PHYSIOLOGY IN MEDICINE
`
`In collaboration with
`The American Physiological Society, Thomas E. Andreoli, MD, Editor
`
`Molecular Biology of K1 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 consider-
`ably from one region of the heart to another. These differences
`are caused by differential cellular expression of several types of
`K1 channel genes. The channels encoded by these genes can be
`grouped into several classes depending on the stimulus that per-
`mits the channels to open and conduct potassium ions. K1
`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 con-
`centration of ATP, can substantially shorten action potential
`
`duration. Inward rectifier K1 channels are unique in that they
`are basically stuck in the open state but can be blocked in a
`voltage-dependent manner by intracellular Mg21, Ca21, and
`polyamines. Other K1 channels have been described that pro-
`vide a small background leak conductance. Many of these car-
`diac K1 channels have been cloned in the past decade, permit-
`ting 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 K1 chan-
`nels 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 un-
`related, can also cause long QT syndrome and induce ventricu-
`lar arrhythmia. Am J Med. 2001;110:50 –59. q2001 by Ex-
`cerpta Medica, Inc.
`
`PHYSIOLOGICAL ROLES AND
`MOLECULAR BASIS OF CARDIAC
`VOLTAGE-GATED K1 CHANNELS
`
`The initial upstroke of the cardiac action potential is
`
`determined by the opening and closing of Na1
`channels. The configuration and rate of repolar-
`ization of action potentials are controlled by many types
`of K1 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 open-
`ing of transient outward K1 channels. This is followed by
`a plateau (phase 2) that is characterized by high mem-
`brane resistance resulting from the almost equal flow of
`outward currents through delayed rectifier K1 channels
`(IKr, IKs, IKur) and inward flow of current through L-type
`Ca21 channels. The rate of terminal repolarization (phase
`3) is enhanced after the plateau phase because of the in-
`creasing conductance of the rapid delayed rectifier K1
`
`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.
`
`current (IKr) and the inward rectifier K1 current (IK1).
`These currents were discovered and characterized using
`voltage clamp techniques, which permit precise control
`of the membrane potential and measurement of ion cur-
`rents under carefully controlled ionic conditions. Al-
`though voltage-clamp studies are useful in defining the
`properties of these currents, their molecular identities
`had to await the advancement of molecular cloning tech-
`niques. Starting with the cloning of the Shaker K1 chan-
`nel from Drosophila in 1987 (1), many K1 channels have
`been cloned. These studies have shown that K1 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 molec-
`ular basis of cardiac K1 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 characteris-
`tics of the currents determined by voltage clamp experi-
`ments. Based on function, cardiac K1 channels can be
`placed into one of four categories: transient outward, de-
`layed rectifier, inward rectifier, and leak channels. Several
`excellent reviews of K1 channel diversity based on se-
`quence and function are recommended for the reader
`
`50 q2001 by Excerpta Medica, Inc.
`All rights reserved.
`
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`K1 Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
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`Table 1. The Molecular Identity of Human Cardiac K1
`Currents
`
`Cloned Channel
`
`Current
`
`Transient outward
`Ito
`
`Delayed rectifier
`IKur
`IKr
`IKs
`Inward rectifier
`IK1
`IKATP
`IKACh
`Leak
`
`Alpha
`Subunit
`
`Kv4.3
`
`Kv1.5
`HERG
`KVLQT1
`
`Kir2
`Kir6.2
`Kir3.1
`
`Beta
`Subunit
`
`Kv1.4
`
`MiRP1
`minK
`
`SUR1
`Kir3.4
`
`TWIK
`
`channels, each subunit has six transmembrane domains
`(S1 to S6), including one domain (S4) that senses trans-
`membrane voltage (Figure 2). The amino and carboxyl
`termini are located on the intracellular side of the mem-
`brane. Movement of the S4 domain in response to mem-
`brane depolarization is coupled to other regions of the
`protein that form the activation gate (8,9). When the ac-
`tivation gate is open, the channel conducts K1 in a direc-
`tion 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 de-
`activated 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 re-
`cover from the inactivated state and again become capa-
`ble of opening in response to membrane depolarization.
`Delayed Rectifier K1 Channels
`The delayed rectifier K1 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 ultra-
`rapidly (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 chro-
`manol 293B (21).
`The amplitude of the delayed rectifier K1 currents var-
`ies during repolarization of the action potential because
`of changes in membrane potential, chemical driving
`
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`
`51
`
`Figure 1. K1 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 out-
`ward (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 K1 currents as
`well as IKur and Ileak counter the depolarizing influence of L-
`type calcium current (not shown). IKr and the inward rectifier
`K1 current (IK1) provide repolarizing current during the termi-
`nal 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 K1 Channels
`Transient outward K1 current (Ito) activates very rapidly
`in response to a rapid depolarization, such as occurs dur-
`ing the upstroke of the action potential. Soon after open-
`ing, these channels close, resulting in the transient nature
`of the net outward current (Figure 1). Ito is the sum of a
`Ca21-dependent Cl2 current and a voltage-dependent
`K1 current. The K1 current component of Ito is con-
`ducted by channels formed by tetrameric assembly of
`Kv1.4, Kv4.2, and/or Kv4.3 subunits (6). A single func-
`tional 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 K1
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`Figure 2. Proposed topology of K1 channel subunits. A. Schematic representation of a voltage-gated K1 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. K1 channel alpha subunits coassemble to form a tetrameric channel composed of four
`identical subunits (homotetramer) or nonidentical subunits (heterotetramer). C. Inward rectifier K1 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 K1 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 ac-
`tion potential. The magnitude of this current decreases
`
`during repolarization solely because of a decrease in elec-
`trochemical driving force. IKr amplitude increases during
`repolarization, reaching a peak at approximately 230
`mV, then decreases as the membrane potential reaches its
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`resting level. This increase in current occurs in spite of a
`decrease in electrochemical driving force, because chan-
`nels recover from inactivation to an open state in a volt-
`age-dependent manner. Fast inactivation of IKr is not me-
`diated by the amino-terminal region (22) but instead re-
`sults 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 K1.
`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, re-
`spectively) 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 pep-
`tide number 1, 123 amino acids) are beta subunits that
`have a single transmembrane domain. It is presently un-
`clear 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 espe-
`cially 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 con-
`ductance and accelerates the rate of HERG channel deac-
`tivation (26). Alternative splicing of HERG (29 –31) pro-
`duces a variant with a shortened amino terminus that also
`deactivates faster than full length HERG. Additional de-
`layed rectifier K1 channels are expressed in the hearts of
`mammals other than humans. For example, Kv2.1 sub-
`units coassemble to form a delayed rectifier K1 channel
`(IK,slow) in the mouse heart (32).
`Inward Rectifier K1 Channels
`In most cardiac cells, the inward rectifier K1 current, IK1,
`largely determines the resting membrane potential. The
`channels that conduct this current are open at all volt-
`ages. However, K1 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 295 mV, the equilib-
`rium potential for K1 (Figure 1). A voltage-dependent
`block by cytosolic Mg21 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 K1 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 recti-
`fier K1 current (IKACh) that is activated by binding of
`acetylcholine to m2 muscarinic receptors located on the
`surface of the cell membrane. M2 receptor binding acti-
`vates a G protein that in turn increases the probability of
`K1 channel opening (36). Activation of IKACh slows the
`spontaneous firing rate of pacemaker cells and shortens
`action potential duration. Most cardiac myocytes also ex-
`press an inward rectifier K1 channel that is inhibited by
`cytosolic ATP (37). The current conducted by these chan-
`nels (IKATP) is activated under conditions of metabolic
`stress that reduce intracellular ATP and can lead to pro-
`nounced shortening of the action potential (38).
`Coassembly of Kir2.1, Kir2.2, Kir2.3, or Kir2.4 sub-
`units form channels that underlie IK1 (5). These subunits
`are smaller than the voltage-gated transient outward or
`delayed rectifier K1 channel subunits. For example, hu-
`man Kir2.1 subunits are composed of 427 amino acids.
`The proposed membrane topology of Kir2 channels is
`similar to all the other inward rectifier K1 channels, hav-
`ing two putative transmembrane domains linked by a
`single pore loop (39) (Figure 2). Analysis of the conduc-
`tion properties of channels constructed by tandem mul-
`timers consisting of three or four Kir2.1 subunits suggest
`that subunits coassemble to form a tetrameric channel
`complex similar to the voltage-gated K1 channels. It is
`presently unclear if the channels form as homo- or het-
`eromultimeric complexes. However, based on conduc-
`tance measurements of single channel currents, there is
`ample evidence that multiple types of inward rectifier K1
`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 chan-
`nels are formed by coassembly of four Kir6.1 subunits
`and four sulfonylurea receptor (SUR) subunits (41). Hu-
`man 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 transmem-
`brane domains flanking a pore region (Figure 2C).
`Leak K1 Channels
`Most cells have a very small background K1 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 K1 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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`Figure 3. The role of K1 channels in mediating phase 3 repolarization of the cardiac action potential. A. Yellow arrows represent K1
`efflux through the rapid (IKr) and slow (IKs) delayed rectifier K1 channels. Outward movement of positively charged K1 hyperpo-
`larizes the cell membrane and terminates the action potential. The surface electrocardiogram is depicted below. The QRS corre-
`sponds 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 K1
`CHANNELS
`
`Long QT syndrome (LQTS) is a disorder of ventricular
`repolarization that predisposes affected individuals to
`cardiac arrhythmias and sudden death. The most com-
`mon form of LQTS is acquired, caused by medications
`that block cardiac K1 channels, such as certain antiar-
`rhythmic 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 se-
`verely affected individuals can have intermittent syncope
`caused by a self-terminating arrhythmia called torsades
`
`54 January 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110
`
`de pointes, characterized by a sinusoidal twisting of the
`QRS axis around the isoelectric line of the electrocardio-
`gram (46). Spatial dispersion of ventricular repolariza-
`tion 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 ven-
`tricular fibrillation.
`Mark Keating and colleagues used a positional cloning
`approach to discover one gene (KVLQT1) and a candi-
`date 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 K1 channel subunits cause a decreased out-
`ward K1 current during the plateau phase of the cardiac
`action potential, delayed ventricular repolarization, and
`an increased QT interval (Figure 3). It is clear that envi-
`ronmental and other genetic factors are likely to contrib-
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`K1 Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
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`Table 2. Drugs That Prolong QT Interval and/or Cause Torsades de Pointes*
`
`Drug Class
`
`Class IA antiarrhythmic agents
`
`Class IC antiarrhythmic agents
`Class III antiarrhythmic agents
`
`Calcium channel antagonists
`Antihistamines
`
`Antidepressants
`
`Antipsychotics
`
`Antimicrobials
`
`Anticonvulsants
`Miscellaneous agents
`
`Drug (Trade Name)
`
`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), trimethoprim-
`sulfamethoxazole, 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)
`
`See website: http://www.dml.georgetown.edu/depts/pharmacology/torsades.html
`
`ute to the pathology of this disorder, because many mu-
`tant 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 pro-
`tein 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 com-
`mon 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 se-
`quence of the channel that forms the K1-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 K1
`through the narrowest region of the pore. Coexpression
`of normal and G628S HERG subunits indicates that coas-
`sembly of even a single G628S subunit in the tetrameric
`channel results in loss of function, a “lethal” dominant-
`negative 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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`Figure 4. Drug trapping within the K1 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
`K1 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 K1 because the drug remains bound.
`
`from rapid recovery from inactivation and slow deactiva-
`tion 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 LQTS-
`associated mutations result in a decrease in the magni-
`tude of delayed rectifier K1 current during the repolar-
`ization phase of ventricular action potentials, and the as-
`sociated 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 usu-
`ally undergo rapid degradation, thus reducing the mag-
`nitude of IKs. Ten mutations have been found in KCNE1,
`and all but one are missense mutations (61). Two muta-
`tions that are located in the putative cytoplasmic region
`of the protein (S74L, D76N) cause a shift in the voltage
`
`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 as-
`sociated with sensorineural deafness and more severe ar-
`rhythmias than the dominantly inherited Romano-Ward
`syndrome. Deafness results from loss of IKs channel func-
`tion in the inner ear. IKs normally conducts K1 into the
`inner ear, creating the potassium-rich fluid, endolymph.
`Recessive mutations of KVLQT1 or KCNE1 cause loss of
`IKs, inadequate endolymph production, and degenera-
`tion of the organ of Corti (64).
`According to a recent tabulation of all known novel
`mutations, there are presently 177 known mutations as-
`sociated with LQTS (61). Mutations in HERG are the
`most common (45%), followed by KVLQT1 (42%),
`SCN5A (8%), KCNE1 (3%), and KCNE2 (2%). At the
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`56 January 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110
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`CFAD V. UPENN
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`K1 Channels and Cardiac Arrhythmias/Tristani-Firouzi et al
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`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 re-
`main to be discovered.
`
`INDUCTION OF VENTRICULAR
`ARRHYTHMIAS CAUSED BY
`PHARMACOLOGICAL BLOCK OF IKr
`Many commonly used medications, including antiar-
`rhythmic, 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 degrada-
`tion of other drugs that block IKr. Thus, drug-induced
`LQTS is mechanistically linked to LQT2 caused by muta-
`tions in HERG (24). Although the factors that determine
`which patients are at greatest risk for developing drug-
`induced LQTS and arrhythmia are not fully understood,
`it has been established that low serum K1 or Mg21, 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 chan-
`nels to open before they can gain access to the high affin-
`ity 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 drug-
`induced LQTS is such a common observation, the devel-
`opment of all new drugs includes procedures to detect
`this unwanted side effect.
`
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