The Molecular Physiology of the Cardiac Transient Outward Potassium Current (I to) in Normal and...

J Mol Cell Cardiol 33, 851–872 (2001)

doi:10.1006/jmcc.2001.1376, available online at http://www.idealibrary.com on

Basic Cardiac Electrophysiology

The Molecular Physiology of the CardiacTransient Outward Potassium Current (Ito)in Normal and Diseased MyocardiumGavin Y. Oudit, Zamaneh Kassiri, Rajan Sah, Rafael J. Ramirez,Carsten Zobel and Peter H. BackxDepartment of Medicine and Physiology, Toronto General Hospital, University Health Network,University of Toronto, Toronto, Canada

(Received 15 February 2001, accepted 2 March 2001)

G. Y. O, Z. K, R. S, R. J. R, C. Z P. H. B. The Molecular Physiology of the CardiacTransient Outward Potassium Current (Ito) in Normal and Diseased Myocardium. Journal of Molecular and CellularCardiology (2001) 33, 851–872. The Ca2+-independent transient outward potassium current (Ito) plays animportant role in early repolarization of the cardiac action potential. Ito has been clearly demonstrated in myocytesfrom different cardiac regions and species. Two kinetic variants of cardiac Ito have been identified: fast Ito, calledIto,f, and slow Ito, called Ito,s. Recent findings suggest that Ito,f is formed by assembly of Kv4.2 and/or Kv4.3 alpha pore-forming voltage-gated subunits while Ito,s is comprised of Kv1.4 and possibly Kv1.7 subunits. In addition, severalregulatory subunits and pathways modulating the level and biophysical properties of cardiac Ito have beenidentified. Experimental findings and data from computer modeling of cardiac action potentials have conclusivelyestablished an important physiological role of Ito in rodents, with its role in large mammals being less well defineddue to complex interplay between a multitude of cardiac ionic currents. A central and consistent electrophysiologicalchange in cardiac disease is the reduction in Ito density with a loss of heterogeneity of Ito expression and associatedaction potential prolongation. Alterations of Ito in rodent cardiac disease have been linked to repolarizationabnormalities and alterations in intracellular Ca2+ homeostasis, while in larger mammals the link with functionalchanges is far less certain. We review the current literature on the molecular basis for cardiac Ito and thefunctional consequences of changes in Ito that occur in cardiovascular disease. 2001 Academic Press

K W: Transient outward potassium current; Myocytes; Regulatory subunits; Cardiac action potential;Intracellular Ca2+; Arrhythmia; Hypertrophy; Congestive heart failure.

and developmental stages can be traced to a com-Introductionmon set of molecular correlates of Kv channel pro-teins and their auxiliary subunits.5,6 TheThe cardiac action potential (AP) profile is governed

by the complex interaction of depolarizing and permutation of various combinations of the pore-forming Kv channels, combined with the existencerepolarizing currents. Variation in the expression

and biophysical properties of voltage-gated K+ of an ever-increasing number of accessory proteinsand modulatory pathways, provides ongoing chal-channels (Kv) in cardiac myocytes from different

species as well as intra-cardiac regional variation lenges for understanding the molecular basis ofmyocardial electrophysiology.largely accounts for the wide variety of myocardial

AP profiles observed.1–4 It is now becoming clear Generally, voltage-gated K+ currents can be clas-sified into two groups based upon their time- andthat electrophysiological diversity of Kv repolarizing

currents between different cardiac regions, species voltage-dependent properties. The first group is the

Please address all correspondence to: Peter H. Backx, Toronto General Hospital, CCRW 3-802, 101 College St., Toronto, Ontario,M5G 2C4, Canada. E-mail: [email protected]

0022–2828/01/050851+22 $35.00/0 2001 Academic Press

G. Y. Oudit et al.852

delayed rectifiers (IK), which activate at variable currents by themselves in heterologous systems andare thought to regulate the activity of the Kv2rates and either do not inactivate or inactivate very

slowly. While these currents can contribute to all subfamily.6

Assembly of four Kv�-subunits into a tetramericphases of repolarization, in most species they aremore important for the later phases of re- structure creates a functional Ito channel.16 The

preponderance of evidence suggests that only Kv�polarization. Delayed rectifiers can be classified intothe ultra-rapid, IKUR, rapid, IKR, and slow, IKS, delayed from the same family can assemble or co-assemble

to form a functional channel. This co-assemblyrectifiers based on their relative rate of activation.7

The other group of currents is the Ca2+-independent depends critically on highly conserved N-terminalregions called T- or Nab-domains17,18 although ex-transient outward potassium current (Ito) which

rapidly activates and inactivates following mem- ceptions occur.19 The pore-forming alpha subunit(Kv�) contains six transmembrane domains (S1–brane depolarization.2–4,8,9

As a result of its contribution to the early phase of S6), flanked by cytoplasmic amino and carboxyltermini. S4 is a highly positively charged segmentrepolarization, Ito strongly affects L-type Ca2+current

magnitude, thereby modulating excitation– that is involved in voltage sensing and channelactivation.16,20 The P-loop (between the S5 and S6contraction coupling processes and myocardial con-

tractility as well as repolarization. As such, Ito adds transmembrane domains) from each subunit projectcentrally to create the K+-selective pore structure20another level of diversity to its functional role via its

interaction with other ionic currents such as the L- with a structure likely to resemble that of the KcsAK+ channel.21type Ca2+and delayed rectifier currents.10–12 Because

of these complex interactions, changes in Ito can have With respect to Ito expression in the heart, onlyKv1.4, Kv1.7, Kv4.2, and Kv4.3 show substantial ex-unexpected consequences on the action potential

(AP) duration10,11 and susceptibility to lethal ar- pression in the mammalian myocardium (Table1),4,6,22 even though other Kv� genes can encoderhythmias.13–15 A more thorough understanding of

the electrical activity in the heart is clearly pivotal to for Ito-like currents (i.e. Kv3.4 and Kv4.1). Of thesecardiac Ito genes, only Kv4.3 is alternatively splicedenable further elucidation of the function of normal

and diseased myocardium as well as the development into two variants that are distinguished by theinsertion of 19 amino acids into the proximal C-of novel strategies for the treatment of cardiovascular

diseases. The purpose of this review article is to dis- terminus of the “long” variant.23–25 Human heartexpresses both alternatively spliced forms,23 whilecuss our current knowledge of the molecular basis

for Ito, including the role of auxillary subunits and the long Kv4.3 variant is predominantly expressedin rat.24 It appears that only the short variantregulatory pathways, and to approve the functional

importance of Ito in regulating the electrical and encodes for the functional Ito in dog heart.25

Following translation, Kv�-subunits are as-mechanical activities of the heart. The alterations inIto in pathological states such as myocardial hyper- sembled in the endoplasmic reticulum and then

undergo further post-translational modificationtrophy and heart failure and the mechanisms in-volved will be highlighted. and maturation in the Golgi apparatus prior to

transport to the sarcolemmae.26 The distributionof these Ito-encoding Kv channels in the sarcolem-mae displays a heterogeneous and tissue-specificpattern of expression. For example, im-Molecular Properties of Itomunofluorescent studies revealed that Kv4.2 wasintensely observed in the peripheral sarcolemmaePore composition and structure of Kv channelsand the intercalated disks in atrial myocytes,whereas in ventricular myocytes Kv4.2 was ob-Following the identification of four Drosophila sub-

families of voltage-gated K+ channels (shaker, shab, served predominantly in the transverse-axial tu-bular system.27 Although the basis for this patternshaw, shal), homologous families of pore-forming

alpha subunits were uncovered in mammals.3,4 is unknown, membrane targeting signals that areresponsible for their differential targeting to theThese K+ channels were classified using the Kvx.y

nomenclature, where Kv indicates a voltage-gated sarcolemmae are known to reside in the C-terminus of Kv channels.28 Such a C-terminal motifK+ channel, x represents the subfamily and y the

number of the gene within the subfamily.3,6 Pres- in Kv1.X channels (including Kv1.4) has recently beenshown to be necessary for plasma membraneently, nine families of pore-forming Kv�-subunits

(Kv1.x to Kv9.x) have been identified.4–6 Members of localization and glycosylation of the Kv subunitsas well as their interaction with beta-subunits.29the Kv5, Kv6, Kv8, and Kv9 subfamilies do not express

Structure and Function of Cardiac Ito 853

Table 1 Ito composition in different mammalian myocardial cell

Species Chamber Subtype Putative Clone Ito density# Referenceclone distribution

Mouse Atrium Ito,f Kv4.2 A<V 6, 22, 78, 80Kv4.3

Ventricle Ito,f Kv4.2 Epi>Endo Epi>EndoIto,s Kv1.4 Endo>Epi Apex>baseIto,s∗ Kv1.7

a Apex>SepRat Atrium Ito,f Kv4.2 A>V 50, 91, 96,

Kv4.3 A>V 106, 159, 237Ventricle Ito,f Kv4.2 RV>Sep Epi>Endo

Kv4.3 LV wall>SepIto,s Kv1.4

Ferret Atrium NR Kv4.2b RA, LA 82, 238

Kv4.3b RA>LA

Kv1.4b RA, LA

Ventricle Ito,f Kv4.2 Base, Epi, RV Epi>EndoKv4.3 Apical Epi

Ito,s Kv1.4 Apical EndoRabbit Atrium Ito,s Kv4.2/3 88, 89, 239,

Kv1.4 240, 241Figure 1

Ventricle Ito,s Kv4.2 Epi>Endo Epi>EndoKv1.4

SA node Ito,f NRAV node Ito,f

Ito,s

Dog Atrium Ito,f NR 92, 114, 189,242, 243

Ventricle Ito,f Kv4.3 Epi>Endo Epi>EndoIto,s Kv1.4 Endo>EpiNR Kv3.4

$ LVHuman Atrium Ito,f Kv4.3 6, 80, 89,

Kv4.2 103, 242, 244Ventricle Ito,f Kv4.3 Epi>Endo

Ito,s Kv1.4c

Kv4.1a

Ito,f and Ito,s refers to fast and slow inactivating Ito, respectively; A=atrium; V=ventricle; N=node; RA=right atrium; LA=left atrium;Sep=septum; Epi-epicardium; Endo=endocardium; #=overall Ito density; NR=not reported; ∗=studied in heterologous system(Xenopus oocytes); $=detected at mRNA level.242

a=detected in whole heart.b=detected in mRNA level, but no Ito density reported in ferret atrial myocytes.c=identified with RT-PCR244 but not with Western immunoblots.89

Regulatory subunits and cytoskeletal interaction reductase enzyme with its active site positioned topotentially interact with the K+ channel voltage

Assembly of the alpha-subunits into pore-forming sensor.5,34,36 �-subunits can also assemble with afour-fold symmetric structure and are able to co-tetramers is sufficient to generate functional K+

channels. However, the level of expression as well assemble with the T1 domain of the Kv�-subunit(T14�4)5,37 which occurs in the endoplasmic re-as the biophysical properties of voltage-gated potas-

sium channels are modulated by cytoplasmic pro- ticulum prior to plasmalemmal insertion.26

Kv�1.3 (human) and Kv�3 (human and ferret)teins, such as �-subunits, KChIP, frequenin, andKChAP. Three highly homologous �-subunit famil- have been cloned from the heart.30–32,38 The ex-

pression of �-subunits appears to be regulated in aies, Kv�1–Kv�3, have been cloned.30–34 The Kv�1(Kv�1.1, Kv�1.2, Kv�1.3), Kv�2 (Kv�2.1, Kv�2.2), and Kv�3 chamber-specific manner since the level of Kv�3

in human myocardium is two-fold higher in the(Kv�3.1, Kv�3.2) families are alternative spliced vari-ants of the same gene.34,35 Each beta-subunit con- ventricle than in the atrium.30 Kv�1, Kv�2, and

Kv�3 families can specifically associate with Kv1.1,tains a conserved core region with variable N-terminal peptides and functions as a complete oxido- Kv1.2, Kv1.4, Kv1.5 and Kv4.3�-subunits thereby mod-


ifying their functional properties, stability, and cell such as cell swelling and disruption of intracellularfilaments can alter ion conductivity indirectly bysurface expression.5,30,31,33,38–40 The N-terminal pep-

tide in Kv�1 and Kv�3 subunits confers a rapid altering the delivery, expression, clustering and/or phosphorylation of cardiac Na+ channel andinactivation to Kv1.1 and Kv1.5 subunits via a pro-

posed N-type inactivation5,39,41,42 while Kv�2.1 only inwardly rectifying K+ channels.52–54 Recent datahave provided supporting evidence for the role ofenhances C-type inactivation in Kv1.5 channels.43

Furthermore, human and ferret Kv�2 and Kv�3 the cytoskeleton in regulating the expression ofIto. For example, insulin-triggered synthesis of Itosubunits can specifically increase the rate of in-

activation of human and ferret Kv1.4 currents,32,38 channel proteins and augmentation of Ito in ratventricular myocytes was prevented by disruptionwhile Kv�2 also affects the level of its expression,

which appears to depend critically on the ox- of the actin microfilament network or microtubules,suggesting cytoskeletal involvement in traffickingidoreductase activity of the �-subunit.44 In contrast,

expression of Kv�1 or Kv�2 subunits does not affect of newly synthesized K+ channels to the plasmamembrane.55 Consistent with a role of the cyto-Kv4.3 channel gating, but does increase current

density and protein expression, which is dependent skeleton in affecting Ito, Kv4.2 subunit has beenshown to be directly linked to the scaffold protein,upon the presence of the C-terminus of Kv4.3.40

Kv channels can also be regulated by KChAP filamin, which mediates its interaction with theactin cytoskeleton resulting in upregulation of Kv4.2(Kv channel-associated protein), a member of the

transcription factor binding protein family, by in- currents56 while the Kv�1.1 subunit associates withcytoskeleton by its amino terminus.57,58creasing the functional cell-surface expression of

specific Kv channels without affecting other channelproperties.45–47 KChAP produces these effects byinteracting with the N-termini of Kv�2 and Kv�1 Mechanisms of Ito inactivationsubunits and the C-termini of Kv�-subunits.45 Co-expression with KChAP increases the amplitude of Inactivation is a hallmark feature of Ito currents in

the heart and refers to the process whereby channelKv1.3, Kv2.1, Kv2.2, and Kv4.3 currents without affectingthe channel kinetics and gating,45,46 suggesting that opening following depolarization leads to con-

formational changes resulting in a stable non-con-KChAP is a true chaperone. Complexes of KChAPand Kv4.3 have been co-immunoprecipitated from rat ducting (inactivated) state of the channel from

which the channel is incapable of reopening unlesshearts implying that KChAP may be an importantregulatory subunit for the native Ito in the heart.46 the membrane potential is repolarized. Recent stud-

ies of the K+ channel have elucidated three mech-Kv channel-interacting proteins (KChIPs) areCa2+-binding proteins that interact with the cyto- anistically different but related types of inactivation,

N-type, C-type and V-type.59,60 N- and C-type in-plasmic amino termini of Kv4 �-subunits and re-constitute several features of native Ito current by activation occurs in Kv3.4,61 Kv1.7

6,22 and Kv1.459,62,63

channels while V-type inactivation occurs in Kv4.2modulating the density, inactivation kinetics andrate of recovery from inactivation of Kv4 channels.48 and Kv4.3 channels.60 The inactivation of the native

cardiac Ito has been stratified into a slow, Ito,s, andAll three KChIPs (KChIP1, KChIP2 and KChIP3)co-localize and co-immunoprecipitate with the nat- a fast component, Ito,f, with distinct recovery from

inactivation in a wide variety of species and inive Kv4 channel and, as such, are considered integralcomponents of Kv channels.48 KChIP2 has tissue- different regions of the heart4 (see Table 1). For

example, in the mouse myocardium Ito,s and Ito,fspecific expression in the heart.48 Co-expression ofKv4.2 with KChIP1, 2 or 3 increased the density of appear to be encoded by Kv1.4 and Kv4.2/4.3 channels,

respectively4,64 (see Table 1).Kv4.2 currents, indicating that KChIPs may promoteand/or stabilize expression of Kv4.2 at the cell surface. N-type inactivation is the best-understood gating

transition in ion channels. It occurs by a “ball-and-In addition, co-expression changes the biophysicalproperties of heterologously expressed currents such chain” type mechanism wherein an N-terminal

domain (inactivation gate) binds to its receptor atthat they match almost precisely the Ito recordedin rat myocytes.48–50 Another KChIP-related Ca2+- the inner vestibule of the channel thereby physically

blocking the pore.63,65,66 Inactivation domains arebinding protein, called frequenin, is also expressedin heart and increases both Ito density and alters contributed by either the pore-forming alpha-sub-

units or certain auxiliary beta-subunits.34,35 Giventhe inactivation characteristics.51

The cytoskeleton is an intracellular filamentous the steric hindrance posed by the �-subunit/T1domain (T14�4) on the intracellular side of the pore,network of F-actin (microfilament), microtubules,

and intermediate filaments.52 Cytoskeletal changes inactivation peptides appear to gain access to the


pore via lateral openings in the T14/�4 macro- Functional Role of Itodomain.37

A second type of slower inactivation, termed C- Molecular basis for heterogeneity of Ito in the hearttype inactivation, has also been elucidated.59,67 Thistype of inactivation involves conformational Understanding the molecular basis for Ito expression,changes in the outer mouth of the pore.68–71 For function and regulation is central for the under-many channels, C- and N-type inactivation co-exist standing of normal and abnormal cardiac elec-and are, in fact, kinetically linked. Indeed, in the trophysiology. Ito currents can broadly be classifiedabsence of N-type inactivation, entry into the C- into two separate types although considerable di-inactivated state is extremely slow but appears to versity and discrepancies remain to be resolved.occur quickly in the presence of the N-terminal The “rapid” or “fast” Ito, referred to as Ito,f, and theinactivation ball for Kv1.4 channels69 and Shaker slower form of Ito, referred to as Ito,s, have verychannels, the fruit fly homologue of Kv1.4.65,66 Clear rapid activation (�a≈2–10 ms) but differing ratesevidence for the interplay between N- and C-type of inactivation, �i≈25–80 ms and 80–200 ms, andinactivation has been well documented in Kv1.4 recovery from steady-state inactivation,channels where the recovery from inactivation is �rec≈25–80 ms and 1–2 s, respectively.6,49,77–79,80

controlled by exit from the C-type inactivated state These distinct forms of Ito can be further distin-while the fast rate of inactivation is determined by guished on the basis of their differential sensitivityN-type inactivation.69 All members of the Kv4 family to blockade by toxins such as heteropodatox-show rapid inactivation and recovery from in- ins,80–82 hanatoxin83,84 and phrixotoxins85 with vary-activation.59 Simultaneous N-and C-terminal de- ing degrees of specificity. In addition, several phar-letions of the Kv4.1, but not individual deletions, macological agents like flecainide, quinidine andresulted in very modest slowing of inactivation,72 4-amino-pyridine (4-AP) can also block Ito.83,86

suggesting that structural interaction between the Marked differences in the densities of Ito,f andN- and C-termini is required for inactivation in Kv4.1 Ito,s exist between different species as well withinchannels. More recent work has definitively shown different regions in the same heart. Ito,f has beenthat inner vestibule residues not associated with identified in adult ventricular and atrial myocytesthe P-loops of Kv4.1 channel pore are critical for this from most species and has been reasonably wellunique inactivation, called V-type inactivation.60 studied in rat, mouse, human, dog and fer-

The interaction of Kv-subunits with a variety of ret.2,4,82,87 By contrast, rabbit atrial and ventricularancillary proteins can have profound effects on myocytes appear to produce primarily Ito,s cur-the inactivation kinetics (see above). In addition, rents.9,88,89 Ito,f density in rats and Ito,s density inphosphorylation of Kv subunits and/or subunit pep- rabbits are higher in atrium than in ven-tides provides another mechanism for regulating tricle,9,90,91 whereas Ito,f density in mouse showsthe inactivation of Ito. Ca2+/Calmodulin-dependent the opposite pattern.78 Regional variations in Ito,f

protein kinase II (CaMKII) are abundant in the density within the ventricle also appears in can-mammalian heart, with �-CaMKII being the pre- ine,92 cat,93 ferret,82 human,15,94 mouse77,78 anddominant isoform.73 CaMKII-mediated phos- rat95–97 hearts. Many species with significant Ito,f

phorylation of the NH2-terminus of Kv1.4 slows its express Ito,s either within the same cell or inrate of inactivation and accelerates the recovery different myocytes isolated from various regionskinetics.74 The inactivation of Ito,f is also slowed of the heart. Although regional differences in theby CaMKII in human atrial myocytes.75 In Kv3.4 expression of Ito,f and Ito,s exist, the general patternchannels, PKC-mediated phosphorylation of several observed is that Ito,s is preferentially expressed inN-terminal residues leads to reduced inactivation.61, regions of the heart with longer APs, such as76 Kv�1, �2, and �3-subunit protein sequences con- the septum, left ventricular endocardium andtain multiple putative PKA and PKC phos- apex of the heart, while Ito,f expression is favoredphorylation sites, which may modulate its role in in epicardial regions, the right ventricle and themediating inactivation of the Kv sub- base of the heart. Furthermore, the current densityunits.5,32,35 Although Ito has been traditionally con- of Ito,f when present appears to be far greatersidered to be a Ca2+-independent current, the as- than the corresponding levels of Ito,s. This pattern ofsociation of Kv subunits with calcium-binding Ito heterogeneity essentially contributes to regionalproteins such as KChIPs and frequenin as well as variations of AP profiles. This in turn leads to atheir regulation by Ca2+-dependent enzymes sug- more synchronous repolarization throughout thegests that functional Ito currents in heart might in ventricle1,98,99 and might also provide a mechanism

for regional modulation of contractility.100fact be regulated by Ca2+.48,74,75


Regional heterogeneity of AP profiles and Ito have against Kv4.2 or Kv4.3,116 while only AODNs targetedagainst Kv4.2 attenuated Ito,f in rat atrial myocytes.50been well documented in human,94 ferret,82 rat,96

rabbit88 and mouse64,77,80 ventricles (Table 1). For Additional corroborative, but circumstantial, evi-dence for contribution of both Kv4.2 and Kv4.3 to Ito,fexample, in right ventricular or left ventricle apical

myocytes only Ito,f is present, while left ventricular in rat ventricle has been provided by expressionstudies at both the transcriptional and translationalseptal myocytes express Ito,s alone or a combination

of Ito,f and Ito,s.78 In addition, mouse Ito,f density is levels.49,96,113,118,120,121

Further evidence for the contribution of Kv4.Xsignificantly higher in apical than septum cells.78

Similarly, Ito,f and Ito,s in rat appear simultaneously currents to Ito,f has been provided in studies usingadenoviral transfection of dominant-negative Kv4.2in most myocytes although the relative level of Ito,f

compared to Ito,s is far greater in the epicardial mutants in adult myocytes.117 Similar methods wererecently used with neonatal myocytes to establishregions than septum and endocardium.96,97 For lar-

ger mammals like human, ferret and dog, Ito,s is that both Ito,f and Ito,s could be selectively eliminatedby adenoviral transfection with dominant-negativepreferentially expressed in left ventricular en-

docardial cells compared to the left ventricular mutant Kv4.2 (Kv4.2N) and mutant Kv1.4 (Kv1.4N) pro-teins, respectively.119 In transgenic mice expressingepicardial and right ventricular myocytes.82,94,101–103

Substantial changes in Ito density and its expression dominant-negative mutants of Kv4.2 (Kv4.2W362Fand Kv4.2N), Ito,f was largely abolished in atrium78pattern also occur during the postnatal de-

velopment in rats and dogs.104–109 For example, Ito and ventricle118,122 (see Table 2). Despite these find-ings, the issue of whether Kv4.2 or Kv4.3 or bothdensities are about two-fold lower in neonatal rat

ventricular mocytes compared with adult myo- genes are primarily responsible for Ito,f in mouseremains unresolved. Strong support for the con-cytes.106 Moreover, in neonatal myocytes Ito,s and

Ito,f contribute almost equally to the Ito density,105,106 nection between Ito,s and Kv1.4 in the mouse wasrecently generated in myocytes isolated from thewhich contrasts with adult rat myocytes where

Ito,s contributes less than 10% to total Ito.106 ventricular septum of Kv1.4 knockout (Kv1.4−/−)

transgenic mice115 and double transgenics createdAs already mentioned, a number of candidateKv� clones are known to generate Ito-like currents by crossing the Kv4.2(W362F) and Kv1.4

−/− mice.64

Finally, in human atrial myocytes Ito,f was at-when heterologously expressed. Specifically, Kv1.4,Kv1.7, Kv3.4 (low level), Kv4.2 and Kv4.3 clones are tenuated following exposure to Kv4.3 AODNs but

not Kv4.2 AODNs,89 which is consistent with theexpressed in the myocardium6,22 (see Table 1). Basedpurely on their biophysical properties Kv4.2 and/ observation that Kv4.3 is the predominant Ito-en-

coding subunit in humans.23–25 Less direct evidenceor Kv4.3 channels could theoretically contribute tocardiac Ito,f while Kv1.4 and Kv3.4

61 and Kv1.722 have supporting the hypothesis that Kv1.4 encodes for Ito,s

and Kv4.2/3 encode for Ito,f has been derived frommany properties in common with Ito,s. However, theability to relate specific Kv� genes to the distinct studies examining the relationship of the expression

patterns of Kv1.4, Kv4.2 and Kv4.3 with the magnitudecomponents has been hampered by inherent com-plexities associated with modulation of Ito channel of Ito,s and Ito,f. For example, regional variations in

ferret left ventricular epicardial and endocardialfunction by heterotetramer assembly, interactionswith accessory subunits, phosphorylation, electrical myocytes show clear relationships between regional

differences in the expression of Kv1.4 and Kv4.2/Kv4.3activity and other possible cellular factors. Never-theless, the general emerging consensus is that with Ito,s and Ito,f, respectively.82 Similarly, regional

differences in Ito,f and Ito,s in rat ventricles are closelyIto,s is encoded primarily by Kv1.4 channel genes,while Ito,f is generated principally by Kv4.2 and/or connected to the differential expression of Kv4.2/Kv4.3

and Kv1.4.96Kv4.3 genes. This assertion is consistent with earlywork suggesting that Kv1.4 encodes for cardiac The underlying basis for quantitative and qual-

itative differences in the endogenous expressionIto110,111 possibly as a heteromultimer with other

Kv1.X subunits112 as well as the later suggestion that pattern of the Kv1.4 and Kv4.2/3 is unknown, althoughcell-specific repressor elements for Kv� channelsa primary determinant of cardiac Ito is Kv4.2.113

Much more definitive evidence for the Kv� chan- have been described.123 A multitude of factors are,however, known to potentially contribute to thisnels underlying Ito,f and Ito,s has emerged recently

particularly in the mouse atrium114,115 and vent- Ito diversity, including hetero-tetrameric �-subunitformation within a gene family,5,112,124 alternativericle,77,78 rat ventricle,116–119 and the rabbit and

human atrium.89 Specifically, Ito,f is significantly splicing,23,24 post-translation modifications such asglycosylation and phosphorylation,6,125 interactionattenuated in rat ventricular myocytes exposed to

antisense oligodeoxynucleotides (AODNs) targeted with the cytoskeletal network and/or ancillary sub-


agonists and angiotensin II (Ang-II) have beenshown to modulate Ito. For example, acute ap-plication of �-adrenergic agonists causes rapid Ito

reduction in adult rat ventricular myocytes,130–132

rabbit atrial133–135 and ventricular136 myocytes viaPKC-dependent130,137 and independent133 pathways.However, recent evidence suggests that one of theagonists used in these studies, methoxamine, dir-ectly blocks Ito

138 thereby leading to an over-estimation of the ability of �-adrenergic stimulationto inhibit Ito.88,132–134 The acute effects of �-ad-renergic stimulation on Ito current density alsodisplay species specificity. For example, acute ap-

Figure 1 Kv1.4 and Kv4.2 protein levels in rabbit and rat plication of phenylephrine failed to inhibit canineright ventricular (RV) wall. Using specific anti-Kv1.4 andventricular epicardial Ito while purkinje myocyte Itoanti-Kv4.2 antibodies, representative gels from Westernwas inhibited.139 The acute reductions in Ito in rabbitblots are shown for Kv1.4 (A) and Kv4.2 (B) levels in samples

obtained from adult rat brain (positive control), adult atrial myocytes following �-adrenergic activationrabbit RV wall, and adult rat RV wall. Equivalent amount coincided with the observations that phorbol ester,of protein from each specimen was loaded; multiple bands an activator of PKC, produces biphasic effects onin a single column represent glycosylation products (see

currents in oocytes expressing Kv1.4 channels with96).an initial 14% increase followed by a 40% reductionin peak Ito.140 However, whether these changesdepend on in vivo phosphorylation of Kv1.4, as shownunits such as �-subunits, frequenin, KChAP and/in vitro, remains to be determined.140

or KChIP proteins (see above), local (autocrineAs for acute applications of �-adrenergic agonists,and/or paracrine) effects of thyroid hormone and

chronic exposure of cultured neonatal rat vent-angiotensin II,106,126–128 and changes in PKA, PKCricular myocytes to the �-adrenergic agonist,and CaMKII-mediated phosphorylation.55,74,75,129 Al-phenylephrine (PE) also produced reductions inthough it is generally accepted that Kv4.2/4.3 encodesIto

137 that were subsequently shown to be associatedfor Ito,f and Kv1.4 is related to Ito,s, there are ex-with reductions in Kv4.2 and increased in Kv1.4 pro-perimental findings which suggest that our under-tein.141 These changes are particularly relevantstanding is far from complete. For example, rabbitsince similar changes in K+ channel expressionIto shows characteristic features consistent withoccur in heart disease (see below) and increasedthis current being entirely generated by Kv1.4�-cardiac adrenergic stimulation is thought to con-subunits.9,49,79 However, treatment of cultured rab-tribute to disease progression. This observationbit atrial myocytes with ADONs targeted againstraises the intriguing question of whether reductionsKv1.4 resulted in only partial reduction of Ito

89 within Ito are mechanistically linked to the chroniceven large Ito reductions being produced by ADONsstimulatory effects from catecholamines. Althoughagainst Kv4.2 and Kv4.3. Our western blot analysis ofchronic application of endothelin-1 to cultured neo-rabbit myocardium (Fig. 1) suggests further thatnatal rat ventricular myoctes resulted in reducedlarge levels of Kv4.2 as well as Kv1.4 are expressed inKv4.2 protein levels,141 acute application of en-rabbit heart. It also seems likely that other Ito-dothelin-1 (End-1) resulted in no change in Itoforming channels might also contribute to cardiacdensity in adult142 and neonatal ventricular myo-Ito. Specifically, despite the fact that the Kv1.7 channelcytes (Kassiri and Backx, unpublished data).has been shown to be expressed in heart at a high

Acute PKC activation also leads to Ito reduction inlevel, no definitive role for this gene in cardiac Itorat ventricular myocytes and in oocytes expressinghas been established.22

Kv4.2 and Kv4.3 channels143 which does not requireprotein tyrosine kinase (PTK) phosphorylation.143

This PKC-mediated effect was not accompanied bychanges in the biophysical properties of Ito in theseRegulation of Itostudies.143 The modulation of Ito by PKC might bean important mechanism for the reduction of Ito inVarious hormonal and/or paracrine systems have

been shown to modulate the expression and mag- diseases since PKC inhibition was able to reversethe reductions in Ito observed in rat myocytes de-nitude of Ito. In particular, the G-protein-coupled

receptor agonists, endothelin-1, �1-adrenergic rived from hypothyroid126,144 and diabetic126,145


hearts.55 In contrast to the results in rat, PKC Changes in fatty acid metabolism have beenlinked to increased arrhythmogenesis and myo-activation has no effect on Ito in normal and failing

canine ventricular myocytes. As such, the shorter cardial dysfunction during myocardial ischemia andin diabetic hearts.151,152 Fatty acids (and their meta-spliced variant of Kv4.3 that presumably lacks a PKC

phosphorylation site encodes for functional Ito in bolites) and arachidonic acid inhibit Ito density withprolongation of the AP in rat ventricular myo-canine ventricle.25

Ang-II has also been shown to have direct effects cytes.142,153,154 The Kv4.3 current underwent a similarreduction in response to a n-3 polyunsaturatedon Ito in the myocardium. Incubation of canine epi-

cardial ventricular myocytes with Ang-II reduces Ito fatty acid.155 The Ito-suppressing activity ofarachidonic acid was PKC-dependent142 but in-density but more importantly transforms the epi-

cardial fast Ito, assumed to be Kv4.3-based,25,102 into dependent of the intracellular cyclooxygenase path-way.153 Although multiple other putative regulatorya current resembling slow Ito, typical of the canine

endocardium.128 Indeed, changes in biophysical factors of Ito have been described, such as glu-cocorticoid (dexamethasone) exposure,156 acido-properties of these currents resemble closely the dif-

ferences observed between Kv4.X-based currents and sis,157 and oxidative stress,87 their precise physio-logical roles remain to be defined.Kv1.4-based currents.49,80 Remarkably, the Ang-II-

mediated effect occurred without measurablechanges in Kv1.4 and Kv4.3 mRNA levels. Conversely,treatment of the endocardial myocytes with the AT1 Role of Ito in modulating action potential profile and

Ca2+ handlingblocker, losartan, converted slow endocardial Ito intoa much faster Ito resembling that observed in epi-

The influence of Ito on AP profile differs remarkablycardium.128 These observations have profound im-plications in the understanding of Ito by suggesting between different species. Differences in AP duration

resulting from variations in Ito depend critically onthat biophysical properties of Ito can be changed dra-matically without alterations in expression. the kinetics and magnitude of the other repolarizing

and depolarizing currents that are present.11,158Thyroid hormone, a member of the steroid hor-mone superfamily, has profound effects on Ito cur- Moreover, the complex interplay between the vari-

ous currents in myocytes can lead to changes inrents. In rat hearts, hypothyroidism prolongs APduration in conjunction with reduced Ito density, AP profile in response to variations in Ito that are

not readily apparent11 (see Fig. 2). Two currents ofdecreases Kv4.2 expression and increases Kv1.4

levels146 which is likely responsible for slowing Ito particular interest in all species when consideringthe net effects of Ito changes on AP profile are ICa,Lrate of recovery from inactivation.127 Conversely,

hyperthyroidism in rat ventricular myocardium in- and INa/Ca, because of their importance in regulatingmyocardial contractility and in generating arrhy-creases Ito current density with elevated Kv4.2 and

Kv4.3 expression and reduced Kv1.4 expression.106,127, thmias such as early and delayed after de-polarizations (EADs and DADs).141,146 The thyroid hormone T3 (tri-iodothyronine)

may be responsible for the postnatal changes in AP In mice and rats Ito dominates repolarization andis largely responsible for the brief triangular APduration, which have been linked to changes in

the transcriptional and protein patterns Kv1.4, Kv4.2 profile.4,78,106,159 Accordingly, numerous studieshave established that Ito reductions in rat97,116,120,and Kv4.3 genes.106,126,127,141,144,146,147 Indeed, in rat

myocardium, changes in pattern of expression of 160–165 (reviewed in 14) and mouse myocardium77,78,

118,122,166 cause prolongation of the AP during allIto-based genes following treatment with T3 mimicclosely the developmental changes.106,127,141 This phases which leads to enhanced myocardial con-

tractility in transgenic mice.118 Moreover, 4-amino-observation suggests that developmental changesin thyroid status play an important role in the age- pyridine (4-AP)-induced prolongation of the AP

leads to elevated contractility in the working mousedependent electrical remodeling that occurs,106,127

although the expression of many other proteins that heart model.167 In myocytes derived from normaland hypertrophied rat hearts, AP prolongation fol-affect electrical properties in heart are influenced by

thyroid hormone.148–150 This pattern of change in lowing Ito reduction has been shown to increaseL-type Ca2+ influx, enhance peak Ca2+ transientIto-encoding genes readily explains the changes in

Ito recovery kinetics which underlies the dis- amplitude and augment unloaded cell shorten-ing.12,13,120 This augmentation of Ca2+ transientappearance of rate-dependent changes in action

potential duration that occur during develop- amplitude occurs in response to a 75% reductionin Ito but not with a comparable reduction in thement,106 suggesting further that Kv1.4 is linked to

Ito,s while Kv4.2/3 encodes for Ito,f. inward rectifier current (IK1) as illustrated in Figure


Figure 2 Numerical simulations of a canine cardiac AP with varying amounts of Ito conductance. The top row showsmodel APs paced at 1 Hz under control conditions (left), and with Ito conductance reduced by 50% (middle) and 90%(right). APD90 (ms) is 173, 203, and 199, and APD50 (ms) is 52, 92, and 88, respectively from left to right.

3. The underlying basis for the potentiation of ICa,L Ito clearly influences the trajectory of early re-polarization of the AP in large mammals,102,103,169–172can be traced to the effects of Ito on the trajectory of

early repolarization of the AP and its close temporal but the net effect on late repolarization is complex.Although some earlier studies from human andassociation with the L-type Ca2+ channel (LCC)

gating.12 Indeed, slowing of early repolarization canine ventricular cells showed an association be-tween reductions in Ito and overall AP prolonga-increases net Ca2+ entry via ICa,L which, in turn,

enhances excitation–contraction coupling and section,102,170,173,174 more recent work in the rabbitMI model,171 canine rapid pacing model,169 and inondarily helps load the sarcoplasmic reticulum with

Ca2+.12,100,168 Collectively, these results also support computer modeling studies10,175,176 suggest that theconsequences of Ito reductions depend critically ona role for changes in Na+/Ca2+ exchanger activity

under conditions where Ito is reduced in rat myo- complex interactions of Ito with ICa,L, INa/Ca, anddelayed rectifier currents. For example, in the can-cytes (see 120, although this has not been previously

studied in a systematic manner). Model com- ine ventricular AP model, reductions in Ito levelsobserved in diseased myocytes had minimal effectsputations of a canine mid-myocardial cell have

nicely illustrated the complex interactions of Ito on AP duration after phase 1 repolarization innormal myocytes, but these Ito reductions producedwith ICa,L and INa/Ca as well as their effects on Ca2+

cycling.11,169 massive prolongation in diseased myocytes whenchanges in Na+/Ca2+ exchange activity as observedIn larger mammals, the role of Ito in setting the

profile of the action potential is more controversial. in disease were included.169,176 Similarly, in a canine


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atrial AP model,177 reduction in Ito beyond 50% and molecular changes have been found to be eitherregionally dependent100,184 or regionally in-does not cause further AP prolongation (Fig. 2)

because of increased voltage-dependent recruitment dependent.181 By contrast, Ito,s as well as Kv1.4 mRNAand protein expression are increased in the ratof the delayed rectifier currents, IKR and IKS. More-

over, using the human atrial AP model,10 APD90 infarct model at 6–8 weeks but not at 3 weekspost-infarction120,121 and in renovascular hyper-is significantly reduced following 50% and 90%

reduction in Ito (APD90=299, 275 and 259 ms at tensive rats,178 suggesting that transcriptional con-trol of Kv1.4 is likely to be both time- and model-100%, 50% and 10% of control Ito, respectively).

On the other hand, simulations in both failing and dependent. A recent transgenic murine model ofheart failure has demonstrated a marked down-non-failing human ventricular myocyte models11

predict that a direct connection between reductions regulation of Ito associated with AP prolongationduring the hypertrophy stage.166in Ito and AP prolongation, as observed in rodents,

occurs when Ito densities are large, as might be the The electrophysiological changes in heart diseasehave also been studied in two canine models. Likecase for human epicardial myocytes.94,170

the rat, subendocardial canine myocytes survivinginfarction show AP prolongation as well as re-ductions in Ito density and changes in its kineticswithin 2–5 days of infarction.186–188 Unfortunately,Role of Ito in Disease Statesno molecular correlates for these electrical changeshave been investigated. In the pacing-induced can-Downregulation of Itoine cardiomyopathy model, AP prolongation hasbeen associated with reductions in fast Ito,f in bothA central and consistent electrophysiological

change in cardiac hypertrophy has been the reduc- the ventricular102 and atrial myocytes.189 The re-ductions in Ito,f in canine ventricle from this modeltion in Ito, namely Ito,f with concomitant changes in the

level of expression of the Kv�-subunits.25,102,103,120,178 are due entirely to reductions in the shorter splicedvariant of Kv4.3.25 Unfortunately, despite measurableCompared to normal patients, myocytes derived

from terminal heart failure patients have prolonged expression of Ito,s in the dog endocardium128 andsignificant increases in Kv1.4 levels in the myo-AP duration and reduced Ito densities in the epi-

cardial myocytes94,170,179 without significant dif- cardium of paced dogs,25 the changes of Ito in theendocardium of the pacing dog model remains toferences in endocardial myocytes.94 These electrical

differences occur without significant kinetic or be determined. In addition, pacing-induced failureis associated with decreased Ito and AP prolongationsteady-state gating changes in the properties of

Ito,180 which are fast in the epicardium (Ito,f) and in rabbits.172,190

As discussed above, the mechanism for Ito down-slow in the endocardium (Ito,s).94 The Ito,f reductionsin the epicardium are linked to decreased mRNA regulation and loss of transmural heterogeneity in

myocardial hypertrophy and heart failure is likelyexpression of Kv4.3, consistent with this protein en-coding for Ito,f in human heart.103 mediated by a wide array of changes in neuro-

humoral and paracrine factors, regulatory subunitsIn the rat ventricle, there are temporal changesin the biophysical properties and expression of Ito and/or cytoskeleton and cell metabolism. A clear

example of the importance of neurohumoral ac-following myocardial infarction, leading to AP pro-longation. Ito and Kv4.2 and/or Kv.3 protein levels are tivation in mediating dysregulation of Ito is the

ability of the angiotensin receptor (AT1) antagonist,decreased while APs are prolonged within 3 daysin the left non-infarcted myocardium163 (Kaprielian losartan, and ACE inhibitors to reverse the changes

in AP duration and Ito density in spontaneouslyand Backx, unpublished data). At 3–8 weeks post-infarction, Ito,f and Kv4.2/3 expression levels are fur- hypertensive rats.182,183 Moreover, the use of an

ACE inhibitor in renovascular hypertensive ratsther decreased in the non-infarcted left121 and rightventricle120 and these changes persist at 4–6 months completely restores Kv4.2 and Kv4.3 mRNA levels,

178 and short exposure to Ang-II modulates thepost-infarction.161,181 Similar reductions in Ito andAP prolongation have been observed in other rat biophysical characteristics of Ito in canine vent-

ricular myocytes.128 In the pacing-induced caninemodels of heart disease in spontaneously hyper-tensive rats,182,183 catecholamine toxicity,184 aortic- model of heart failure, a local renin–angiotensin

system (RAS) is upregulated with increased localbanded rats,97 and monocrotaline-induced rightventricular hypertrophy.185 The expression levels of production of Ang-II.191 The important patho-

physiological role for the intra-cardiac and systemicKv4.2 and Kv4.3 mRNA were reduced in renovascularhypertensive rats.178 Furthermore, these electrical RAS191–193 is highlighted by clinical data which


show that ACE inhibitors and AT1 receptor blockers Nevertheless, changes in early repolarization inresponse to decreases of Ito will influence the levelreduce morbidity and mortality, particularly from

sudden cardiac death, in patients with congestive of activity of the L-type Ca2+ channel (LCC), Na+/Ca2+ exchangers and other currents.11,12,100,171 APheart failure.194–197 It is intriguing to speculate

whether the protective effects of these agents are profile is an important regulator of intracellularCa2+ handling11,176,211–214 and primarily involvesrelated, in part, to effects on Ito.modulation of the LCC and electrogenic Na+/Ca2+

exchanger. In the rodent heart, prolonged de-polarization enhances Ca2+ entry via the LCC andLinking Altered Ito Physiology to Ca2+ Dysregulation and

Arrhythmogenesis retards Ca2+ extrusion via the Na+/Ca2+ exchanger,thereby loading the cell with Ca2+ and enhancing

About 50% of heart failure patients die from sudden SR Ca2+ release.12,13,215 Since increases in the amp-litude of the [Ca2+]i transient exert a positive ino-cardiac death,198 often as a result of ventricular

tachycardia or fibrillation.199,200 Heart failure and tropic effect, it seems plausible that the reductionin K+ channel expression and AP prolongationmyocardial hypertrophy are associated with elec-

trical remodeling and defects in repolarization in- represents an early compensatory response of theheart to increased demand. These membrane-de-volving a wide and complex array of changes in

ion channels, transporters and calcium-handling pendent changes in Ca2+ homeostasis can also beimportant determinants of gene expression in aproteins.201 In addition, changes in Ito may have a

pro-arrhythmogenic role in iron-overload (hemo- number of excitable cells and might be linked todisease pathogenesis.218–220 A cardiac-specific over-chromatosis) cardiomyopathy,202 atrial fib-

rillation203 and drug-induced arrhythmias.204,205 expression of the �-subunit of the LCC, which res-ulted in increased ICa,L current density, myocardialCurrently, the relationship between these ab-

normalities in repolarization and arrhythmias, hypertrophy and an age-dependent cardio-myopathy, has highlighted the pathophysiologicalcausing sudden death, are still poorly understood.

AP profiles in normal and disease myocytes depend importance of the LCC.216,217 Elevated [Ca2+]i tran-sients have also been recorded in rodent models ofon a delicate balance between depolarizing (L-type

Ca2+, ICaL, sodium, INa, and sodium-calcium ex- moderate cardiac hypertrophy120,162 and in 3–4-week-old transgenic mice over-expressing Kv4.2N tochanger, INa/Ca) and hyperpolarizing (Ito, IK, IK1, ICl

and Na+/K+-ATPase) currents. There is increasing reduce Ito,f.118 In addition, changes in gene ex-pression induced by neurohumoral factors (no-evidence that K+ current downregulation con-

tributes significantly to altered repolarization in repinephrine, End-1 and Ang-II) and the activationof their corresponding signaling cascades have allheart disease.99,206 As already discussed, Ito density

appears to be reduced in hypertrophied and failing been shown to be dependent on Ca2+.221–230

AP prolongation also predisposes the heart tohearts regardless of the species, precipitating factorsor the stage of the disease. characteristic EADs and/or DADs.231–233 EADs arise

from an imbalance between depolarizing currentsDecreased Ito would, therefore, appear to be aplausible contributor to AP prolongation in cardiac (primarily ICa,L with possible contributions from the

Na+/Ca2+ exchanger) and repolarizing K+ currentshypertrophy and failure, although the role of otherrepolarizing or depolarizing currents also needs to during late phase 2 of the AP. DADs on the other

hand are linked to elevated [Ca2+]i and spontaneousbe considered.14,169,207 Indeed, studies in the dogpacing model, in human patients and rat models Ca2+ release leading to membrane depolarization

via the Na+/Ca2+ exchanger.231,234–236 While theof disease have suggested that reductions in re-polarizing currents are critical factors in AP pro- precise contribution of reductions of Ito to AP pro-

longation and arrhythmias remains uncertain inlongation,102,120,160,208–210 despite the fact that Ito

primarily affects the early repolarization period. large mammals, its influence is almost certain tovary regionally and this might exaggerate the dis-While this result seems solid in rodents, as es-

tablished by the recent transgenic results in which persion of refractoriness which predispose to re-entry types of arrhythmias.76,233 By contrast, directIto,f and Ito,s have been eliminated,64,99,118,122 recent

results in the dog pacing model have suggested that links between reductions in Ito, AP prolongationand arrhythmias have recently been demonstratedchanges in other currents generated by inward

rectifier channels and Na+/Ca2+ exchangers are in binary transgenic mice lacking both Ito,s andIto,f.64 These binary mice show evidence for AV nodalessential for explaining AP prolongation.169,207 Spe-

cifically, a bimodal effect on AP duration is observed heart block, and multiple isorhythmic tachycardicventricular dissociation64 which are precursors forwhen Ito density changes (see above).


Table 2 Gene-targeted murine models of Ito downregulation

Model K change APD QT interval Arrhythmias HYP/ Referencefailure

Kv1.1N206 ↔Ito ↑APD50 ↑ Spontaneous No 99, 245, 246Tag DN ↓Iss ↑APD90 and inducible

↓Kv1.4 VT↓Kv1.5

Kv1.4 ↔Ito,f NR ↔ NR No 115Knockout ↔Kv4.2/3

↓Ito,s ↓Iss

Kv4.2W362F ↑Ito,s (V. apex) ↑APD50 ↑ No inducible or No 122DN ↔Ito,s (septum) ↑APD90 spontaneous

↓Kv4.2 VT↑Kv1.4

Kv4.2N ↓Ito ↑APD50 ↑ NR Yes∗ 118DN ↓Ik1 ↑APD90

Kv4.2W362F/ Ito,f and Ito,s ↑APD50 ↑ Spontaneous No 64Kv1.4

−/− eliminated ↑APD90 VT; EADAV block

DN=dominant-negative; V. apex=ventricular apex; EAD=early afterdepolarization; HYP=hypertrophy; AV block=atrio-ventricularblock; VT=ventricular tachycardia; NR=not reported; ↑=increased; ↔=no change.∗ Preceded by a hypercontractile state.

fibrillation. At the cellular level, there was also an physiological role of Ito has still not been fullyresolved due to complex interplay with other ionicincreased frequency of early after-depolarizations

in these binary transgenic mice. By contrast, elim- currents which are only now being understoodwith the help of computer modeling. Althoughination of Ito,f alone, which comprises most of the

normal adult Ito in the mouse,80 did not increase the there is strong evidence for transcriptional andtranslational regulation of Ito, further studies arepropensity for arrhythmias or abnormal myocyte

repolarization78,122 which is presumably related to clearly needed to dissect the molecular mechanismsunderlying the alterations in Ito that occur duringthe upregulation of Ito,s in the Ito,f knockout model

(see Table 2). The unique presence of cardiac hyper- development, within different regions of the heart,in response to various neurohumoral factors andtrophy and dilated cardiomyopathy in the Kv4.2N

dominant-negative murine model may represent a in cardiovascular disease. The in vivo modulation ofIto using gene transfer techniques may also provide acombination of altered Ito physiology and other

biochemical and/or molecular changes.64,118 Al- useful tool to elucidate its precise physiological roleand to explore any potential therapeutic role forthough a primary reduction in Ito was not ac-

companied by myocyte hypertrophy,64,122 there changing the biophysical properties of Ito.remains the intriguing possibility that alterationsin Ito physiology may play an important role inmodulating the hypertrophic response to neuro-humoral hormones and/or mechanical stress.

Acknowledgements

We acknowledge the financial support from theFuture PerspectivesCanadian Institute for Health Research (formerlyMRC) (GYO, RS, PHB), Heart and Stroke FoundationThe transient outward potassium current (Ito) plays

an important role in repolarization of the cardiac of Ontario (ZK, PHB), Heart and Stroke/RichardLavar Centre of Excellence (RJR), VERUM Founda-AP. The biophysical and molecular basis for Ito is

beginning to be understood along with a better tion for Behavior and Environment and DeutscheForschungsgemeinschaft (ZO 112/1-1) (CZ). PHBappreciation of the species and regional differences

of its expression. Despite being one the best studied is a Career Investigator of the Heart and StrokeFoundation of Ontario.currents in cardiac electrophysiology, the precise


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