PHYSIOLOGY IN MEDICINE
In collaboration with
The American Physiological Society, Thomas E. Andreoli, MD, Editor
Molecular Biology of Kⴙ Channels and
Their Role in Cardiac Arrhythmias
Martin Tristani-Firouzi, MD, Jun Chen, MD, John S. Mitcheson, PhD,
Michael C. Sanguinetti, PhD
The configuration of cardiac action potentials varies considerably from one region of the heart to another. These differences
are caused by differential cellular expression of several types of
K⫹ channel genes. The channels encoded by these genes can be
grouped into several classes depending on the stimulus that permits the channels to open and conduct potassium ions. K⫹
channels are activated by changes in transmembrane voltage or
binding of ligands. Voltage-gated channels are normally the
most important players in determining the shape and duration
of action potentials and include the delayed rectifiers and the
transient outward potassium channels. Ligand-gated channels
include those that probably have only minor roles in shaping
repolarization under normal conditions but, when activated by
extracellular acetylcholine or a decrease in the intracellular concentration of ATP, can substantially shorten action potential
duration. Inward rectifier K⫹ channels are unique in that they
are basically stuck in the open state but can be blocked in a
voltage-dependent manner by intracellular Mg2⫹, Ca2⫹, and
polyamines. Other K⫹ channels have been described that provide a small background leak conductance. Many of these cardiac K⫹ channels have been cloned in the past decade, permitting detailed studies of the molecular basis of their function and
facilitating the discovery of the molecular basis of several forms
of congenital arrhythmias. Drugs that block cardiac K⫹ channels and prolong action potential duration have been developed
as antiarrhythmic agents. However, many of these same drugs,
as well as other common medications that are structurally unrelated, can also cause long QT syndrome and induce ventricular arrhythmia. Am J Med. 2001;110:50 –59. 䉷2001 by Excerpta Medica, Inc.
PHYSIOLOGICAL ROLES AND
MOLECULAR BASIS OF CARDIAC
VOLTAGE-GATED Kⴙ CHANNELS
current (IKr) and the inward rectifier K⫹ current (IK1).
These currents were discovered and characterized using
voltage clamp techniques, which permit precise control
of the membrane potential and measurement of ion currents under carefully controlled ionic conditions. Although voltage-clamp studies are useful in defining the
properties of these currents, their molecular identities
had to await the advancement of molecular cloning techniques. Starting with the cloning of the Shaker K⫹ channel from Drosophila in 1987 (1), many K⫹ channels have
been cloned. These studies have shown that K⫹ channels
are formed by coassembly of four subunits (2) and are
sometimes associated with auxiliary beta subunits that
can modify the gating properties of the heteromultimeric
channel complex. With only a few exceptions, the molecular basis of cardiac K⫹ currents have been defined (Table
1). These channels can be grouped in many ways, most
logically by amino acid sequence homology (3). Another
classification scheme is based on biophysical characteristics of the currents determined by voltage clamp experiments. Based on function, cardiac K⫹ channels can be
placed into one of four categories: transient outward, delayed rectifier, inward rectifier, and leak channels. Several
excellent reviews of K⫹ channel diversity based on sequence and function are recommended for the reader
T
he initial upstroke of the cardiac action potential is
determined by the opening and closing of Na⫹
channels. The configuration and rate of repolarization of action potentials are controlled by many types
of K⫹ channel currents that differ with respect to their
kinetics and density in the plasma membrane (Figure 1).
Initial repolarization (phase 1) is mediated by the opening of transient outward K⫹ channels. This is followed by
a plateau (phase 2) that is characterized by high membrane resistance resulting from the almost equal flow of
outward currents through delayed rectifier K⫹ channels
(IKr, IKs, IKur) and inward flow of current through L-type
Ca2⫹ channels. The rate of terminal repolarization (phase
3) is enhanced after the plateau phase because of the increasing conductance of the rapid delayed rectifier K⫹
Am J Med. 2001;110:50 –59.
From the Department of Medicine, Division of Cardiology, University
of Utah, Salt Lake City, Utah.
Requests for reprints should be addressed to Michael C. Sanguinetti,
Department of Medicine, Division of Cardiology, University of Utah,
15 N 2030 E Room 4220, Salt Lake City, Utah 84112.
50
䉷2001 by Excerpta Medica, Inc.
All rights reserved.
0002-9343/01/$–see front matter
PII S0002-9343(00)00623-9
K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
Table 1. The Molecular Identity of Human Cardiac K⫹
Currents
Cloned Channel
Current
Transient outward
Ito
Alpha
Subunit
Beta
Subunit
Kv4.3
Kv1.4
Delayed rectifier
IKur
IKr
IKs
Inward rectifier
IK1
IKATP
IKACh
Leak
Kv1.5
HERG
KVLQT1
MiRP1
minK
Kir2
Kir6.2
Kir3.1
SUR1
Kir3.4
TWIK
Figure 1. K⫹ currents responsible for repolarization of a typical
ventricular action potential. Ventricular action potential (top).
Phase 0, rapid upstroke; phase 1, initial repolarization; phase 2,
plateau; phase 3, terminal repolarization; phase 4, diastolic
membrane potential. The rapid repolarization of phase 1 is the
result of the contribution of the rapidly activating transient outward (Ito), the ultra-rapid delayed rectifier (IKur), and the leak
(Ileak) currents (middle and bottom). During the plateau phase,
the rapid (IKr) and slow (IKs) delayed rectifier K⫹ currents as
well as IKur and Ileak counter the depolarizing influence of Ltype calcium current (not shown). IKr and the inward rectifier
K⫹ current (IK1) provide repolarizing current during the terminal phase of the action potential [modified from (71). Reprinted
with permission from the American Heart Association].
interested in a more comprehensive view of this subject
(4 – 6).
Transient Outward K⫹ Channels
Transient outward K⫹ current (Ito) activates very rapidly
in response to a rapid depolarization, such as occurs during the upstroke of the action potential. Soon after opening, these channels close, resulting in the transient nature
of the net outward current (Figure 1). Ito is the sum of a
Ca2⫹-dependent Cl⫺ current and a voltage-dependent
K⫹ current. The K⫹ current component of Ito is conducted by channels formed by tetrameric assembly of
Kv1.4, Kv4.2, and/or Kv4.3 subunits (6). A single functional channel forms in the endoplasmic reticulum by
coassembly of four identical subunits. In human atrial
myocytes, the Ito channel is formed by coassembly of four
Kv4.3 protein subunits (7). Like other voltage-gated K⫹
channels, each subunit has six transmembrane domains
(S1 to S6), including one domain (S4) that senses transmembrane voltage (Figure 2). The amino and carboxyl
termini are located on the intracellular side of the membrane. Movement of the S4 domain in response to membrane depolarization is coupled to other regions of the
protein that form the activation gate (8,9). When the activation gate is open, the channel conducts K⫹ in a direction that depends on the electrochemical gradient across
the plasma membrane. Immediately after depolarization,
repetitive opening (activation) and closing (deactivation)
of the activation gate determines how long the channel is
in a conducting state. However, soon (within 10 to 100s
of msecs) a portion of the amino terminus binds to a
specific site near the inside of the pore region and closes
the channel, a process called inactivation. Unlike the deactivated state, the inactivated state is a long-lived closed
state. The channel remains closed until the membrane is
repolarized to the resting potential, where channels recover from the inactivated state and again become capable of opening in response to membrane depolarization.
Delayed Rectifier K⫹ Channels
The delayed rectifier K⫹ current, IK, is comprised of at
least three distinct currents, IKur, IKr, and IKs that can be
distinguished on the basis of kinetics of activation and
pharmacologic properties (10 –15). IKur activates ultrarapidly (16), IKr activates rapidly, and IKs activates very
slowly. IKur is blocked by 4-aminopyridine (17,18), IKr is
blocked by several antiarrhythmic agents (eg, dofetilide)
(19,20), and IKs is blocked by a compound called chromanol 293B (21).
The amplitude of the delayed rectifier K⫹ currents varies during repolarization of the action potential because
of changes in membrane potential, chemical driving
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K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
Figure 2. Proposed topology of K⫹ channel subunits. A. Schematic representation of a voltage-gated K⫹ channel alpha subunit
composed of six membrane-spanning alpha helices (S1 to S6). The fourth membrane-spanning unit (S4) contains positively charged
residues at approximately every third position and is the voltage sensor. The residues between S5 and S6 (shown in orange) form the
ion selective pore. Auxiliary beta subunits (shown in green) modify the gating properties and protein trafficking of the pore-forming
alpha subunits. Kvbeta subunits are cytoplasmic proteins that bind to the N-terminus. MinK, a component of the IKs channel, is a
membrane-spanning beta subunit. B. K⫹ channel alpha subunits coassemble to form a tetrameric channel composed of four
identical subunits (homotetramer) or nonidentical subunits (heterotetramer). C. Inward rectifier K⫹ channels are formed by
subunits containing two membrane-spanning alpha helices, separated by a pore domain. Like the six transmembrane voltage-gating
ion channel, four subunits coassemble to form the inward rectifier K⫹ channel. TWIK channels are a unique class of channels formed
by subunits containing four membrane-spanning domains and two pore loops.
force, and relative rates of activation and inactivation
(Figure 1). IKur activates extremely rapidly and does not
inactivate appreciably during the time course of the action potential. The magnitude of this current decreases
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THE AMERICAN JOURNAL OF MEDICINE威 Volume 110
during repolarization solely because of a decrease in electrochemical driving force. IKr amplitude increases during
repolarization, reaching a peak at approximately ⫺30
mV, then decreases as the membrane potential reaches its
K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
resting level. This increase in current occurs in spite of a
decrease in electrochemical driving force, because channels recover from inactivation to an open state in a voltage-dependent manner. Fast inactivation of IKr is not mediated by the amino-terminal region (22) but instead results from a mechanism believed to involve a slight
constriction of the outer pore region of the channel (9).
IKs activates extremely slowly and, therefore, increases in
magnitude throughout the plateau phase. Only during
phase 3 repolarization does IKs decrease in accordance
with a decrease in electrochemical driving force for K⫹.
The Kv1.5 gene encodes subunits (613 amino acids)
that coassemble to form IKur channels in most species,
including myocytes of the human atrium (23). HERG and
KCNE2 genes encode subunits (HERG and MiRP1, respectively) that coassemble to form IKr channels (24 –26).
KVLQT1 and KCNE1 encode subunits (KvLQT1 and
minK, respectively) that coassemble to form IKs channels
(27,28) (Table 1). HERG (1,159 amino acids) and
KvLQT1 (676 amino acids) are alpha subunits that have
an overall structure similar to the Kv1 and Kv4 subunits.
MinK (129 amino acids) and MiRP1 (minK-related peptide number 1, 123 amino acids) are beta subunits that
have a single transmembrane domain. It is presently unclear what regions of the alpha and beta subunits interact
to stabilize the heteromultimeric complex, but it is clear
that this association alters the gating of the tetrameric
alpha subunit channel. The change in kinetics is especially remarkable for KvLQT1, where association with
minK greatly slows the rate of activation and shifts the
voltage dependence of the channel opening to a more
positive membrane potential (27,28). HERG-MiRP1
channels have properties more similar to IKr in native
myocytes than do channels formed by coassembly of
HERG alone. MiRP1 decreases the single channel conductance and accelerates the rate of HERG channel deactivation (26). Alternative splicing of HERG (29 –31) produces a variant with a shortened amino terminus that also
deactivates faster than full length HERG. Additional delayed rectifier K⫹ channels are expressed in the hearts of
mammals other than humans. For example, Kv2.1 subunits coassemble to form a delayed rectifier K⫹ channel
(IK,slow) in the mouse heart (32).
Inward Rectifier K⫹ Channels
In most cardiac cells, the inward rectifier K⫹ current, IK1,
largely determines the resting membrane potential. The
channels that conduct this current are open at all voltages. However, K⫹ is preferentially allowed to conduct in
the inward direction (from the extracellular space to the
cytosol). The conductance of outward current becomes
progressively less as the membrane potential is made
more positive than approximately ⫺95 mV, the equilibrium potential for K⫹ (Figure 1). A voltage-dependent
block by cytosolic Mg2⫹ and polyamines of the inner
channel pore causes low outward conductance (33–35).
The pacemaker cells of the sinoatrial and atrioventricular
node do not express these inward rectifier K⫹ channels,
and therefore the maximum diastolic potential is more
depolarized than nonpacing cells of the atria or ventricles.
Atrial pacemaker cells have another type of inward rectifier K⫹ current (IKACh) that is activated by binding of
acetylcholine to m2 muscarinic receptors located on the
surface of the cell membrane. M2 receptor binding activates a G protein that in turn increases the probability of
K⫹ channel opening (36). Activation of IKACh slows the
spontaneous firing rate of pacemaker cells and shortens
action potential duration. Most cardiac myocytes also express an inward rectifier K⫹ channel that is inhibited by
cytosolic ATP (37). The current conducted by these channels (IKATP) is activated under conditions of metabolic
stress that reduce intracellular ATP and can lead to pronounced shortening of the action potential (38).
Coassembly of Kir2.1, Kir2.2, Kir2.3, or Kir2.4 subunits form channels that underlie IK1 (5). These subunits
are smaller than the voltage-gated transient outward or
delayed rectifier K⫹ channel subunits. For example, human Kir2.1 subunits are composed of 427 amino acids.
The proposed membrane topology of Kir2 channels is
similar to all the other inward rectifier K⫹ channels, having two putative transmembrane domains linked by a
single pore loop (39) (Figure 2). Analysis of the conduction properties of channels constructed by tandem multimers consisting of three or four Kir2.1 subunits suggest
that subunits coassemble to form a tetrameric channel
complex similar to the voltage-gated K⫹ channels. It is
presently unclear if the channels form as homo- or heteromultimeric complexes. However, based on conductance measurements of single channel currents, there is
ample evidence that multiple types of inward rectifier K⫹
channels are present in myocytes. KAch channels are
formed by coassembly of two Kir3.1 and two 3.4 subunits
into a tetrameric complex (40). Kir3.1 and 3.4 subunits
have 501 and 419 amino acids, respectively. KATP channels are formed by coassembly of four Kir6.1 subunits
and four sulfonylurea receptor (SUR) subunits (41). Human Kir6.1 and SUR1 subunits have 424 and 1,581 amino
acids, respectively. Kir3 and Kir6 subunits have the same
overall structure as Kir2 subunits, having two transmembrane domains flanking a pore region (Figure 2C).
Leak K⫹ Channels
Most cells have a very small background K⫹ conductance
that contributes to maintenance of the resting potential
and repolarization of the action potential. In the heart
this conductance may be the result of a weakly inward
rectifying K⫹ channel, TWIK-1 (42) or Kcnk3 (43). The
TWIK channel is 336 amino acids in length with four
transmembrane domains. This channel has an unusual
structure, because it has two pore domains. Thus, TWIK
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K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
Figure 3. The role of K⫹ channels in mediating phase 3 repolarization of the cardiac action potential. A. Yellow arrows represent K⫹
efflux through the rapid (IKr) and slow (IKs) delayed rectifier K⫹ channels. Outward movement of positively charged K⫹ hyperpolarizes the cell membrane and terminates the action potential. The surface electrocardiogram is depicted below. The QRS corresponds to the rapid upstroke of the action potential. The T wave represents the change in membrane potential associated with
repolarization. B. Mutations in the genes encoding subunits of the IKr and IKs channels reduce the amount of repolarizing current
available during the terminal phase of the cardiac action potential. Decreased repolarizing current prolongs the action potential,
which is reflected on the surface electrocardiogram as prolongation of the QT interval.
is like two Kir channels that are connected in tandem
(Figure 2).
LONG QT SYNDROME CAUSED BY
MUTATIONS IN GENES ENCODING
SUBUNITS OF CARDIAC RAPID AND
SLOW DELAYED RECTIFIER Kⴙ
CHANNELS
Long QT syndrome (LQTS) is a disorder of ventricular
repolarization that predisposes affected individuals to
cardiac arrhythmias and sudden death. The most common form of LQTS is acquired, caused by medications
that block cardiac K⫹ channels, such as certain antiarrhythmic drugs, antihistamines, and antibiotics, and is
exacerbated by bradycardia and hypokalemia (44).
LQTS can also be inherited as an autosomal dominant
(Romano-Ward syndrome) or recessive (Jervell and
Lange-Nielsen syndrome) disorder (45). The more severely affected individuals can have intermittent syncope
caused by a self-terminating arrhythmia called torsades
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de pointes, characterized by a sinusoidal twisting of the
QRS axis around the isoelectric line of the electrocardiogram (46). Spatial dispersion of ventricular repolarization and an alteration in the predominance of two ectopic
foci have been postulated to be the underlying cause of
torsades de pointes (47). Sudden cardiac death can occur
if torsades de pointes arrhythmia degenerates into ventricular fibrillation.
Mark Keating and colleagues used a positional cloning
approach to discover one gene (KVLQT1) and a candidate gene approach to identify three other genes (SCN5A,
HERG, KCNE1, KCNE2) that cause LQTS (48 –52).
SCN5A encodes the cardiac sodium (INa) channel and so
will not be discussed further in this review. As discussed
above, the HERG and KCNE2 genes encode subunits that
form the IKr channel, and KVLQT1 and KCNE1 genes
encode subunits that form the IKs channel. Mutations in
any of these K⫹ channel subunits cause a decreased outward K⫹ current during the plateau phase of the cardiac
action potential, delayed ventricular repolarization, and
an increased QT interval (Figure 3). It is clear that environmental and other genetic factors are likely to contrib-
K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
Table 2. Drugs That Prolong QT Interval and/or Cause Torsades de Pointes*
Drug Class
Drug (Trade Name)
Class IA antiarrhythmic agents
Quinidine, procainamide (Procan, Procanbid, Pronestyl), disopyramide
(Norpace)
Flecainide (Tambocor)
Amiodarone (Cordarone), sotalol (Betapace), ibutilide (Corvert),
dofetilide (Tikosyn)
Bepridil (Vascor), nicardipine (Cardene)
Astemizole (Hismanol), terfenadine (Seldane), diphenhydramine
(Benadryl), clemastine (Tavist)
Amitriptyline (Elavil, Endep), desipramine (Norpramin), doxepin
(Sinequan, Zonalon), fluoxetine (Prozac), imipramine (Tofranil),
venlafaxine (Effexor)
Chlorpromazine (Thorazine), haloperidol (Haldol), risoperidone
(Risperdal), thioridazine (Mellaril)
Erythromycin, clarithromycin (Biaxin), grepafloxacin (Raxar),
moxifloxacin (Avelox), sparfloxacin (Zagam), trimethoprimsulfamethoxazole, amantidine, forscarnet (Foscavir), pentamidine
(Pentacarinat, Pentam, NebuPent), fluconazole, ketoconazole,
itraconazole, miconazole, halofantrine, chloroquine
Felbamate (Felbatol), fosphenytoin (Cerebyx)
Cisapride (Propulsid), droperidol (Inapsine), naratriptan (Amerge),
pimozide (Orap), probucol (Lorelco), indapamide (Lozol),
sumatriptan (Imetrex), tacrolimus (Prograf), tamoxifen (Nolvadex),
zolmitriptan (Zomig)
Class IC antiarrhythmic agents
Class III antiarrhythmic agents
Calcium channel antagonists
Antihistamines
Antidepressants
Antipsychotics
Antimicrobials
Anticonvulsants
Miscellaneous agents
See website: http://www.dml.georgetown.edu/depts/pharmacology/torsades.html
ute to the pathology of this disorder, because many mutant gene carriers are asymptomatic.
The different forms of LQTS are commonly referred to
by their original loci assignment. Therefore, mutations in
KVLQT1, HERG, KCNE1, and KCNE2 cause LQT1,
LQT2, LQT5, and LQT6 forms of LQTS, respectively
(53). Mutations of ion channel genes cause channel protein dysfunction by a variety of mechanisms. Most LQTS
is the result of a dominant pattern of inheritance, where
an offspring carries a single mutant gene from one parent
and a normal gene from the other parent. The most common mutations are the result of a single base-pair change
(missense mutation) that results in a change in a single
amino acid. This type of mutation often causes subunit
misfolding, which disrupts the coassembly of subunits
and usually leads to early degradation of the channel
complex. This “dominant-negative effect” causes a
greater than 50% reduction in the number of functional
channels. A dominant-negative effect can also occur if the
missense mutation results in change in an amino acid
with a function vital to the operation of the channel. An
example is the G638S missense mutation in HERG, where
the glycine (G) at amino acid position 638 is changed to a
serine (S) residue. G638 is part of a highly conserved sequence of the channel that forms the K⫹-selective pore.
Mutation of this amino acid has no effect on the folding
of the channel complex or trafficking of the complete
channel to the surface membrane (54), but evidently pre-
vents the channel from permitting the flow of K⫹
through the narrowest region of the pore. Coexpression
of normal and G628S HERG subunits indicates that coassembly of even a single G628S subunit in the tetrameric
channel results in loss of function, a “lethal” dominantnegative effect (55). Deletion of one or more nucleotides
often leads to a premature stop codon and truncation of
the resulting protein. If the truncated protein no longer
contains a subunit association domain, then the mutant
subunit cannot interact with normal subunits. The net
effect is a reduction in the number of functional channel
proteins by approximately 50%, a condition referred to as
haploinsufficiency. In this case, the resulting phenotype
would display reduced current amplitude without any
change in biophysical properties.
Other missense mutations result in subunits that can
still coassemble with normal subunits but alter one or
more properties of the channel. For example, specific
mutations in HERG have been shown to shift the voltage
dependence of gating associated with either activation or
inactivation (56). Either a shift in the voltage dependence
of inactivation to a more negative potential or a shift in
the voltage dependence of activation to a more positive
potential causes a reduction in IKr amplitude. Missense
mutations in the amino terminus of HERG cause the
channels to deactivate (close) much faster than normal
(57). An increase in the rate of deactivation blunts the
voltage-dependent increase in IKr that normally results
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K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
Figure 4. Drug trapping within the K⫹ channel vestibule. Class III antiarrhythmic agents traverse the lipid bilayer as neutral
molecules and equilibrate in the cytosol as positively charged molecules (top left). In the resting state, the activation gate (blue) of the
K⫹ channel (green) remains closed. Upon depolarization, the activation gate opens and the drug enters the vestibule to block the
channel (top right). The channel then enters a long-lasting closed state (inactivation), which increases the affinity of drug binding
(bottom right). Upon repolarization, the activation gate closes (deactivation) and traps the drug within the channel vestibule
(bottom left). On subsequent depolarizations, the channel is not available to conduct K⫹ because the drug remains bound.
from rapid recovery from inactivation and slow deactivation of channels during repolarization. Two different
missense mutations in KCNE1 have also been shown to
cause an increase in the rate of IKs deactivation and a
reduction in magnitude (51). In all cases, these LQTSassociated mutations result in a decrease in the magnitude of delayed rectifier K⫹ current during the repolarization phase of ventricular action potentials, and the associated prolongation of the QT interval on the ECG.
Dominant missense mutations in KvLQT1 cause loss
of function and a dominant-negative effect (58 – 60).
When expressed alone, the mutant subunits do not form
functional channels. However, when coexpressed with
normal subunits, they combine to form dysfunctional
heterotetramers. These abnormally folded proteins usually undergo rapid degradation, thus reducing the magnitude of IKs. Ten mutations have been found in KCNE1,
and all but one are missense mutations (61). Two mutations that are located in the putative cytoplasmic region
of the protein (S74L, D76N) cause a shift in the voltage
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dependence of IKs activation to more positive potentials
and increase the rate of deactivation; one (D76N) has a
strong dominant-negative effect (51). These biophysical
changes would also reduce IKs.
Recessive mutations in KVLQT1 or KCNE1 cause a
more rare and severe form of LQTS known as Jervell and
Lange-Nielsen syndrome (50,62,63). This disorder is associated with sensorineural deafness and more severe arrhythmias than the dominantly inherited Romano-Ward
syndrome. Deafness results from loss of IKs channel function in the inner ear. IKs normally conducts K⫹ into the
inner ear, creating the potassium-rich fluid, endolymph.
Recessive mutations of KVLQT1 or KCNE1 cause loss of
IKs, inadequate endolymph production, and degeneration of the organ of Corti (64).
According to a recent tabulation of all known novel
mutations, there are presently 177 known mutations associated with LQTS (61). Mutations in HERG are the
most common (45%), followed by KVLQT1 (42%),
SCN5A (8%), KCNE1 (3%), and KCNE2 (2%). At the
K⫹ Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
present rate of discovery, many more LQTS-associated
mutations in these genes are likely to be described in the
future. Moreover, because mutations were not found in
some affected families, other genes that cause LQTS remain to be discovered.
INDUCTION OF VENTRICULAR
ARRHYTHMIAS CAUSED BY
PHARMACOLOGICAL BLOCK OF IKr
Many commonly used medications, including antiarrhythmic, antihistamine, antipsychotic, and antibiotic
agents, are associated with acquired LQTS (Table 2). The
mechanism(s) responsible for drug-induced LQTS has
not been definitively determined for all these agents, but
for those that have been studied, a common effect has
been identified. These drugs either block IKr or inhibit
liver enzymes that are important for metabolic degradation of other drugs that block IKr. Thus, drug-induced
LQTS is mechanistically linked to LQT2 caused by mutations in HERG (24). Although the factors that determine
which patients are at greatest risk for developing druginduced LQTS and arrhythmia are not fully understood,
it has been established that low serum K⫹ or Mg2⫹, or
congenital LQTS are important risk factors (44,53).
The most extensively characterized IKr blockers are the
methanesulfonanilide class III antiarrhythmic agents (eg,
E4031, MK-499, dofetilide, d-sotalol). These compounds
were developed to prevent ventricular fibrillation and are
quite effective in canine models of arrhythmia (65,66).
Unfortunately, these drugs also have the side effect of
inducing ventricular arrhythmias in some patients. The
methanesulfonanilide compounds require HERG channels to open before they can gain access to the high affinity binding site located inside the channel vestibule (67).
This requirement for channel opening indicates that the
resting state of the channel is not blocked by drug and
that the binding site is located behind the activation gate
(Figure 4). Once inside the channel vestibule, closure of
the activation gate (deactivation) traps the drug inside the
channel and greatly slows recovery of the channel from
the blocked state (68). Most experimental evidence also
suggests that these drugs bind with greater affinity to
channels in an inactivated state (69,70). Because druginduced LQTS is such a common observation, the development of all new drugs includes procedures to detect
this unwanted side effect.
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