellular pathways coupled to
these proteins. The physiological import of these interactions and the impact of the disruption of each of these
interactions on the generation of normal cardiac rhythms
is potentially staggering.
Extrapolating this concept further, it is interesting to
note that there is now a growing body of evidence in the
cardiovascular (and other) system that functional Nav
(and other) channels interact directly and/or indirectly
with the actin cytoskeleton and with a variety of regulatory and signaling molecules (Fig. 6) which might well
play a role in the regulation of channel trafficking and
channel expression and/or in the modulation of channel
properties and functioning (418). It has, for example, been
reported that syntrophins, proteins thought to provide a
link between the actin cytoskeleton and other membraneassociated proteins, interact directly with Nav ␣-subunits,
including Nav1.5 and the skeletal muscle Nav channel
␣-subunit Nav1.4 (182, 212). Because the syntrophins also
interact directly with dystrophin and dystrobrevin (117)
and, therefore, with the entire dystrophin-associated complex (151) in cardiac and skeletal muscle, it seems reasonable to suggest further that alterations in the properties of any of the protein components of this macromolecular complex (Fig. 5) could alter myocardial Nav
channel functioning or expression. It is of further interest
to note that cardiomyopathy is often evident in patients
with congenital (skeletal) muscular dystrophies, attributed to mutations in the dystrophin gene (343), as well as
to mutations in other genes that are part of the dystrophin-sarcoglycan protein complex (144). With the assumption that the model of functional cardiac Nav channels proposed in Figure 6 is at least qualitatively correct,
it would seem reasonable to speculate that the mutations
in any of the genes encoding any of the components of the
depicted macromolecular complex could lead to altered
Nav channel functioning and cardiac arrhythmias alone or
in the background of other myocardial disease, particularly structural heart disease. If complexes such as those
illustrated in Figure 6 are indeed shown to be the physiologically important units of cardiac Nav functioning, exploring the molecular mechanisms involved in mediating
the many protein-protein interactions important in controlling the assembly, trafficking and functioning of these
macromolecular channel protein complexes might well
provide insights into the link between structural heart
disease and the electrophysiological abnormalities that
are linked to the generation of life-threatening cardiac
arrhythmias in a wide variety of myocardial disease
states.
Other potentially important signaling molecules in
cardiac physiology and pathophysiology are also linked to
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JEANNE M. NERBONNE AND ROBERT S. KASS
C. Cav Channel Pore-Forming ␣-Subunits
Similar to Nav channels, voltage-gated Ca2⫹ (Cav)
channel pore-forming ␣-subunits belong to the “S4”
superfamily of voltage-gated ion channel genes (92,
395), and functional voltage-gated Ca2⫹ (Cav) channels
reflect the multimeric assembly of one Cav ␣-subunit
(␣1) and auxiliary Cav␤ and Cav␣2␦, as well, at least in
some cases, as Cav␥, subunits (Fig. 5). Also similar to
Nav channels, Cav ␣-subunits comprise four homologous domains (domains I–IV), each of which is composed of six transmembrane segments (S1–S6), with an
“S4” voltage-sensing domain and a Ca2⫹-selective pore
region between S5 and S6 (92, 395). Four distinct subfamilies of Cav channel pore-forming ␣1-subunits, Cav1,
Cav2, Cav3, and Cav4 (47), each with many subfamily
members (Table 3), and alternately spliced transcripts
(476) have been identified. The Cav ␣1-subunits are
differentially expressed, and studies in heterologous
expression systems have revealed that the various Cav
␣1-subunit genes encode Cav channels with distinct
time- and voltage-dependent properties and pharmacological sensitivities. Heterologous expression of any
TABLE
3.
Diversity of voltage-gated Ca2⫹ (Cav) channel ␣- and ␤-subunits
Locus
Subfamily
Protein
Gene
Human
Cav␣1
Cav1.1 (␣11.1) (␣1S)
CACNA 1S
1q31-32
Cav1.2 (␣11.2) (␣1C)
CACNA1C
12p13.3
Locus
Mouse
Cardiac
Current
Subfamily
Cav ␤
1E4
6E3
ICa(L)
Cav1.3 (␣11.3) (␣1D)
CACNA1D
3p14.3
14A3
Cav1.4 (␣11.4) (␣1F)
CACNA1F
Xp11.23
XA1.1
Cav␣2␦
Protein
Gene
Human
Mouse
␤1
CACNB1
17q11.2
11D
␤2
CACNB2
10p12
2A1
␤3
CACNB3
12q12
15F1
␤4
CACNB4
2q23
2C1.1
␣2␦ ⫺1
CACNA2D1
7q11.2
5A1
ICa(L)
␣2␦ ⫺2
CACNA2D2
3p14
9F1
??
␣2␦ ⫺3
CACNA2D3
3p13
14A3
␣2␦ ⫺4
CACNA2D4
12p13
␥1
CACNG1
17q26
␥2
CACNG2
22q13
15D3
␥3
CACNG3
16p12
7F2
␥4
CACNG4
17q26
11E1
␥5
CACNG5
17q26
11E1
␥6
CACNG6
19q13.4
7A1
␥7
CACNG7
19q13.4
7A1
␥8
CACNG8
19q13.4
7A1
Cav␣2
Cav2.1 (␣12.1) (␣1A)
CACNA1A
19p13
8C3
Cav␥
Cav2.2 (␣12.2) (␣1B)
Cav2.3 (␣12.3) (␣1E)
CACNA1B
CACNA1E
9q34
1q25-31
2A3
1G1
??
Cav␣3
Cav3.1 (␣13.1) (␣1G)
CACNA1G
17q21
11D
ICa(T)?
Cav3.2 (␣13.2) (␣1H)
CACNA1H
16p13.3
17A3.3
ICa(T)?
Cav3.3 (␣13.3) (␣1I)
CACNA1I
22q13
Boxes denote cardiac expression.
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one of the four members of the Cav1 subfamily, Cav1.1,
Cav1.2, Cav1.3, or Cav1.4 (Table 3), for example, reveals L-type HVA Cav channel currents (92, 395),
whereas heterologous expression of Cav3 ␣-subunits
produces T-type LVA Cav channel currents (92, 395).
Numerous studies, exploiting both heterologous expression systems in vitro and transgenic strategies in vivo
(363), have provided important (and new) molecular insights into Cav channel composition and functioning in
cardiac (and other) cells. In the past decade, a number of
mutations in Cav channel ␣- and ␤-subunit genes have
also been identified in both humans and mice that result
in disorders of excitability, such as epilepsy, ataxia, periodic paralysis, and migraine (153, 245, 388, 402, 410). Until
very recently, there have been no established links between inherited disorders of myocardial membrane excitability and mutations in the subunits encoding cardiac
Cav channels. It has now been demonstrated, however,
that a de novo point mutation in the CACNA1C gene,
which encodes the Cav1.2 channel ␣-subunit, underlies
Timothy syndrome, a multisystem disorder with sporatic
inheritance (479). Individuals with Timothy syndrome
have profound cardiac arrhythmias, as well as dysfunc-
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
Physiol Rev • VOL
D. Cav Channel Accessory Subunits and Other
Interacting Proteins
There are a number of Cav accessory subunits that
coassemble with Cav␣1 (Fig. 5) and play a role in the
generation of functional Cav channels in cardiac, as well
as in other, cells. Three distinct types of Cav channel
accessory subunits, Cav␤, Cav␣2␦, and Cav␥ (Table 3), for
example, have been identified (28, 110). Of these subunits,
only the accessory Cav␤ and Cav␣2␦ subunits appear to
be expressed in the myocardium (Table 3) and to contribute to the formation of functional cardiac Cav channels
(110). The accessory Cav ␤-subunits are cytosolic proteins that assemble with Cav1 ␣-subunits and regulate the
expression of functional cell surface HVA Cav channels,
including cardiac L-type Cav channels. Four different
Cav␤ subunit-encoding genes, CACNB1, CACNB2,
CACNB3, and CACNB4, which encode the Cav␤1 (408,
434), Cav␤2 (222, 396), Cav␤3 (89, 222, 396), and Cav␤4
(89, 505) proteins, respectively, have been identified (Table 3). It appears, however, that Cav␤2 is most prominently expressed in the heart (222, 396). In each Cav␤
subunit, there are three variable regions flanking two
highly conserved domains (89, 222, 396, 408, 434, 505).
The variable regions are in the COOH termini, the NH2
termini, and a small (⬃100 amino acids) region in the
center of the linear protein sequence between the two
conserved domains (89, 222, 396, 408, 434, 505). The conserved domains of the Cav ␤-subunits mediate interactions with the pore-forming Cav ␣1-subunits, whereas the
variable domains influence the functional effects of Cav
␤-subunit coexpression on the properties of the resulting
Cav channels (407). In heterologous expression systems,
coexpression of Cav ␤-subunits with Cav ␣1-subunits
markedly increases Cav channel current amplitudes and
densities (59, 187, 541, 565), effects which could reflect
increased cell surface channel expression, increased
channel open probability, and/or the stabilization of the
Cav␣1-Cav␤ channel complexes in the cell membrane (98,
99, 565). In addition to increasing current amplitudes,
coexpression of Cav ␤-subunits also modifies the kinetics
and the voltage dependences of Cav current activation
and inactivation (70, 242, 279, 353).
A highly conserved sequence motif in Cav ␣1-subunits, called the alpha subunit interaction domain, appears to mediate ␣-subunit interaction(s) with accessory
Cav ␤-subunits (407). The Cav␣1 interaction domain (QqxExxLxGYxxWIxxxE) is located in the cytoplasmic loop
between domains I and II, exactly 24 amino acids from the
S6 transmembrane region of domain I (63, 64, 132, 211).
Interestingly, the Timothy syndrome mutation, G406R, is
close to this subunit interaction domain (479), suggesting
that the (G406R) mutations might disrupt Cav␣1-Cav␤
subunit-subunit interactions. Regions outside of this interaction domain, including low-affinity binding sites in
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tion in multiple organ systems, including the immune and
nervous systems (479).
All available molecular and biochemical evidence
suggests that Cav1.2, which encodes the ␣1C-subunit, is
the prominent Cav ␣-subunit expressed in the mammalian
myocardium. The CACNA1C gene is large, comprising 44
invariant and 6 alternative exons (474), and the Cav1.2
message is widely expressed. From the many possible
splice sites, a number of different variants of the ␣1C
protein, including Cav1.2a, Cav1.2b, and Cav1.2c, are generated (6, 348, 474, 475). Interestingly, although nearly
identical (⬎95%) in amino acid sequence, the various ␣1C
splice variants appear to be expressed in different cells/
tissues, and the cardiac specific isoform is Cav1.2a, which
encodes cardiac L-type HVA Cav channels (6, 92). Thus
similar to cardiac Nav channels and consistent with the
similarities in the properties of the L-type cardiac Cav
channel currents, it appears that a single pore-forming
␣1-subunit (Cav1.2a) is responsible for the generation of
HVA channels throughout the myocardium (92, 395). Interestingly, however, it has been reported that sinus node
dysfunction is seen in mice with a targeted disruption
(363) of the Cav1.3 ␣-subunit gene, CACNAID (585), suggesting that SA nodal HVA Cav channels are encoded by
Cav1.3, rather than by Cav1.2 (585). These observations
raise the interesting possibility that, with the right tools,
one would be able to manipulate selectively the functioning of atrial/ventricular (Cav1.2) and/or nodal (Cav1.3)encoded myocardial Cav channels.
The recently identified linkage between Timothy syndrome and a point mutation in the CACNA1C gene encoding Cav1.2a (479) demonstrates, as likely would have been
expected, that defective Cav channel (like defective Na
and Kv channel) functioning can lead to cardiac arrhythmias. The Timothy syndrome mutation is a missense mutation that results in a single amino acid change, glycine
(G) to arginine (R), at residue 406 (479), which is in the
cytoplasmic loop between domains I and II, immediately
C terminal to S6 transmembrane segment in domain I
(Fig. 3). Heterologous expression studies reveal that the
G406R mutation in Cav1.2a markedly reduces voltagedependent channel inactivation, resulting in increased
persistent inward Ca2⫹ current (479). The biophysical
consequence of the Timothy syndrome mutation in
Cav1.2a, therefore, is highly reminiscent of several Nav1.5
channel mutations associated with long QT and Brugada
syndromes that result in increased persistent inward Na⫹
currents (and in action potential prolongation). Interestingly, however, in contrast to the LQT and Brugada syndromes, Timothy syndrome is a multisystem disorder
(479). This latter observation is consistent with the hypothesis that Cav1.2a, unlike Nav1.5, is expressed widely
and that mutations in Cav1.2a result in phenotypic consequences in many different organ systems.
1223
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JEANNE M. NERBONNE AND ROBERT S. KASS
Physiol Rev • VOL
rents (250). In addition, the Cav ␥-subunits that are expressed in the nervous system, Cav␥2, Cav␥3, Cav␥4, and
Cav␥8, all have COOH-terminal PDZ-binding domain motifs (250). These observations suggest the interesting possibility that the Cav ␥-subunits play a role in controlling
the localization and/or trafficking of functional Cav channels (250). Interestingly, it has also been reported that
Cav␥2 interacts with the AMPA subtype of neuronal glutamate receptors, suggesting that the Cav ␥-subunits may,
like other channel accessory subunits, be multifunctional
proteins (96). Although Cav ␥-subunits appear to be
widely expressed in the nervous system (250), it is not
clear at present whether one or more of the CACNG genes
is expressed in the heart and/or if these subunits play a
functional role(s) in the generation of cardiac L-type Cav
channels. Clearly, further studies focused on exploring
this topic and determining directly the role(s) of the various Cav channel accessory subunits in the generation of
cardiac Cav channels are warranted.
As noted in section IIB, it is now very well documented that HVA myocardial Cav channels undergo rapid
Ca2⫹- and voltage-dependent inactivation (44, 166, 281,
326). Fundamentally important insights into the likely
molecular mechanism underlying the Ca2⫹-dependent
component of inactivation were revealed with the demonstration that the EF-hand domain containing protein,
calmodulin, that binds Ca2⫹ and modulates a variety of
Ca2⫹-dependent processes, is associated with the COOHterminal cytoplasmic domain of L-type HVA channels
(398). Several subsequent studies have provided many of
the molecular details of the calmodulin:Cav channel ␣1subunit association and interaction domains (17, 149, 293,
355, 428). In addition, the generality of the calmodulinmediated mechanism of Ca2⫹-dependent inactivation of
Cav channels was documented with the demonstration
that P/Q-type neuronal HVA channels are also regulated
by calmodulin binding (128).
In addition to the regulation of channel gating by
Ca2⫹ and calmodulin, the properties and the functional
expression of myocardial Cav channels are also regulated
by a variety of extracellular signals and intracellular signaling pathways. Prominent among these are the rather
well studied ␤-adrenergic G protein-coupled receptor-mediated augmentation of cardiac L-type Cav channel currents, increased Ca2⫹ entry, and positive inotropy (255,
509). Considerable experimental evidence suggests that
the pore-forming Cav1.2 ␣-subunit and Cav ␤-subunits are
targets of posttranslational modifications by a variety of
protein kinases that impact the functional cell surface
expression and the properties of cardiac L-type Cav channels (255, 509). It has also been reported that cardiac HVA
Cav channels are actually associated with ␤-adrenergic
receptors in macromolecular complexes that likely also
include heterotrimeric G proteins, adenylate cyclase, protein kinases, phosphatases and protein kinase A binding
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the COOH termini of the Cav ␣1-subunits, however, have
also been suggested to participate in Cav␤-Cav␣1 subunitsubunit interactions (412, 493, 523). Indeed, it now appears that these COOH-terminal regions in Cav ␣1-subunits also interact specifically with a second, highly conserved domain in the Cav ␤-subunits to produce the
observed modulatory effects of accessory Cav ␤-subunit
coexpression (131, 181).
In addition to the Cav ␤-subunits, another type of
accessory subunit, referred to as Cav␣2␦, has also been
shown to be part of functional Cav channel complexes
(146). Unlike Cav␤, the Cav␣2␦ subunits are transmembrane accessory subunits (Fig. 5), the first of which,
Cav␣2␦-1, was cloned from skeletal muscle (146). At least
four different Cav␣2␦-1 subunit-encoding genes,
CACNA2D1, CACNA2D2, CACNA2D3, and CACNA2D4,
have been identified (Table 3), and all produce heavily
glycosylated proteins that are cleaved posttranslationally
to yield ␣2 and ␦ proteins that then become linked via
disulfide bridges (Fig. 5). In each of the Cav␣2␦-1 complexes, the Cav␣2 domain is located extracellularly,
whereas the Cav␦ domain, which has a large hydrophobic
region, inserts into the membrane (Fig. 5) and serves as
an anchor to secure the entire (Cav␣2␦) complex (197,
198, 554). In contrast to the accessory Cav␤ subunits, the
functional roles of accessory Cav␣2␦ subunits are variable
and appear to depend, at least in part, on the identities of
the coexpressed Cav␣1 and Cav␤ subunits, as well as on
the expression environment. In general, however, coexpression of Cav␣2␦-1 shifts the voltage dependence of
activation of Cav␣/Cav␤-encoded channels, accelerates
current activation and inactivation, and increases current
amplitudes, compared with the channels/currents produced on expression of the Cav␣1 and Cav␤ subunits
alone (38, 158, 197, 198, 260, 472). The increase in functional cell surface Cav current densities on coexpression
of Cav␣2␦-1 (and Cav␤) subunits appears to reflect improved targeting of Cav ␣1-subunits to the plasma membrane (469). This effect (improved targeting) is produced
through interactions with Cav␣2, whereas the changes in
channel kinetics are attributed to the presence of the
Cav␦ protein (469).
A distinct type of Cav channel accessory subunit was
revealed with the identification of the Cav␥ subunit,
Cav␥1, that is expressed in mammalian skeletal muscle,
and that contributes to the formation of functioning of
skeletal muscle Cav channels (462). A number (seven) of
additional Cav␥-encoding genes, CACNG1-CACNG8 (Table 3), have now been identified in skeletal muscle and in
brain (250). All Cav␥ subunits have four transmembrane
spanning domains with the COOH and NH2 termini predicted to be intracellular (462). Coexpression of ␥-subunits with various combinations of Cav␣ and Cav␤ subunits has been shown to affect both the time- and the
voltage-dependent properties of the resulting Cav cur-
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
VI. MOLECULAR COMPONENTS OF
MYOCARDIAL KV CHANNELS
A. Kv Channel Pore-Forming ␣-Subunits
Similar to Nav and Cav ␣-subunits, voltage-gated K⫹
channel (Kv) pore-forming (␣) subunits (Fig. 3) belong to
the “S4” superfamily of voltage-gated channels (405). In
contrast to Nav and Cav channel ␣-subunits, however, Kv
␣-subunits are six transmembrane-spanning domain proteins (Fig. 3, B and C), and functional Kv channels comprise four ␣-subunits (Fig. 5). A very large number of Kv
␣-subunit genes have been identified, and a systematic
terminology for naming these subunits (Table 4) has been
developed (199). Heterologous expression of Kv ␣-subunits in the Kv1-Kv4 subfamilies reveals functional Kv
channels with distinct time- and voltage-dependent properties (116), whereas Kv ␣-subunits of the Kv5–9 subfamilies (Table 4) are electrically silent (88, 142, 221, 441).
Coexpression of Kv5-Kv9 subunits with Kv2 ␣-subunits,
however, attenuates the amplitudes of the Kv2-encoded
K⫹ currents (441). Nevertheless, the functional roles of
the “silent” Kv ␣-subunits in the generation of myocardial
Kv channels remains to be determined.
Physiol Rev • VOL
Further functional Kv channel diversity in cardiac
and other cells could, in principle, arise through alternative splicing of transcripts (29), as well as through the
formation of heteromultimeric channels (116) between
two or more Kv ␣-subunit proteins in the same Kv subfamily. Kv channel assembly, as well as the properties of
the resulting channels, are largely determined by the intracellular NH2- and COOH-terminal ␣-subunit domains
(100). Molecular and biochemical studies have revealed
that, of the many Kv1-Kv9 ␣-subunits identified, only a
small subset is expressed in the heart (Table 4). Although
many studies have characterized the detailed time- and
voltage-dependent properties of the various Kv ␣-subunitencoded Kv channels in heterologous expression systems,
these studies have provided little insight into the molecular correlates of functional cardiac Kv channels. The
difficulties encountered in these studies probably reflect
the fact that Kv channel properties depend on the expression environment (397), likely owing to cell-type specific
differences in posttranslational processing of the Kv
channel ␣-subunit proteins and/or the expression of Kv
channel accessory subunits or other Kv channel interacting, regulatory proteins (397).
Additional subfamilies of Kv ␣-subunit genes in the
KCNQ and KCNH subfamilies (Table 4) have been identified, and one member of each of these subfamilies,
KCNQ1 and KCNH2, has been shown to be the loci of
mutations leading to congenital long QT syndromes, LQT1
(Fig. 3C) and LQT2 (Fig. 3B), respectively (40, 119, 447,
448, 499, 528). Heterologous expression of human
KCNH2, which encodes the ether-a-go-go-related protein
ERG1, reveals Kv currents (448, 499) that are similar to
cardiac IKr (Table 4). Similar to SCN5A mutations linked
to the LQT3 and Brugada syndromes (Fig. 3A), LQT2
mutations in KCNH2 are found throughout the ERG1
protein sequence (Fig. 3B). These (LQT2) mutations are
all “loss of function” and result in reduced functional IKr
channel expression owing to dominant negative effects or
to alterations in channel processing or trafficking (23, 126,
220, 246, 253, 273, 584). Interestingly, a novel “gain of
function” mutation in KCNH2, which results in increased
IKr channel densities, has recently been identified and
linked to one form of short QT syndrome (78).
There are six additional members of the KCNH subfamily, KCNH3-KCNH8 (Table 4). Two of these, KCNH3
and KCNH4, appear to be nervous system specific (465),
and it is presently unclear whether any of the others are
present in the myocardium. Alternatively processed forms
of KCNH2, with unique NH2 and COOH termini, however,
have been cloned from both mouse and human heart
cDNA libraries and postulated to contribute to the generation of functional cardiac IKr channels (272, 282, 304).
Indeed, coexpression of the NH2-terminal splice variant
ERG1b with the full-length ERG1a produces Kv currents
that more closely resemble cardiac IKr than the currents
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proteins, or AKAPs (18, 122), which appear to subserve a
scaffolding function (18). Unlike Nav channels, however,
no direct links between cardiac Cav channel subunits and
actin or actin-binding proteins have been demonstrated to
date. Nevertheless, a number of Ca2⫹-binding proteins,
including calmodulin, have been shown to be linked both
directly and indirectly to the actin cytoskeleton (452). In
addition, it has been reported that the time- and voltagedependent properties of L-type HVA channels are altered
in skeletal muscle from dystrophin-deficient animals, an
effect interpreted as resulting from remodeling of the
subcellular actin cytoskeleton (111). Similarly, neuronal
HVA Cav channel inactivation is differentially affected by
agents that stabilize and destabilize the actin cytoskeleton
(239). In retinal ganglion neurons, for example, stabilization or disruption of the actin cytoskeleton affects functional cell surface Cav channel expression (454). It seems
reasonable to suggest, therefore, that Cav channels interact directly or indirectly with the actin cytoskeleton (556)
and that, similar to cardiac Nav channels, the functioning
of myocardial Cav channels likely also depends importantly on interactions with the actin cytoskeleton. In support of this hypothesis, targeted deletion of endothelial
NOS eliminates the muscarinic modulation of myocardial
L-type Cav channels (202). Further investigations focused
on delineating the molecular mechanism controlling functional Cav channel expression will be needed to define the
role of the cytoskeleton in regulating myocardial Cav (and
Nav) channel expression and functioning.
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TABLE
JEANNE M. NERBONNE AND ROBERT S. KASS
4.
Diversity of voltage-gated K⫹ (Kv) channel ␣-subunits
Locus
Subfamily
Protein
Gene
Human
Locus
Mouse
Cardiac
Current
Kv1
Subfamily
Protein
Gene
Human
Mouse
Cardiac
Current
Kv8
Kv1.1
KCNA1
12p13
6F2
Kv1.2
KCNA2
1p11
3F2.2
Kv1.3
KCNA3
1p21
3F2.2
IK,slow
(IK,DTX)
Kv9
Kv8.1
KCNV1
8q21.1
Kv8.2
KCNV2
9p24
Kv9.1
Kv9.2
KCNS1
KCNS2
20q12
2H3
Kv9.3
KCNS3
2p25
15B3.1
KCNA4
11p14
2E2
Ito,s
KCNA5
12p13
6F2
IKur
Kv1.6
KCNA6
12p13
6F2
eag
KCNH1
1q32
1H6
Kv1.7
KCNA7
19q13
7B3
erg1
KCNH2
7q36
5A3
Kv1.10
KCNA10
1p11
erg2
KCNH3
erg3
KCNH4
erg4
KCNH5
14q22
IK,slow2
erg5
KCNH5
17q24
??
erg6
KCNH7
2
erg7
KCNH8
3p24
KvLQT1
KCNQ1
11p15
IK,slow1
eag
Kv2
Kv2.1
KCNB1
20q13.1
Kv2.2
KCNB2
8q13
2H3
Kv3
IKr
15
17q21
2C1.1
KvLQT
Kv3.1
KCNC1
11p15
Kv3.2
KCNC2
12q21
7B3
IKs
7F6
Kv3.3
KCNC3
19q13.4
7B2
KCNQ2
KCNQ2
20p11.1
2H4
Kv3.4
KCNC4
1p11
3F2.2
KCNQ3
KCNQ3
8q24.3
15D1
Kv4.1
KCND1
Xp11.2
Kv4
??
Kv4.2
KCND2
7q32
6A2
Ito,f
Kv4.3
KCND3
1p11
3F2.2
Ito,f
Kv5.1
KCNF1
2p25
Kv6.1
KCNG1
20q13.1
Kv6.2
KCNG2
18q23
Kv6.3
KCNG3
2p21
Kv6.4
KCNG4
16q24
KCNQ4
KCNQ4
1p34.3
KCNQ5
KCNQ5
6q11
Kv5
??
Kv6
17E3
Boxes denote cardiac expression.
produced on expression of ERG1a alone (304). Although
it has been reported that only the full-length ERG1 protein(s) are detected in adult rat, mouse, and human hearts
(404), raising some doubts about the functional significance of alternative splicing of KCNH2 transcripts, more
recent studies have identified ERG1b protein in adult rat,
human, and canine heart (240). Presumably, these disparate results reflect the fact that different anti-ERG1 antibodies were used (240, 404). Further studies will be
needed to explore this and other possible explanations.
Using antibodies targeting the specific ERG1 isoforms, it
Physiol Rev • VOL
was also demonstrated that ERG1a and ERG1b coimmunoprecipitate from heart, suggesting that functional cardiac IKr channels reflect the heteromeric assembly of
ERG1a and ERG1b subunits (240). The expression, distribution, and functioning of the COOH-terminal variant of
ERG, ERG-USO (272), in contrast, remains to be explored.
As noted previously, mutations in the KCNQ1 gene
have been linked to LQT1 (253, 329). Heterologous expression of KvLQT1 (KCNQ1) alone yields rapidly activating and noninactivating outward Kv currents, whereas
coexpression with the Kv channel accessory subunit,
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Kv1.4
Kv1.5
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
Physiol Rev • VOL
FIG. 7. Simulations reveal the effects of loss of function (LQT1) and
gain of function (short QT) mutations in KCNQ1. Steady-state action
potential waveforms (A and C) and outward IKs currents (B and D) were
simulated (103, 105). Control action potential and current waveforms
simulated for wild-type KCNQ1-encoded IKs currents are depicted as the
solid black lines in A–D. The corresponding simulated voltage and
current waveforms depicting the effects of KCNQ1 mutations are illustrated by the dashed purple (LQT1) and red (short QT) lines in A–D.
“Loss of function” LQT1 mutations (Fig. 3C), resulting in a decrease in
the maximum amplitude and a slowing of the time to peak of IKs (B),
lead to marked action potential prolongation (A). In contrast, “gain of
function” short QT mutations in KCNQ1 increase the maximal amplitude
of IKs (D) and shorten action potential durations.
B. Kv Channel Accessory Subunits
Similar to the Nav and Cav channels, a number of
different types of Kv channel accessory subunits have
been identified (Table 5) and postulated to contribute to
the generation of functional myocardial Kv channels. The
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minK (see sect. VB), produces slowly activating K⫹ currents that resemble the slow component of cardiac delayed rectification, IKs (40, 447). Similar to the SCN5A
mutations linked to the LQT3 and Brugada syndromes
(Fig. 3A) and KCNH2 mutations linked to LQT2 (Fig. 3B),
KCNQ1 mutations linked to LQT1 have been identified
throughout the protein sequence (Fig. 3C). Expression
studies suggest that the various LQT1-associated mutations in KCNQ1 are all loss of function, resulting in reductions in functional IKs cell surface channel expression.
Simulations demonstrate that reductions in IKs density
(Fig. 7B) result in markedly prolonged ventricular action
potential waveforms (Fig. 7A). Given the intrinsic heterogeneities in IKs (and other) channel densities and action
potential waveforms throughout the myocardium (Fig. 1),
the effects of LQT1 mutations in KCNQ1 might also be
heterogeneous, further impacting the arrhythmogenic potential of these mutations. Importantly, a novel “gain of
function” mutation in KCNQ1 (V307L) was identified and
linked to short QT interval syndrome (46). Heterologous
expression studies revealed that expression of KCNQ1
V307L, alone or with wild-type KCNQ1, in the presence of
KCNE1, produces IKs-like currents with markedly altered
activation kinetics and voltage-dependent properties (46)
relative to the channels produced by wild-type KCNQ1
and KCNE1. A gain of function mutation (S140G) in
KCNQ1 has also been identified in a family with hereditary persistent atrial fibrillation (97). Computer simulations incorporating the KCNQ1 short QT mutant channels
reveal that IKs densities are increased (Fig. 7D) and that
action potentials are shortened markedly (Fig. 7C). As
noted above for LQT1 mutations, the impact of gain of
function mutations in KCNQ1 on different cell types and
regions of the heart will likely be heterogeneous, owing to
the existing heterogeneity in IKs (and other current) densities and action potential waveforms, an effect which
may acerbate the arrhythmogenic potential of alterations
in IKs densities.
Similar to the multiplicity of ␣-subunits in the Kv and
the KCNH subfamilies, there are a number (four) of additional members of the KCNQ subfamily (Table 4), although none of these appears to be expressed in heart.
Two of the KCNQ subfamily members, KCNQ2 and
KCNQ3, however, are expressed in the nervous system
and have been identified as loci of mutations leading to
benign familial neonatal convulsions (65, 329, 453, 526).
Heterologous expression of KCNQ2 or KCNQ3 results in
the generation of slowly activating, noninactivating K⫹selective channels that also deactivate very slowly on
membrane repolarization (329, 453, 526). Interestingly,
the properties of the heteromeric KCNQ2/KCNQ3 channels closely resemble neuronal muscarinic acetylcholine
receptor regulated ion channel currents, typically referred
to as “M” currents/channels (329, 526).
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JEANNE M. NERBONNE AND ROBERT S. KASS
TABLE
5.
Family
Auxiliary Kv channel subunits
Subunit
Gene
Human
Mouse
Current
Kv␤
Kv␤1
KCNAB1
3q25
3D
??
Kv␤2
KCNAB2
1p36.3
4E2
??
Kv␤3
KCNAB3
17p13
11B3
Mink
KCNE1
21q22
16C4
IKs
KCNE
KCNE2
21q22
16C4
IKr??, Ito,f??
KCNE3
11q13
7E1
??
MiRP3
KCNE4
2q36.3
MiRP4
KCNE5
Xq22
XF1
KChAP
PIAS3
1q12
3F1
KChIP1
KCNIP1
5q35
11A4
KChIP2
KCNIP2
10q25
19C3
KChIP3
KCNIP3
KChIP4.2
CSEN
2q11.1
2F1
KChIP4.3
KCNIP4
4p15.3
NCS-1
FREQ
9q34
KChAP
Ito,f??, IK??
KChIP
Ito,f, others??
NCS
2A3
Ito,f, others??
Boxes denote cardiac expression.
first of these was cloned from human (362), and later from
rat (170), heart and was referred to as minK, i.e., “minimal
K⫹” channel subunit. MinK, which is encoded by the
KCNE1 gene on chromosome 21 in human (Table 5), is a
small (130 amino acids) protein with a single transmembrane spanning domain (170, 288, 362). Although initial
characterizations of minK in Xenopus oocytes suggested
that this small protein could produce functional Kv channels when expressed alone (170, 362), subsequent studies
demonstrated the presence of a KCNQ1 homolog in oocytes that combines with the heterologously expressed
minK to generate Kv channels that very closely resemble
cardiac IKs (447). As noted above, these observations have
led to suggestions that minK coassembles with the KvLQT1 protein to produce functional cardiac IKs channels
(40, 447). It has also been reported, however, that minK
coassembles with the ERG1 protein in heterologous expression systems, observations interpreted as suggesting
a role for minK in the generation of cardiac IKr channels
(341). It has become increasingly clear, however, that
accessory Kv subunits, such as minK, can, at least in
heterologous expression systems, associate with multiple
different Kv␣ subunits. It is not a given, however, that
these interactions occur in intact tissues. As a result, it is
presently unclear whether minK subunits actually associate with both KvLQT1 and ERG1 (and other Kv?) ␣-subunits in the myocardium and contribute to the function of
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MiRP1
MiRP2
both cardiac IKs and IKr (and other Kv?) channels. Biochemical studies focused on exploring these questions
are clearly warranted. Although the details of minK functioning remain to be clarified, it is important to emphasize
that the physiological significance of this subunit in the
generation of cardiac membrane currents was clearly
demonstrated with the identification of mutations in
KCNE1 that are associated with one type of inherited long
QT syndrome, LQT5 (62, 478, 481).
Several additional members of the minK-related peptide, MiRP (KCNE), subfamily (Table 5) have also been
identified and characterized in coexpression studies with
Kv ␣-subunits (1–3, 339). One of these, MiRP1 (KCNE2),
has been suggested to function as an accessory subunit of
ERG1 (KCNH2) to generate cardiac IKr (1, 5). As noted
above, however, it has previously also been suggested
that minK associates with ERG1 to produce IKr channels
(341). Although the resolution of this seeming controversy must await further experimentation, particularly
biochemical studies, it is reasonable to conclude that
MiRP1 (KCNE2) is functionally important in the regulation of myocardial membrane excitability, as evidenced
by the fact that KCNE2 variants are associated with sporadic and drug-induced long QT syndromes (5, 227, 457,
478). It is also interesting to note that studies in heterologous systems have revealed that the MiRP subfamily of
Kv channel accessory subunits can assemble with Kv
␣-subunits in several different subfamilies (4, 583) to
modify the properties and/or the cell surface expression
of Kv ␣-subunit-encoded channels. Heterologous expression studies, for example, have shown that MiRP1 also
interacts with Kv4 ␣-subunits (583). In addition, it has
been demonstrated that MiRP2 (KCNE3) forms Kv channels with Kv3.4 ␣-subunits in skeletal muscle and that
mutations in MiRP2 result in reduced Kv3.4-encoded Kv
current densities, membrane depolarization, and periodic
paralysis (4). Biochemical and coexpression studies have
also suggested that MiRP1 can associate with hyperpolarization-activated cyclic nucleotide-gated (HCN) cation
channels, suggesting a distinct function for the MiRP1
subunit in the regulation of myocardial pacemaker currents, rather than, or in addition to, the regulation of
myocardial Kv channels (574). Taken together, these observations suggest the interesting possibility that members of the KCNE subfamily might be multifunctional
proteins, coassembling with several different Kv (3)
and/or other (e.g., HCN) ion channel pore-forming ␣-subunits and contributing to the formation of multiple types
of cardiac Kv (and other) channels. Experiments focused
on testing this hypothesis and on defining the functional
roles of the various MiRP (KCNE) subunits in the generation of myocardial Kv (and other) channels will be of
considerable interest.
Another type of Kv channel accessory subunit was
revealed with the biochemical identification (360) and
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Coexpression of Kv␤1 subunits has also been reported to
modulate the cell surface expression of Kv4.3-encoded
currents, an effect attributed to Kv␤1 binding to the
COOH terminus of Kv4.3 (566). In addition, although without any detectable effect on current properties or densities, coexpression (in Xenopus oocytes) of Kv␤1.2 with
Kv4.2 ␣-subunits modulates the redox sensitivity of Kv4.2encoded channels (393).
Similar to the KCNE subfamily of Kv accessory subunits, therefore, the functional roles assigned to the Kv
␤-subunits in the generation of myocardial Kv channels
have been largely a matter of speculation. Interestingly,
however, recent studies, completed on ventricular myocytes isolated from mice with a targeted disruption in the
Kv␤1 locus, reveal that the loss of Kv␤1 affects the functional cell surface densities of Kv4- and Kv2-encoded, but
not Kv1-encoded, Kv channels (12). It has also been reported that Kv ␤-subunits associate with ␣-subunits of the
eag (KCNH) subfamily (553). On the basis of all the
available data, therefore, it seems reasonable to suggest
that the Kv ␤-subunits subserve multiple functions in the
generation of myocardial Kv channels. Further studies
focused on providing the molecular details of Kv ␤-functioning are clearly warranted.
A novel Kv channel accessory protein, KChAP (K⫹
channel accessory protein) (Table 5), was identified in a
yeast two-hybrid screen using the NH2 terminus of Kv4.2
as the bait (550). Sequence analysis of KChAP revealed a
574-amino acid protein with no transmembrane domains
and no homology to Kv ␣- or Kv ␤-subunits (550). Coexpression of KChAP with Kv2.1 (or Kv2.2) in Xenopus
oocytes, however, markedly increases functional Kv2.xinduced current densities without measurably affecting
the time- and/or voltage-dependent properties of the currents (550), suggesting that KChAP functions as a chaperone protein (277). Yeast two-hybrid assays also revealed that KChAP interacts with the NH2 termini of
␣-subunits in the Kv1 subfamily and with the COOH termini of Kv ␤1-subunits (278, 550). Interestingly, it was
subsequently demonstrated that KChAP belongs to the
protein inhibitor of the activated STAT family of proteins
that interact with a variety of transcription factors and
play a role in programmed cell death (549). The relationship between the apoptotic and chaperone functions of
KChAP, as well as the functional role of KChAP in the
generation/regulation of Kv channels in the normal and
the diseased myocardium, however, remain to be determined.
With the use of the intracellular NH2 terminus (amino
acids 1–180) of Kv4.2 as the “bait” in a yeast two-hybrid
screen, three novel Kv channel interacting proteins,
KChIP1, KChIP2, and KChIP3 (Table 5), were identified
(21). The KChIPs belong to the recoverin family of neuronal Ca2⫹-sensing (NCS) proteins, particularly in the
“core” regions, which contain multiple EF-hand domains
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subsequent cloning (419) of low molecular mass (⬍45
kDa) cytosolic Kv ␤-subunits from brain. Three distinct,
but homologous, Kv ␤-subunits, Kv ␤1, Kv ␤2, and Kv ␤3,
encoded on three different (KCNAB) genes (Table 5), as
well as alternatively spliced transcripts (337), have now
been identified (90, 124, 147, 148, 317, 352). Of these,
Kv␤1.1, Kv␤1.2, Kv␤1.3, and Kv␤2 have been shown to be
expressed in the heart (12, 90, 124, 147, 148, 278, 317, 352).
The Kv ␤-subunits share a conserved COOH-terminal
“core” region, related in amino acid sequence to aldoketone reductases, members of the triose phosphate
isomerase enzyme family (101, 338). The NH2-terminal
domains of the Kv ␤-subunits are unique, and members of
the Kv␤1 subfamily, as well as Kv␤3.1, have long NH2terminal sequences that are structurally similar to the
Shaker (Kv1) channel inactivation gate that functions in a
“ball and chain”-like mechanism (217) to accelerate Kv1
channel inactivation (300 301). Although the core region
of the Kv ␤-subunits contains an NAPH/NADPH binding
site (101, 338) and Kv ␤-subunits crystallize with NADPH
bound (191), the role of this binding in regulating the
functional interactions between Kv ␤- and Kv ␣-subunits
and/or in controlling the expression/properties of the resulting Kv channels has not been defined.
Previous studies have demonstrated that the Kv
␤-subunits interact with the intracellular T1 tetramerization domain of the Kv ␣-subunits of the Kv1 subfamily,
combining in a 1:1 stoichiometric ratio (190, 192). Heterologous coexpression studies have revealed that Kv
␤-subunits affect the functional properties and the cell
surface expression of Kv1 ␣-subunit-encoded channels (9,
10, 90, 147, 148, 317, 352, 464). In some cases, the functional consequences of Kv␤ coexpression have been
shown to be Kv1 ␣-subunit specific (10). Coexpression of
Kv␤2, for example, increases the expression of Kv1.2encoded channels and decreases the expression of Kv1.5encoded channels (9, 10). Because Kv1␣ and Kv␤ subunits coassemble in the endoplasmic reticulum (369), the
observed increases in functional cell surface Kv1-encoded
channel expression suggest that the Kv␤ subunits affect
Kv1 channel assembly, processing or stability or, possibly,
function as chaperone proteins.
The facts that the Kv ␤-subunits were originally identified in association with Kv1 ␣-subunits (360) and that
heterologous expression studies suggest that Kv␤1 and
Kv␤2 interact only with the Kv1 ␣-subunits (370, 458)
have been interpreted as suggesting that the Kv ␤-subunits function as specific accessory subunits in the generation of Kv channels encoded by Kv1 ␣-subunits. In
expression systems, however, Kv␤3 has also been shown
to interact specifically with Kv2 subunits (167). Biochemical studies also suggest that Kv ␤-subunits might well be
functionally more diverse (370, 393, 458). Both Kv␤1.1 and
Kv␤1.2, for example, coimmunoprecipitate with Kv4
␣-subunits following coexpression in COS-1 cells (370).
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revealed that Kv4␣ and KChIP accessory subunits assemble in a 4:4 stoichiometry and provide new insights into
the intracellular interactions between the NH2 termini of
Kv4 subunits and the EF hand domains of the KChIPs
(258, 588). In addition, it had been shown that myristoylation of KChIP1 appears necessary for the normal trafficking of newly synthesized (KChIP1) protein to the endoplasmic reticulum where the association with Kv4
␣-subunits occurs (385). It may be that palmitoylation of
KChIP2 and KChIP3 plays a similar functional role. Mutagenesis and structural studies have also revealed that
two regions in the NH2 termini of Kv4 subunits are necessary for KChIPx interaction with (and modulation of)
Kv4-encoded channels and that residues 71–90 (in Kv4.x)
form a “contact loop” that mediates the interaction with
the KChIP protein(s) (451).
Biochemical methods were exploited in efforts that
led to the identification of another Kv channel accessory
subunit, DPPX or DPP6, that also appears to interact
specifically with Kv4 ␣-subunits (368). A novel protein of
previously unknown function, DPP6 is structurally related
to CD26, which is a dipeptidyl aminotransferase and a cell
adhesion protein (368). Interestingly, DPP6 actually belongs to a family of nonclassical serine proteases, although DPP6 itself has no enzymatic activity (368). In
contrast to the KChIPs, DPP6 is an integral membrane
glycoprotein with a rather large extracellular COOH-terminal domain (368). Coexpression of DPP6 with Kv4
␣-subunits affects the trafficking and the membrane targeting of Kv4 ␣-subunits and modifies the kinetic properties of expressed cell surface Kv4-encoded channels
(368). Although expressed in brain and thought to function in the generation of neuronal Kv4-encoded transient
outward Kv currents, DPP6 does not appear to be expressed in heart and, therefore, cannot contribute to the
formation of functional cardiac Kv channels. Another
member of the dipeptidyl transferase family, DPP10, has
also been shown to associate with Kv4 ␣-subunits in
heterologous expression systems and to modify the biophysical properties of Kv4.x-encoded channels (235). The
effects of DPP10 on Kv4 channels are qualitatively similar
to the effects of DPP6 (235), although, like DPP6, DPP10
also appears to be expressed predominantly in the brain
(235). It also seems unlikely, therefore, that DPP10 plays
a role in the generation of cardiac Kv channels. It is
certainly possible, however, that there are additional
members of this family that are expressed in the myocardium and that remain to be identified and characterized.
C. Molecular Correlates of Cardiac Transient
Outward Kv Channels
All available evidence suggests that Kv ␣-subunits of
the Kv4 subfamily encode rapidly activating, inactivating,
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(81). Unlike other NCS-1 proteins, however, KChIP2 and
KChIP3 lack NH2-terminal myristoylation sites, and the NH2
termini of each of the KChIP proteins are unique (21). Nevertheless, KChIP2 and KChIP3 have several potential palmitoylation (on cysteine residues) sites, and metabolic labeling
studies suggest that these sites are palmitoylated in situ
(491). It is now clear that KChIP3 is identical to the previously identified protein calsenilin, which is a Ca2⫹-binding
protein that interacts with presenilin-1 and presenilin-2 and
regulates the proteolytic processing of these two proteins
(82). In addition, however, KChIP3 is also identical to another previously identified protein called DREAM, which is
a Ca2⫹-regulated transcriptional repressor (87). The DREAM
protein has been shown to bind to the downstream regulatory elements (DRE) of several genes in the absence of Ca2⫹
and to dissociate from the DRE sequence when Ca2⫹ is
elevated (87). Thus DREAM is thought to act as an activitydependent regulator of gene expression (87). An additional
member of the KChIP family, KChIP4, also referred to as
calsenilin-like-protein or CALP, was subsequently identified
in biochemical studies focused on identifying the binding
partners of the presenilin proteins (356). The interactions
between KChIP3 (calsenilin) and KChIP4 (CALP) and the
presenilin proteins are also Ca2⫹ dependent (356).
Of the four KChIP genes, only KChIP2 appears to be
expressed in the heart (21, 431). There are, however,
numerous splice variants of KChIP2 that have now been
identified (33, 125, 129, 390, 391, 430, 431). Studies in
heterologous systems have revealed that coexpression of
any one of the (full-length) KChIP proteins with Kv4
␣-subunits increases the functional cell surface expression of Kv4.x-encoded Kv channels, slows current inactivation, speeds recovery from inactivation and shifts the
voltage dependence of channel activation (21, 193, 195).
In contrast, KChIP expression reportedly does not affect
the properties or the densities of the K⫹ currents produced on expression of other Kv ␣-subunits, including
Kv1.4 and Kv2.1 (21). These observations were interpreted as suggesting that the modulatory effects of the
KChIP proteins are specific for ␣-subunits of the Kv4
subfamily (21). In addition, although the binding of the
KChIP proteins to Kv4 ␣-subunits is not Ca2⫹ dependent,
mutations in EF hand domains 2, 3, and 4 of KChIP1
reportedly eliminate the modulatory effects of KChIP1 on
Kv4.2-encoded K⫹ currents in CHO cells (21). It has,
however, also been reported that a splice variant of
KChIP2, KChIP2d, which lacks three of the four EF hand
domains of full-length KChIP2, modifies the inactivation
kinetics of heterologously expressed Kv4.3-encoded K⫹
currents, but does not alter the kinetics of channel recovery from steady-state inactivation (390). Taken together,
these findings suggest that distinct regions of the (fulllength) KChIP proteins underlie the various modulatory
effects of KChIPs on the properties and cell surface expression of Kv4-encoded channels. Structural analysis has
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(193, 431), and it appears that differences in Kv4.2 expression underlie the regional variations in Ito,f densities in
rodents (137, 193). Thus there seem to be two potentially
important differences between Ito,f in rodents and Ito,f in
large mammals, including humans. In rat and mouse, Ito,f
channels reflect the heteromeric assembly of Kv4.2,
Kv4.3, and KChIP2, and differences in Kv4.2 expression
underlie regional differences in Ito,f densities. In large
mammals, however, Ito,f channels appear to be produced
by the coassembly of Kv4.3 and KChIP2, and KChIP2
appears to be the primary determinant of the observed
regional differences in Ito,f densities.
Although the Kv␤ accessory subunits were originally
identified based on association with Kv1 ␣-subunits and
have been considered to be Kv1 ␣-subunit specific, recent
studies suggest a functional role for Kv␤1 subunits in the
generation of cardiac Ito,f channels (12). Electrophysiological studies, for example, have revealed that Ito,f densities are decreased in ventricular myocytes isolated from
mice bearing a targeted deletion of the KCNAB1 gene,
which encodes Kv␤1 subunits (12). In addition, biochemical studies revealed that Kv4.2 and Kv4.3 coimmunoprecipitate with the Kv␤1 splice variants, Kv␤1.1 and Kv␤1.2,
from adult mouse ventricles (12). Taken together, these
observations suggest that (mouse) ventricular Ito,f channels function as multimeric protein complexes comprising the Kv4.2 and Kv4.3 pore-forming ␣-subunits and the
accessory Kv␤1.1, Kv␤1.2, and KChIP2 subunits (Fig. 5).
The targeted disruption of Kv␤1 reduces the cell surface
membrane expression of Kv4 ␣-subunits (12), further suggesting that Kv␤1 functions to regulate the assembly
and/or the trafficking of mouse ventricular Ito,f channels
from the endoplasmic reticulum to the cell surface (12).
The Kv␤1 COOH-terminal “core” domain has been
shown to interact with NH2-terminal tetramerization (T1)
domains in Kv1 ␣-subunits (191), and recent studies suggest that Kv4 ␣-subunit NH2-terminal domains structurally
resemble Kv1 T1 domains (451). It seems reasonable to
suggest, therefore, that Kv4 NH2 termini are likely involved in mediating the interaction with Kv␤1 subunits.
As noted above, however, it has also previously been
demonstrated that Kv4 ␣-subunit NH2-terminal domains
are also important in mediating the interactions with
KChIPs (21, 451). Taken together, these observations suggest that Kv4 NH2-terminal domains are multifunctional,
mediating ␣-subunit/␣-subunit interactions, as well as the
associations with the accessory KChIP2 and Kv␤1 subunits. It has also been reported, however, that Kv␤1 subunits regulate the cell surface expression of Kv4.3 subunits in heterologous expression systems through interactions with the COOH, not the NH2, terminus (566). It is
not clear if Kv␤1 subunits play a role in the generation of
Ito,f (and/or other) channels in large mammals, including
humans, primarily because this possibility has not been
explored directly. Given the heterogeneity of subunits
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and recovering cardiac transient outward Kv channels
referred to as Ito,f (Table 1). In rat and mouse ventricular
myocytes exposed to antisense oligodeoxynucleotides
(AsODNs) targeted against Kv4.2 or Kv4.3, for example,
Ito,f density is reduced by ⬃50% (169, 193). Significant
reductions in rat ventricular Ito,f density are also seen in
cells exposed to an adenoviral construct encoding a truncated Kv4.2 subunit (Kv4.2ST) that functions as a dominant negative (238). In addition, it has been reported that
Ito,f is eliminated in ventricular myocytes isolated from
transgenic mice expressing a pore mutant of Kv4.2,
Kv4.2W362F, that functions as a dominant negative,
Kv4.2DN (43). Taken together, these results demonstrate
that members of the Kv4 subfamily underlie Ito,f in mouse
and rat ventricles. Biochemical studies have also shown
that Kv4.2 and Kv4.3 are associated in adult mouse ventricles, suggesting that functional mouse ventricular Ito,f
channels reflect the heteromeric assembly of the Kv4.2
and Kv4.3 ␣-subunits (193). Given that the properties of
the currents classified as Ito,f in other species (Table 1)
are very similar to mouse (and rat) Ito,f, it seems reasonable to suggest that Kv4 ␣-subunits also underlie Ito,f in
other species. In dog and human myocardium, however,
Kv4.2 appears not to be expressed (266), suggesting that
only Kv4.3 contributes to Ito,f in larger mammals. Direct
biochemical and/or molecular evidence to support this
hypothesis, however, has not been provided to date. In
addition, multiple splice variants of Kv4.3 have been identified in human (387) and rat (490) heart, although the
functional roles of these variants in the generation of
cardiac Ito,f channels remain to be determined.
It has been demonstrated that KChIP2 coimmunoprecipitates with Kv4.2 and Kv4.3 ␣-subunits from adult
mouse ventricles, consistent with a role for this subunit in
the generation of functional Kv4-encoded mouse ventricular Ito,f channels (193). An important structural role of
KChIP2 in the generation of myocardial Ito,f channels is
suggested by the observation that Ito,f is eliminated in
ventricular myocytes isolated from mice with a targeted
disruption of the KChIP2 locus (271). In both canine and
human heart, it has been demonstrated that there is a
gradient in KChIP2 message expression across the thickness of the (left and right) ventricular walls (429, 431),
observations interpreted as suggesting that KChIP2 underlies the observed differences in Ito,f densities in myocytes isolated from the epicardial, midmyocardial, and
endocardial layers of the (human and canine) ventricles
(429, 431). Although this point remains somewhat controversial (129), it has been reported that KChIP2 protein
expression in canine ventricles parallels KChIP2 message
expression (429), lending further support to the hypothesis that KChIP2, not Kv4.3, underlies the gradient in canine (and human) ventricular Ito,f densities. In rat and
mouse, however, there is no detectable gradient in
KChIP2 message or protein expression in the ventricles
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ventricles of Kv4.2DN-expressing transgenic animals (43,
194, 196), suggesting that electrical remodeling occurs in
the myocardium when Ito,f is eliminated. When the
Kv4.2DN transgene is expressed in the Kv1.4 ⫺/⫺ null
background, however, both Ito,f and Ito,s are eliminated
and, interestingly, no further electrical remodeling is evident (194). Indeed, electrophysiological recordings from
Kv4.2DN-expressing Kv1.4 ⫺/⫺ cells revealed that the
waveforms of the Kv currents in RV, LV, and interventricular septum cells are indistinguishable (194). Although
these observations suggest that the molecular mechanisms underlying the observed electrical remodeling in
Kv4.2DN ventricles is highly specific for Kv1.4, it is presently unclear which of the many possible transcriptional,
translational, and/or posttranslational mechanisms (430)
might be operative. Future studies focused on delineating
the molecular mechanisms involved in the regulation of
ion channel remodeling in this and other mouse models
will likely provide important new mechanistic insights.
D. Molecular Correlates of Cardiac Delayed
Rectifier Kv Channels
As noted above, KCNH2 has been identified as the
locus of mutations underlying one form of familial long
QT syndrome, LQT2 (119). Heterologous expression of
KCNH2 cRNA in Xenopus oocytes reveals voltage-gated,
inwardly rectifying K⫹-selective channels with properties
similar to cardiac IKr channels (448, 499), observations
interpreted as suggesting that KCNH2 encodes IKr (448).
Subsequent studies identified NH2- and COOH-terminal
splice variants of the ERG1 protein (272, 282, 304), and
recent biochemical studies suggest that an NH2-terminal
ERG1 splice variant, ERG1b, coassembles with the fulllength ERG1a protein to form heteromeric IKr channels in
rat, human, and canine heart (240). The role of the COOHterminal variants of ERG1, ERG1-USO (272) in the generation of functional cardiac IKr channels, however, is presently unclear. It has been reported that heterologously
expressed KCNH2 and minK (KCNE1) coimmunoprecipitate (341) and that antisense oligodeoxynucleotides targeted against minK attenuate IKr amplitudes in AT-1 (an
atrial tumor line) cells (567). It has also been reported
that heterologous coexpression of another member of the
KCNE subfamily of accessory subunits, MiRP1 (KCNE2),
modifies the properties of KCNH2-encoded Kv currents
(5). It is presently unclear, however, whether the minK or
MiRP1 (or both) accessory subunits associate with
ERG1a and/or ERG1b in adult human heart and contribute to the generation of functional cardiac IKr channels.
The availability of specific anti-ERG1 antibodies that can
be exploited to immunoprecipitate ERG1 proteins from
heart (240) should make it possible to explore directly the
association between the minK/MiRP accessory subunits
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that can affect Kv4 channel properties in heterologous
expression systems (130), it seems reasonable to suggest
that additional accessory subunits or regulatory proteins
might be involved in mediating the interaction(s) between
Kv4␣ and Kv␤1 subunits. It is certainly also possible that
the interactions between Kv4␣ and Kv␤1 subunits are
indirect, mediated, for example, by other accessory subunits, such as KChIP2 or KChAP (278) or through scaffolding proteins (39) or components of the actin cytoskeleton (401, 529). In addition, there could well be further
complexity in the subunit composition of Ito,f channels, as
well as in Ito,f channel regulation and posttranslational
processing in some cell types/species. Further studies
focused on defining all of the molecular components of
functional myocardial Ito,f (and other) channels are
needed to provide insights into the detailed molecular
mechanisms involved in the regulation and modulation of
these channels in the normal and in the diseased myocardium.
Electrophysiological studies on atrial myocytes isolated from Kv4.2DN mice revealed that, similar to the
findings in ventricular cells (43), Ito,f is eliminated (563).
There are some differences, however, in the properties of
mouse (and rat) ventricular and atrial Ito,f (26, 43, 68, 69,
75, 79, 194, 562, 563), differences that may reflect variations in the subunit composition of the channels and/or in
posttranslational processing of these subunits. Further
studies focused on detailing the molecular compositions
and the mechanisms controlling the expression and functioning of Ito,f channels in other cell types, particularly
atrial, nodal, and Purkinje cells, in rodents and in large
animals, are needed to define definitively the similarities/
differences in the molecular compositions of Ito,f channels
in different cell types/species.
The kinetic and pharmacological properties of slow
transient outward myocardial Kv currents, referred to as
Ito,s (Table 1), are different from Ito,f, observations interpreted as suggesting that the molecular correlates of Ito,s
and Ito,f channels are also distinct. Direct support for this
hypothesis was provided in studies (196) completed on
myocytes isolated from (Kv1.4 ⫺/⫺) mice with a targeted
disruption in the KCNA4 (Kv1.4) locus (305). The waveforms of the outward currents in cells isolated from the
ventricles of Kv1.4 ⫺/⫺ animals are indistinguishable
from those recorded in wild-type ventricular cells (196).
In cells isolated from the interventricular septum of Kv1.4
⫺/⫺ animals, however, Ito,s is undetectable, thereby demonstrating directly that Kv1.4 underlies Ito,s (196). Given
the similarities in the time- and voltage-dependent properties of Ito,s (Table 1) in other species (77, 83, 178, 294,
545, 546), it seems reasonable to suggest that Kv1.4 also
encodes Ito,s in ferret, rabbit, canine, and human atrial and
ventricular myocytes.
Interestingly, it has also been reported that Ito,s and
the Kv1.4 protein are upregulated in the right and left
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of the KvLQT1 protein with minK, with fh12 and/or with
any other Kv channel accessory subunits (Table 5) in the
myocardium has not been provided, and the subunit stoichiometry of functional myocardial IKs channels remains
to be determined. Similar to KCNH2, splice variants of
KCNQ1, which exert a dominant negative effect when
coexpressed with the full-length KvLQT1 protein (236),
have also been described, although the roles of these
variants in the generation of IKs channels in vivo remain to
be determined.
A variety of experimental strategies, primarily in
mice, have been exploited in studies focused on defining
the molecular correlates of several of the other types of
cardiac delayed rectifier Kv currents (Table 1). A role for
Kv1 ␣-subunits in the generation of mouse ventricular
IK,slow, for example, was revealed with the demonstration
that IK,slow is selectively attenuated in ventricular myocytes isolated from transgenic mice expressing a truncated Kv1.1 ␣-subunit, Kv1.1N206Tag, that functions as a
dominant negative (303). It was subsequently shown,
however, that IK,slow is also reduced in ventricular myocytes expressing a dominant negative mutant of Kv 2.1,
Kv2.1N216 (560). Further analyses revealed that there are
actually two distinct components of wild-type mouse ventricular IK,slow: one that is sensitive to micromolar concentrations of 4-AP and encoded by Kv1 ␣-subunits, and
another that is sensitive to TEA and encoded by Kv2
␣-subunits (263, 560, 587). These currents are now referred to as IK,slow1 and IK,slow2, respectively (263, 291,
587). Subsequent studies revealed that IK,slow1 is selectively eliminated in ventricular myocytes isolated from
mice in which Kv1.5 has been deleted, suggesting that
Kv1.5 encodes the micromolar 4-AP-sensitive mouse ventricular IK,slow1 (302). These findings, together with the
previous results obtained on cells isolated from Kv1.4
⫺/⫺ animals (305), in which Ito,s is eliminated (196),
suggest that, in contrast to the Kv4 ␣-subunits (193), the
Kv1 ␣-subunits, Kv1.4 and Kv1.5, do not associate in adult
mouse ventricles in situ. Rather, functional Kv1 ␣-subunitencoded Kv channels in mouse ventricular myocytes appear to be homomeric, composed of Kv1.4 ␣-subunits
(Ito,s) or Kv1.5 ␣-subunits (IK,slow1). The roles of Kv channel accessory subunits in the generation of these myocardial Kv1 ␣-subunit-encoded Kv channels, however, remain
to be defined.
Electrophysiological studies completed on isolated
rat atrial myocytes (74, 75), and later on canine (577),
human (19, 531), and mouse (69) atrial myocytes, demonstrated the presence of a novel component of delayed
rectification, referred to as IKur (IKultrarapid), with timeand voltage-dependent properties that are quite distinct
from IKr and IKs (479). Although IKur appears to be an
atrial specific current in large mammals, the properties of
IK,slow1 in mouse ventricular myocytes are indistinguishable from (rat, human, and canine) atrial IKur (168, 562,
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and the pore-forming ERG1 subunits and the functional
roles of these interactions in the generation of myocardial
IKr channels.
Biochemical studies have now revealed that the heat
shock proteins, Hsp70 and Hsp90, coimmunoprecipitate
with heterologously expressed ERG1 and that geldanamycin, a specific inhibitor of Hsp90, prevents the maturation
(posttranslational processing) and increases the proteosomal degradation of the ERG1 protein (163). Interestingly, the interactions between the ERG1 protein and
Hsp70/Hsp90 are increased in LQT2 trafficking deficient
KCNH2 mutants, such as ERG1G601S (180). In addition,
the mutant ERG1G601S protein is retained in the endoplasmic reticulum (163). Importantly, it has also been
demonstrated that inhibition of Hsp90 decreases functional IKr densities in isolated ventricular myocytes (163).
Taken together, these results suggest that Hsp70 and
Hsp90 function as chaperone proteins, bringing mature
ERG1 protein complexes to the cell surface to generate
functional IKr channels (163). It is certainly possible that
there are additional components of myocardial IKr channels that influence the properties and/or the functional
cell surface expression of these channels, and further
studies are needed to test these hypotheses directly.
Heterologous expression of KCNQ1, the locus of mutations in LQT1 (522), reveals rapidly activating, noninactivating Kv currents, whereas coexpression with KCNE1
(minK) produces slowly activating Kv currents similar to
cardiac IKs (40, 447). These observations, together with
biochemical data demonstrating that heterologously expressed KvLQT1 and minK proteins associate (447), have
been interpreted as suggesting that minK coassembles
with KvLQT1 to form functional cardiac IKs channels (40,
447). In addition, the finding that mutations in the transmembrane domain of minK alter the properties of the
KCNQ-1 encoded Kv channels was interpreted as suggesting that the transmembrane segment of minK contributes
to the channel pore (185, 487, 492, 527). Nevertheless, and
similar to the suggested interaction between ERG1 and
MiRP1 (and/or minK), there is presently no direct biochemical/molecular evidence demonstrating a functional
interaction between the minK and KvLQT1 proteins
and/or that minK/KvLQT1 interactions play a role in the
generation of cardiac IKs channels.
A yeast two-hybrid screen, using the intracellular
cytoplasmic COOH terminus of minK as the bait, led to
the identification of a novel LIM-domain-containing protein, fh12 (274). Heterologous expression studies further
suggest that fh12 is required for the generation of functional cell surface KvLQT1/minK (IKs) channels (274).
These observations suggest that fh12 is required for the
proper assembly of the KvLQT1 and minK subunits, the
trafficking of assembled channels, and/or the cell surface
expression of functional KvLQT1/minK (IKs) channels.
Nevertheless, direct biochemical evidence for coassembly
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JEANNE M. NERBONNE AND ROBERT S. KASS
VII. MOLECULAR COMPONENTS OF OTHER
CARDIAC POTASSIUM CHANNELS
A. Inwardly Rectifying Cardiac Kⴙ (Kir) Channel
Pore-Forming ␣-Subunits
Similar to the Kv channels, functionally distinct types
of myocardial inwardly rectifying K⫹ channels (378) are
formed by the association of diverse inward rectifier K⫹
(Kir) channel pore-forming ␣-subunit genes (140). Several
Kir subunit subfamilies, Kir1 through Kir6, most with
several members, have been identified (Table 6) and, like
Kv ␣-subunits, Kir ␣-subunits also assemble as tetramers
to form functional K⫹ selective channels (Fig. 5). Also
similar to Kv channel ␣-subunits, a unifying terminology
Physiol Rev • VOL
has been developed for naming the Kir ␣-subunit proteins
(Kir1.x–Kir6.x) and the genes (KCNJ1–KCNJ15) encoding these proteins (199). In contrast to the Kv ␣-subunits,
however, the Kir ␣-subunits have two (not six) transmembrane domains (Fig. 5).
Based on the properties of heterologously expressed
Kir subunits, it was suggested that ␣-subunits of the Kir2
subfamily likely encode the strongly inwardly rectifying
Kir channels, IK1, in cardiac cells (140, 378), and all
(three) members of the Kir2 subfamily (Table 6) are expressed in the myocardium (298, 488). Interestingly, the
KCNJ2 gene, which encodes Kir2.1, has been identified as
the locus of mutations in Andersen’s syndrome (243, 403),
an inherited disorder that is often life-threatening owing
to QT prolongation and cardiac (ventricular) arrhythmias.
Similar to Timothy’s syndrome (479), however, Andersen’s syndrome is actually a multisystem disorder involving the cardiovascular, skeletomuscular, and other systems, and typically, Andersen’s syndrome patients
present initially with developmental abnormalities (494).
The mutations in KCNJ2 that are associated with Andersen’s syndrome that have been described to date appear
to result in mutant Kir2.1 proteins that function in a
dominant negative fashion to suppress Kv2.x-encoded IK1
currents (11, 280, 409). Individuals carrying Andersen’s
syndrome mutations in KCNJ2 can display QT prolongation (Long QT7), periodic paralysis, as well as craniofacial
malformations (11, 22, 494, 498), alone or in combination.
Because only the KCNJ2 gene appears to be affected in
Andersen’s syndrome, the multisystem nature of this disorder likely reflects the fact that Kir2.x-encoded channels
are expressed and are functional in a variety of cells/
tissues. Myocardial IK1 (and other K⫹ channels) have been
shown to be regulated directly by phosphatidylinositol
bisphosphate (PIP2) (209, 219, 470, 489). Interestingly,
many of the Andersen’s mutations are in the PIP2 binding
region of Kir2.1 (139), suggesting that the regulation/modulation of IK1 channels by PIP2 is altered and that it is the
alterations in the modulatory effects of PIP2 that underlie
the phenotypic consequences of the Andersen’s syndrome
mutations.
The first direct molecular evidence that Kir2 ␣-subunits encode cardiac IK1 channels was provided in studies
completed on myocytes isolated from mice bearing a
targeted disruption of the coding region of Kir2.1 (Kir2.1
⫺/⫺) or Kir 2.2 (Kir2.2 ⫺/⫺) (580, 581). Although the
Kir2.1 ⫺/⫺ mice have cleft palate and die shortly after
birth, thereby precluding electrophysiological studies on
adult cells (580), experiments completed on isolated newborn Kir2.1 ⫺/⫺ ventricular myocytes revealed that IK1 is
absent (581). Interestingly, however, an inwardly rectifying current, with properties distinct from the wild-type
IK1, is evident in Kir2.1 ⫺/⫺ myocytes (581), suggesting
either that an additional Kir current component is
present, but difficult to resolve in wild-type cells in the
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586). Human, rat, and canine atrial IKur, like mouse ventricular IK,slow1, activates rapidly and undergoes little or
no inactivation during brief depolarizations, properties
similar to those seen on heterologous expression of several different Kv ␣-subunits, including Kv1.2, Kv1.5, Kv3.1,
and others. In addition, IKur, like IK,slow1, is sensitive to
micromolar concentrations of 4-AP (168, 562, 586). The
later finding led to the hypothesis that Kv1.5 likely encodes human and rat atrial IKur (75, 533). Direct experimental support for this hypothesis was provided with the
demonstration that exposure to antisense oligodeoxynucleotides targeted against Kv1.5 selectively attenuates IKur in isolated adult human (159) and rat (68) atrial
myocytes. The important physiological role for Kv1.5 in
human atria is suggested by the finding that IKur densities
and Kv1.5 protein expression are reduced markedly in the
atria of patients with chronic atrial fibrillation (511).
Although it was reported that Kv3.1, rather than
Kv1.5, functions in canine atria to encode IKur (479),
subsequent work demonstrated that Kv3.1 is not detectable in canine atria, whereas Kv1.5 (message and protein)
is robustly expressed (157). It seems reasonable to conclude, therefore, that, similar to other Kv channels, the
molecular correlate of cardiac IKur (Kv1.5) is similar
across species. At present, it is unclear if Kv accessory
subunits play a role in the generation of atrial (mouse, rat,
canine, or human) IKur. Unexpectedly, however, it has
now been demonstrated that Kv␤1 subunits do not associate with Kv1.5 in adult mouse ventricles and that the
targeted deletion of Kv␤1 has no detectable effect on
mouse ventricular IKur (IK,slow1) (12). It may well be,
however, that other Kv channel accessory subunits contribute to the generation of IKur channels. Further studies,
focused on defining the molecular composition of IKur
channels and the roles of accessory subunits, are needed
to define the underlying molecular mechanisms involved
in the regulation of IKur channels in the normal and diseased myocardium.
1235
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
TABLE
6.
Diversity of inwardly rectifying K⫹ (Kir) and two-pore domain K⫹ (K2P) channel ␣-subunits
Location
Family
Subfamily
Protein
Gene
Human
Mouse
Location
Cardiac
Current
Family
Kir1
Subfamily
Protein
Gene
Human
Mouse
8E2
Cardiac
Current
K2P
Kir1
TWIK
Kir1.1
KCNJ1
11q25
9A4
??
TWIK-1
KCNK1
1q42
TWIK-2
KCNK6
19q11
TWIK-3
KCNK7
11q12
TWIK-4
KCNK8
11q12
TREK-1
KCNK2
1q41
TREK-2
KCNK10
14q32
TASK-1
KCNK3
2p24
TASK-2
KCNK5
6p21.1
TASK-3
KCNK9
8q24.3
TASK-4
KCNK14
TASK-5
KCNK15
20q12
TRAAK-1
KCNK-4
11q12
19A
12E
??
??
Kir2
Kir2.1
KCNJ2
17q23
11E1
IK1
KCNJ12 17p11.2 11B1.3
Kir2.3
KCNJ4
22U
??
Kir2.4
KCNJ14 19q13.4 7B3
??
Kir3.1
KCNJ3
Kir3.2
KCNJ6
TREK
IK1
21q22
IKACh
16C4
KCNJ7
Kir3.3
KCNJ9
1q21
Iss??
TASK
Kir3
2C1.1
1H6
1H2.3
??
14A1
TRAAK
Kir3.4
KCNJ5
11q25
9A4
IKACh
Kir4
THIK
Kir4.1
KCNJ10 1q21
1H2.3
THIK-1
KCNK13
14q32
Kir4.2
KCNJ15 21q22
16C4
THIK-2
KCNK12
2p21
Kir5.1
KCNJ16 17q25
Kir6.1
KCNJ8
Kir6.2
KCNJ11 11p15
Kir5
??
TALK
Kir6
12p11.1 6G2
783
??
TALK-1
KCNK16
6p21
TALK-2
KCNK17
6p21
??
IKATP
Boxes denote cardiac expression.
presence of IK1 or, alternatively, that a novel IK1 is upregulated in Kir2.1 ⫺/⫺ hearts. In contrast to the findings
in Kir2.1 ⫺/⫺ cells, voltage-clamp recordings from adult
Kir2.2 ⫺/⫺ ventricular myocytes revealed that IK1 densities are reduced, compared with IK1 densities in wild-type
cells, and that the properties of the residual IK1 currents
(in Kir2.2 ⫺/⫺ cells) are indistinguishable from wild-type
IK1 (581). These results were interpreted as suggesting
that both Kir2.1 and Kir2.2 contribute to (mouse) ventricular IK1 channels, and subsequent studies provided biochemical and molecular evidence to support this hypothesis (342, 592). The observation that the inwardly rectifying channels remaining in the absence of Kir2.1 have
properties distinct from the endogenous IK1 channels further suggests that functional cardiac IK1 channels are
heteromeric. Consistent with this hypothesis, detailed
comparisons of the properties of heterologously expressed Kir2.1, Kir2.2, and Kir2.3 ␣-subunits and endogenous guinea pig and sheep atrial and ventricular myocytes
Physiol Rev • VOL
suggests marked regional and cell type specific differences in the molecular composition of IK1 channels (133).
Further studies focused on defining the molecular compositions of myocardial IK1 channels in different cell types
and in different species, including humans, are needed to
define the molecular diversity and the functioning of these
channels.
In the heart, weakly inwardly rectifying IKATP channels are thought to play a role in both myocardial ischemia and preconditioning (232, 377, 380). In heterologous
systems, IKATP channels can be reconstituted by coexpression of Kir6.x subunits with ATP-binding cassette
proteins that encode the sulfonylurea receptors, SURx
(31, 456). Although previous pharmacological and molecular studies suggest that cardiac sarcolemmal IKATP channels reflect the heteromeric assembly of Kir6.2 and
SUR2A subunits, Kir6.1 is also expressed in the heart
(406), and exposure of isolated (rat neonatal) ventricular
myocytes to antisense oligodeoxynucleotides against
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Kir2.2
19A
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JEANNE M. NERBONNE AND ROBERT S. KASS
Physiol Rev • VOL
ological conditions, particularly those involving metabolic
stress (74, 577). Interestingly, however, it has been demonstrated that action potential durations are also largely
unaffected in transgenic animals expressing mutant IKATP
channels with markedly (40-fold) reduced ATP sensitivity
(268). The mutant IKATP channels would be expected to be
open (owing to the reduced sensitivity to closure by ATP)
at rest and to markedly affect cardiac membrane excitability. The fact that action potentials are unaffected in
ventricular myocytes expressing mutant IKATP channels
clearly suggests that additional inhibitory regulatory
mechanisms play a role in the physiological control of
cardiac IKATP channel activity in vivo (268). Further studies focused on defining and characterizing these regulatory mechanisms will be of considerable interest.
B. Two-Pore Domain Kⴙ (K2P) Channel
Pore-Forming ␣-Subunits
In addition to the many Kv (Table 4) and Kir (Table 6)
channel ␣-subunits, a novel type of K⫹ pore-forming
␣-subunit with four transmembrane spanning regions and
two pore domains (K2P) was identified with the cloning of
TWIK-1 (289), now referred to as KCNK1 (199). Studies in
heterologous systems suggest that functional K2P channels, unlike Kv and Kir channels that assemble as tetramers, reflect the dimeric assembly of (two) K2P ␣-subunits and that each of the (two) pore domains in each
␣-subunit contributes to the formation of the K⫹-selective
pore (286). Subsequent to the identification of TWIK-1, a
rather large number of K2P ␣-subunit genes, KCNK1–
KCNK17, were identified, and a subset of these appears to
be expressed in the myocardium (Table 6). Similar to the
Kv and Kir channels, a systematic terminology has been
developed for naming the (KCNK) genes encoding K2P
␣-subunits.
Heterologous expression studies have demonstrated
that the members of various K2P subunit subfamilies give
rise to K⫹-selective currents with distinct time- and voltage-dependent properties and differential sensitivities to
a variety of modulators, including pH, fatty acids, and
anesthetics (286, 287). It seems likely, therefore, that K2P
subunit-encoded K⫹ channels could be important in regulating the normal physiological functioning of the adult
mammalian heart, as well, perhaps, as influencing myocardial responses to pathophysiological stimuli. Direct
experimental support for this hypothesis was provided
with the demonstration that the pathophysiological effects of platelet activating factor on the myocardium are
directly linked to inhibition of KCNK3 (TASK-1)-encoded
(or closely related) K⫹ channels in ventricular myocytes
(39). Interestingly, the effect of platelet activating factor is
dependent on protein kinase C (39), although the underlying molecular mechanisms have not been detailed. Al-
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SUR1 reduces IKATP channel densities (572). These observations suggest the interesting possibility that there may
be some molecular heterogeneity among cardiac IKATP
channels. The absolute requirement for the Kir6.2 subunit
in the generation of cardiac IKATP channels, however, was
unequivocally demonstrated in studies completed on
mice in which the Kir6.2 gene was disrupted by homologous recombination (292, 456, 484). Voltage-clamp recordings from ventricular myocytes isolated from these
(Kir6.2 ⫺/⫺) animals revealed no detectable IKATP channel activity (292, 484). These findings clearly suggest that
Kir6.1 alone (i.e., in the absence of Kir6.2) cannot generate functional myocardial IKATP channels. Nevertheless, it
is certainly still possible that Kir6.1 coassembles with
Kir6.2 to form Kir6.1/Kir 6.2 heteromeric cardiac IKATP
channels.
The suggestion that SUR2 plays a pivotal role in the
generation of cardiac IKATP channels is supported by the
finding that IKATP channel density is reduced in myocytes
from animals (SUR2 ⫺/⫺) in which SUR2 has been deleted (411). In contrast, there are no measurable cardiac
effects of the targeted disruption of SUR1 (455, 456).
Nevertheless, it is interesting to note that IKATP channel
density is reduced, i.e., the channels are not eliminated, in
SUR2 ⫺/⫺ ventricular myocytes, and the properties of the
residual IKATP channels in SUR2 ⫺/⫺ ventricular myocytes are similar to those of the channels produced on
heterologous coexpression of Kir6.2 and SUR1 (411).
These findings strongly suggest that SUR1 likely also
coassembles with Kir 6.2 in ventricular myocytes to produce functional IKATP channels (at least in the absence of
SUR2). Immunohistochemical studies suggest that Kir6.2
and SUR2A assemble to form plasmalemmal cardiac IKATP
channels, whereas Kir6.1, Kir6.2 and SUR2A are expressed in mitochondria, observations interpreted as suggesting that the molecular compositions of functional IKr
channels in different cellular compartments are distinct
(473). Similar to IK1 channels, myocardial IKATP channels
are also modulated by the binding of PIP2 and other
membrane lipids (209, 470).
The waveforms of action potentials recorded from
isolated Kir6.2 ⫺/⫺ ventricular myocytes are indistinguishable from those recorded from wild-type cells (484).
These observations clearly suggest that IKATP channels do
not play a role in shaping action potential waveforms (in
mouse ventricles) under normal physiological conditions.
The action potential shortening typically observed in
wild-type ventricular cells during ischemia or metabolic
blockade, however, is abolished in Kir6.2 ⫺/⫺ ventricular
cells (484). In addition, the protective effect of ischemic
preconditioning is abolished in Kir6.2 ⫺/⫺ hearts (456,
485), and infarct size in Kir6.2 ⫺/⫺ animals, with and
without preconditioning, is the same (485). These observations are consistent with the hypothesis that cardiac
IKATP channels play an important role under pathophysi-
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
VIII. MYOCARDIAL POTASSIUM CHANNELS
AND THE ACTIN CYTOSKELETON
Similar to myocardial Nav channels, considerable evidence has now accumulated to suggest that several different types of plasmalemmal K⫹ channels in cardiac cells
also interact with components of the actin cytoskeleton
and that these interactions play important roles in regulating the properties, the trafficking, and/or the anchoring
of these channels. It has been shown, for example, that
Physiol Rev • VOL
myocardial IKATP channels likely are linked to, and regulated by, the actin cytoskeleton (179, 336). Exposure to
cytochalasin D, which disrupts/destabilizes actin filaments, for example, accelerates the rundown of cardiac
IKATP channels, whereas actin filament stabilizers inhibit
channel rundown (179). It appears that cytochalasin D
exerts its effects by interfering with the interaction between SUR2A and Kir6.2 subunits, thereby modifying
SUR-mediated regulation of the IKATP channels (76, 571).
These observations suggest that the biophysical properties, as well as the cell surface expression of IKATP channels, are affected by cytoskeletal interactions. Similarly,
the biophysical properties, including rectification and
Ca2⫹ (but not Mg2⫹) sensitivity, of myocardial IK1 channels are affected by treatment with cytochalasin D (336).
There is also experimental evidence suggesting that
the functioning of Kv channels in myocardial (and other)
cells is regulated and/or modulated through interactions
with the actin cytoskeleton. It has been demonstrated, for
example, that exposure to phalloidin, which stabilizes
actin filaments, markedly reduces action potential durations, whereas treatment with cytochalasin D (or cytochalasin B) prolongs action potential durations, in hypertrophied rat ventricular myocytes (568). Voltage-clamp studies revealed that the cytochalasin- and phalloidinmediated effects on action potentials reflect the specific
attenuation or augmentation, respectively, of Ito,f (568).
These observations suggest that functional cardiac Kv4
␣-subunit-encoded Ito,f channels are regulated/modulated
directly or indirectly through interactions with the actin cytoskeleton. Interestingly, experiments in heterologous expression systems also suggest that the modulation of Kv1.5, which encodes cardiac IKur channels, by
protein kinases and phosphatases, requires an intact
cytoskeleton (333).
Similar to cardiac Nav channels, the interactions between functional myocardial Kir and Kv channels and the
actin cytoskeleton are assumed to be mediated through
association with actin-binding proteins and/or other scaffolding proteins, suggesting that Kir and Kv channels also
function as multimeric protein complexes (Fig. 6). Consistent with this hypothesis, it was recently demonstrated
that Kir2.x ␣-subunits associate with several scaffolding
proteins, including CASK, veli-3, mint-1, and SAP-97 (285).
Interestingly, Kir subunits in brain also interact with a
very large number and variety of PDZ domain-containing
proteins (285, 372). In addition, it has been reported that
Kir6.x subunits interact directly with the 14 –3-3 protein
and that this interaction is requisite for the functional cell
surface expression of assembled Kir6.x-SUR-encoded
IKATP channels (575). It has also been reported that Kv
␣-subunits in several subfamilies bind to PDZ-containing
proteins, including PSD-95 and SAP-97 (145, 237, 557,
558), although the physiological significance of these observations in terms of the expression and/or the function-
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though it has been demonstrated that different KCNKencoded K2P ␣-subunits coassemble to form heteromeric
channels (55), it is presently unclear whether heteromeric
K2P ␣-subunit assembly is physiologically relevant in the
myocardium. Similarly, there is very little information
presently available about the role(s) of accessory subunits and/or other regulatory molecules in the generation
of K2P ␣-subunit-encoded myocardial channels.
The facts that there are so many K2P ␣-subunits
(Table 6), that many of them are ubiquitously expressed,
and that the properties of K2P ␣-subunit-encoded channels are regulated by a variety of potentially relevant
physiological (and pathophysiological) stimuli suggest
that channels encoded by K2P ␣-subunits likely subserve
a variety of important physiological functions. Experimental support for this hypothesis was provided with the
demonstration that mice bearing a targeted disruption of
the KCNK2 gene (which encodes TREK-1, Table 6) display increased sensitivity to epilepsy and ischemia (208).
It is unclear, however, whether there is a cardiac phenotype in the KCNK2 ⫺/⫺ mice, primarily because this
possibility appears not to have been addressed (208). The
physiological roles of TREK-1 and of each of the other
K2P channel ␣-subunits expressed in the myocardium, as
well as in other cell types, therefore, remain largely unknown. Both TREK-1 and TASK-1 are expressed in the
heart, and heterologous expression of either of these
subunits alone gives rise to instantaneous, noninactivating K⫹ currents that display little or no voltage dependence (286). These observations have led to suggestions
that these subunits contribute to myocardial “background” or “leak” K⫹ currents (32), although presently,
there is no direct experimental evidence to support this
hypothesis. Interestingly, however, the properties of the
currents produced on expression of TREK-1 or TASK-1
are similar to those of the current referred to as IKp
identified in guinea pig ventricular myocytes (576), as well
as to Iss in mouse ventricular myocytes (79, 562). Further
studies focused on defining the roles of each of the K2P
␣-subunits in the generation of myocardial K⫹ channels,
and the roles of these channels in the physiological, as
well as the pathophysiological, functioning of the heart,
are needed to clarify these issues.
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JEANNE M. NERBONNE AND ROBERT S. KASS
Physiol Rev • VOL
and functioning, as well as those focused on probing the
underlying molecular mechanisms, will likely provide important new insights into the physiological and pathophysiological roles of these interactions.
IX. SUMMARY AND CONCLUSIONS
Electrophysiological studies have identified multiple
types of voltage-gated inward and outward currents expressed in cardiac cells (Table 1). The outward K⫹ currents are more numerous and more diverse than the inward (Na⫹ and Ca2⫹) currents, and most cardiac myocytes express multiple voltage-gated, as well as inwardly
rectifying, K⫹ channels (Table 1). These (K⫹) channels
are the primary determinants of myocardial action potential repolarization, and regional differences in K⫹ channel
densities and properties underlie observed variations in
action potential waveforms and contribute to the generation of normal cardiac rhythms. Voltage-gated inward
Ca2⫹ channel currents and the Na⫹ channel “window”
current, however, also contribute to myocardial action
potential repolarization. The pivotal role played by the
Nav channel “window” current, for example, has been
elegantly demonstrated in electrophysiological studies
characterizing mutations in SCN5A that underlie long
QT3, as well as in computer-based simulations (Fig. 4) of
cellular electrical activity (73, 90, 141, 188).
Molecular cloning has revealed an unexpected diversity of ion channel pore-forming ␣-subunits (Tables 2, 4,
and 6) and accessory subunits (Tables 3 and 5) that
contribute to the formation of the various inward and
outward current-carrying channels (Table 1) identified
electrophysiologically in myocardial cells. Similar to the
electrophysiological diversity of myocardial K⫹ channels
(Table 1), the molecular analysis has revealed that multiple voltage-gated (Kv) (Table 4) and inwardly rectifying
(Kir) (Table 6) K⫹ channel pore-forming ␣-subunits, as
well as a number of accessory subunits of these (Kir and
Kv) channels (Table 5), are expressed in the myocardium.
A variety of in vitro and in vivo experimental approaches
have been exploited to probe the relationship(s) between
these subunits and functional myocardial K⫹ channels,
and important insights have been provided through molecular genetics and the application of techniques that
allow functional channel expression to be manipulated
directly. In contrast to the progress made in defining the
roles of the various Kv and the Kir ␣-subunits in the
generation of functional myocardial Kv and Kir channels,
there is very little known about the functional roles of the
K2P ␣-subunits (Table 6). In addition, the specific and/or
multiple functional roles of most of the known K⫹ channel accessory subunits (Table 5) remain to be clarified.
Defining the molecular correlates/compositions of the
various myocardial K⫹ channels will facilitate future ef-
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ing of cardiac Kv channels has not been determined. The
interactions between Kv1 and Kv4 ␣-subunits and PSD-95
impact the recruitment of Kv1- and Kv4-encoded channels
into lipid rafts (558). This finding may explain early observations suggesting that the expression of Kv4 ␣-subunits alone fails to reveal targeting to lipid rafts (327).
More importantly, these observations suggest that specific associations between Kv ␣-subunits and PDZ-containing scaffolding proteins play an important role in the
targeting of functional Kv channels to specific subcellular
domains. The targeting of Kv channels to specific subcellular compartments would be expected to have rather
profound effects on the regulation of membrane excitability and conduction through the myocardium (270, 463). In
addition, Kv channel targeting could facilitate specific
interactions between Kv channels and modulatory/regulatory proteins, including protein kinases and phosphatases, as has been clearly demonstrated in the protein
kinase A-mediated regulation of cardiac IKs channels, that
appears to be mediated by an A-kinase anchoring protein
or AKAP (330, 331).
Interestingly, it has also been demonstrated that Kv1
␣-subunits contain PDZ-binding domains (145) and that
Kv1.5 binds directly to the actin-binding protein ␣-actinin-2 (329). Further studies revealed that members of
three subfamilies of Kv ␣-subunits, Kv1.5, Kv2.1, and
Kv4.2, bind to ␣-actinin-2, interactions that affect the
properties and the functional expression of the resulting
Kv ␣-subunit-encoded K⫹ currents (329). These observations suggest that several Kv ␣-encoded Kv channels
likely also interact directly with the actin cytoskeleton via
␣-actinin-2 (Fig. 6). It has also been reported that Kv4
␣-subunits interact directly with filamin (401) and that
this interaction regulates the functional cell surface expression and the localization of Kv4-encoded channels
(401). Subsequent studies revealed that actin depolymerization modulates the cell surface expression of heterologously expressed Kv4-encoded channels (529). Similar to
Nav channels, these observations suggest the interesting
and potentially important hypothesis that myocardial Kv
channels also function as components of macromolecular
complexes containing the channel components and a variety of scaffolding and regulatory proteins linked to the
actin cytoskeleton (Fig. 6).
Recently, it was also suggested that Kir3-encoded
channels interact with integrin (344), suggesting that myocardial K⫹ channel expression and functioning may also
be linked to the extracellular matrix. Although clearly in
the very early stages, it seems reasonable to suggest that
the link between the cytoskeleton (as well, perhaps, as
the extracellular matrix) in the regulation of myocardial
K⫹ channel expression, localization, and functioning has
been made. Further studies, aimed at exploring the roles
of the cytoskeleton and the extracellular matrix in regulating myocardial K⫹ channel expression, distribution,
MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION
ACKNOWLEDGMENTS
We thank past and present members of our laboratories for
their contributions to the understanding of the molecular basis
of cardiac repolarization. In addition, we are indebted to Rick
Wilson for his expert assistance with the generation of the tables
Physiol Rev • VOL
and figures presented in this review and to Dr. Kevin Sampson
for conducting the simulations illustrated in Figures 4 and 7.
Address for reprint requests and other correspondence:
J. M. Nerbonne, Dept. of Molecular Biology and Pharmacology,
Washington University Medical School, 660 South Euclid Ave.,
St. Louis, MO 63110 (E-mail: [email protected]).
GRANTS
We gratefully acknowledge the long-standing and continued financial support for our research endeavors provided by
the National Heart, Lung, and Blood Institute of the National
Institutes of Health.
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