Cardiac ion channels in health and disease
2009; Elsevier BV; Volume: 7; Issue: 1 Linguagem: Inglês
10.1016/j.hrthm.2009.08.005
ISSN1556-3871
AutoresAhmad S. Amin, Hanno L. Tan, Arthur A.M. Wilde,
Tópico(s)Cardiac pacing and defibrillation studies
ResumoCardiac electrical activity depends on the coordinated propagation of excitatory stimuli through the heart and, as a consequence, the generation of action potentials in individual cardiomyocytes. Action potential formation results from the opening and closing (gating) of ion channels that are expressed within the sarcolemma of cardiomyocytes. Ion channels possess distinct genetic, molecular, pharmacologic, and gating properties and exhibit dissimilar expression levels within different cardiac regions. By gating, ion channels permit ion currents across the sarcolemma, thereby creating the different phases of the action potential (e.g., resting phase, depolarization, repolarization). The importance of ion channels in maintaining normal heart rhythm is reflected by the increased incidence of arrhythmias in inherited diseases that are linked to mutations in genes encoding ion channels or their accessory proteins and in acquired diseases that are associated with changes in ion channel expression levels or gating properties. This review discusses ion channels that contribute to action potential formation in healthy hearts and their role in inherited and acquired diseases. Cardiac electrical activity depends on the coordinated propagation of excitatory stimuli through the heart and, as a consequence, the generation of action potentials in individual cardiomyocytes. Action potential formation results from the opening and closing (gating) of ion channels that are expressed within the sarcolemma of cardiomyocytes. Ion channels possess distinct genetic, molecular, pharmacologic, and gating properties and exhibit dissimilar expression levels within different cardiac regions. By gating, ion channels permit ion currents across the sarcolemma, thereby creating the different phases of the action potential (e.g., resting phase, depolarization, repolarization). The importance of ion channels in maintaining normal heart rhythm is reflected by the increased incidence of arrhythmias in inherited diseases that are linked to mutations in genes encoding ion channels or their accessory proteins and in acquired diseases that are associated with changes in ion channel expression levels or gating properties. This review discusses ion channels that contribute to action potential formation in healthy hearts and their role in inherited and acquired diseases. Cardiac electrical activity starts by the spontaneous excitation of "pacemaker" cells in the sinoatrial node (SAN) in the right atrium. By traveling through intercellular gap junctions, the excitation wave depolarizes adjacent atrial myocytes, ultimately resulting in excitation of the atria. Next, the excitation wave propagates via the atrioventricular node (AVN) and the Purkinje fibers to the ventricles, where ventricular myocytes are depolarized, resulting in excitation of the ventricles. Whereas on the surface electrocardiogram, atrial and ventricular excitation are represented by the P wave and the QRS complex, respectively, depolarization of each atrial or ventricular myocyte is represented by the initial action potential (AP) upstroke (phase 0), where the negative resting membrane potential (approximately −85mV) depolarizes to positive voltages. Restitution of the resting membrane potential during AP phases 1, 2, and 3 results in atrial and ventricular repolarization (Figures 1A and 1B).APs constitute changes in the membrane potential of cardiomyocytes. The membrane potential is established by an unequal distribution of electrically charged ions across the sarcolemma (electrochemical gradient) and the presence of conducting ion channels in the sarcolemma. Opening and closing (gating) of ion channels enable transmembrane ion currents and, as a result, AP formation. Ion channels consist of pore-forming α-subunits and accessory β-subunits.1Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Crossref PubMed Scopus (735) Google Scholar Commonly, α-subunits and β-subunits are members of large protein families that evolutionary possess comparable amino acid sequences. This is reflected in the names of the subunits and their genes. For example, the gene encoding the α-subunit of the cardiac Na+ channel is called SCN5A: sodium channel, type 5, α-subunit. The α-subunit is termed Nav1.5: Na+ channel family, subfamily 1, member 5; the subscript "V" means that channel gating is regulated by transmembrane voltage changes (voltage dependent).The direction of ion currents (into the cell [inward] or out of the cell [outward]) is determined by the electrochemical gradient of the corresponding ions. The current amplitude (I) depends on the membrane potential (V) and the conductivity (G) of the responsible ion channels. This relation is expressed in equation form as I = V · G (as resistance [R] is the reverse of conductivity: I = V/R [Ohm's law]), implying that the current amplitude reacts linearly ("ohmically") in response to membrane potential changes. However, some currents do not act ohmically (so-called rectifying currents). The conductivity of channels carrying such currents is not constant but alters at different membrane potentials. Rectifying currents in the heart are the inward rectifying current (IK1) and the outward rectifying currents (see below). Channels carrying outward rectifying currents preferentially conduct K+ ions during depolarization (potentials positive to K+ equilibrium potential [approximately −90 mV]) when the currents are outwardly directed. Channels carrying IK1 preferentially conduct K+ ions at potentials negative to K+ equilibrium potential when the currents are inwardly directed. Nevertheless, IK1 channels also conduct a substantial outward current at membrane potentials between −40 and −90 mV. Within this voltage range, outward IK1 is larger at more negative potentials. Because membrane potentials negative to the K+ equilibrium potential are not reached in cardiomyocytes, only the outward IK1 plays a role in AP formation.Cardiac APIn general, the resting potential of atrial and ventricular myocytes during AP phase 4 (resting phase) is stable and negative (approximately −85 mV) due to the high conductance for K+ of the IK1 channels. Upon excitation by electrical impulses from adjacent cells, Na+ channels activate (open) and permit an inward Na+ current (INa), which gives rise to phase 0 depolarization (initial upstroke). Phase 0 is followed by phase 1 (early repolarization), accomplished by the transient outward K+ current (Ito). Phase 2 (plateau) represents a balance between the depolarizing L-type inward Ca2+ current (ICa,L) and the repolarizing ultra-rapidly (IKur), rapidly (IKr), and slowly (IKs) activating delayed outward rectifying currents. Phase 3 (repolarization) reflects the predominance of the delayed outward rectifying currents after inactivation (closing) of the L-type Ca2+ channels. Final repolarization during phase 3 is due to K+ efflux through the IK1 channels (Figure 1C).In contrast to atrial and ventricular myocytes, SAN and AVN myocytes demonstrate slow depolarization of the resting potential during phase 4. This is mainly enabled by the absence of IK1, which allows inward currents (e.g., pacemaker current [If]) to depolarize the membrane potential. Slow depolarization during phase 4 inactivates most Na+ channels and decreases their availability for phase 0. Consequently, in SAN and AVN myocytes, AP depolarization is mainly achieved by ICa,L and the T-type Ca2+ current (ICa,T; Figure 1D).2Mangoni M.E. Nargeot J. Genesis and regulation of the heart automaticity.Physiol Rev. 2005; 88: 919-982Crossref Scopus (417) Google ScholarSubstantial differences in the expression levels of ion channels underlie substantial heterogeneity in AP duration and configuration between cardiomyocytes located in different cardiac regions.1Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Crossref PubMed Scopus (735) Google Scholar Changes in expression levels or gating properties of ion channels in pathologic conditions may aggravate such regional heterogeneities, thereby generating spatial voltage gradients that are large enough to initiate excitation waves from regions with more positive potentials to regions with less positive potentials. Such excitation waves may travel along a constant or variable circuit to excite cells repeatedly (reentry); this represents the arrhythmogenic mechanism of many inherited and acquired cardiac diseases.1Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Crossref PubMed Scopus (735) Google ScholarNa+ current (INa)By enabling phase 0 depolarization in atrial, ventricular, and Purkinje APs, INa determines cardiac excitability and electrical conduction velocity. The α-subunit of cardiac Na+ channels (Nav1.5, encoded by SCN5A) encompasses four serially linked homologous domains (DI–DIV), which fold around an ion-conducting pore (Figure 2A). Each domain contains six transmembrane segments (S1–S6). S4 segments are held responsible for voltage-dependent activation. At the end of phase 0, most channels are inactivated and can be reactivated only after recovery from inactivation during phase 4. Some channels remain open or reopen during phases 2 and 3, and they carry a small late Na+ current (INaL).3Meregalli P.G. Wilde A.A. Tan H.L. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?.Cardiovasc Res. 2005; 67: 367-378Crossref PubMed Scopus (298) Google Scholar Despite its minor contribution in healthy hearts, INaL may play an important role in diseased hearts. Cardiac Na+ channels are blocked by high concentrations of tetrodotoxin. Their gating properties usually are studied by expression of SCN5A in heterologous systems (e.g., Xenopus oocytes or human embryonic kidney cells). INa amplitude increases and its gating properties accelerate when SCN5A is co-expressed with its β-subunits (Table 1). Nav1.5 also interacts with several regulatory proteins that can alter its expression or function.3Meregalli P.G. Wilde A.A. Tan H.L. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?.Cardiovasc Res. 2005; 67: 367-378Crossref PubMed Scopus (298) Google Scholar, 4Ueda K. Valdivia C. Medeiros-Domingo A. et al.Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex.Proc Natl Acad Sci U S A. 2008; 105: 9355-9360Crossref PubMed Scopus (267) Google Scholar, 5Morita H. Wu J. Zipes D.P. The QT syndromes: long and short.Lancet. 2008; 372: 750-763Abstract Full Text Full Text PDF PubMed Scopus (258) Google ScholarFigure 2α-Subunits of cardiac ion channels. A: α-Subunits of Na+ and Ca2+ channels consists of four serially linked homologous domains (DI–DIV), each containing six transmembrane segments (S1–S6). B, C: α-Subunits of channels responsible for Ito, IKur, IKr, IKs, IK1, and If consist of one single domain with six (B) or two (C) (IK1) transmembrane segments. Four subunits (domains) co-assemble to form one functional channel.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Genetic and molecular basis of cardiac ion currentsCurrentα-SubunitGeneβ-subunit(s)/accessory proteinsGeneBlocking agentINaNav1.5SCN5Aβ1β2β3β4SCN1BSCN2BSCN3BSCN4BTetrodotoxinIto,fastKv4.3KCND3MiRP1MiRP2KChIPsDPP6KCNE2KCNE3Multiple genesDPP64-aminopyridineHeteropoda spider toxinsIto,slowKv1.4KCNA4Kvβ1Kvβ2Kvβ3Kvβ4KCNB1KCNB2KCNB3KCNB44-aminopyridineICa,LCav1.2CACNA1CCavβ2Cavα2δ1CACNB2CACNA2D1Cations (Mg2+, Ni2+, Zn2+)DihydropyridinesPhenylalkylaminesBenzothiazepinesICa,TCav3.1Cav3.2CACNA1GCACNA1HSimilar as ICa,L (potency may differ)IKurKv1.5KCNA5Kvβ1Kvβ2KCNAB1KCNAB24-aminopyridineIKrKv11.1KCNH2MiRP1KCNE2E-4031IKsKv7.1KCNQ1minKKCNE1Chromanol-293BIK1Kir2.1KCNJ2Ba2+If (pacemaker current)HCN1-4HCN1-4Cs+ Open table in a new tab Inherited diseasesNa+ channel dysfunction is linked to several inherited arrhythmia syndromes, emphasizing the important role of this channel in cardiac electrical activity. Long QT syndrome (LQTS) is a repolarization disorder with QT interval prolongation and increased risk for torsades de pointes ventricular tachycardia and ventricular fibrillation. In LQTS type 3 (LQT3), mutations in SCN5A delay repolarization, mostly by enhancing INaL (Figure 3). Delayed repolarization may trigger early afterdepolarizations (EADs; abnormal depolarizations during phase 2 or 3 due to reactivation of L-type Ca2+ channels). EADs are believed to initiate torsades de pointes.5Morita H. Wu J. Zipes D.P. The QT syndromes: long and short.Lancet. 2008; 372: 750-763Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar Accordingly, drugs that block INaL (e.g., ranolazine, mexiletine) may effectively shorten repolarization in LQT3 patients.6Moss A.J. Zareba W. Schwarz K.Q. Rosero S. McNitt S. Robinson J.L. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome.J Cardiovasc Electrophysiol. 2008; 19: 1289-1293Crossref PubMed Scopus (216) Google Scholar Moreover, mutations in genes encoding Na+ channel regulatory proteins may cause rare types of LQTS (Table 2), indicating the importance of these proteins for normal channel function.4Ueda K. Valdivia C. Medeiros-Domingo A. et al.Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex.Proc Natl Acad Sci U S A. 2008; 105: 9355-9360Crossref PubMed Scopus (267) Google Scholar, 5Morita H. Wu J. Zipes D.P. The QT syndromes: long and short.Lancet. 2008; 372: 750-763Abstract Full Text Full Text PDF PubMed Scopus (258) Google ScholarFigure 3Long QT syndrome (LQTS). A: Typical ECG abnormalities in LQTS type 2. B: QT prolongation corresponds to prolonged action potential duration, which may induce early afterdepolarizations (EADs). C: Ion current dysfunctions linked to different types of LQTS.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Genetic basis of inherited cardiac diseasesTypeOccurrence (or % of genotyped)GeneProteinProtein functionAffected currentLong QT Syndrome142%–54%KCNQ1Kv7.1α-subunit IKs channelIKs decrease235%–45%KCNH2Kv11.1α-subunit IKr channelIKr decrease31.7%–8%SCN5ANav1.5α-subunit Na+ channelINaL increase4<1%ANK2Ankyrin-BAdaptor proteinNone5<1%KCNE1minKβ-subunit IKs channelIKs decrease6<1%KCNE2MiRP1β-subunit IKr channelIKr decrease7RareKCNJ2Kir2.1α-subunit IK1 channelIK1 decrease8RareCACNA1CCav1.2α-subunit Ca2+ channelICa,L increase9Rare (1.9% in one study)CAV3Caveolin-3Component of caveolae (co-localizes with Nav1.5 at sarcolemma)INaL increase10<0.1%SCN4Bβ4β-subunit Na+ channelINaL increase11Rare (2% in one study)AKAP9YotiaoMediates IKs channel phosphorylationInadequate IKs increase during β-adrenergic stimulation12Rare (2% in one study)SNTA1α1-syntrophinRegulates Na+ channel functionINaL increaseShort QT Syndrome1Three familiesKCNH2Kv11.1α-subunit IKr channelIKr increase2Two case reportsKCNQ1Kv7.1α-subunit IKs channelIKs increase3One family (two members)KCNJ2Kir2.1α-subunit IK1 channelIK1 increaseBrugada Syndrome—10%–30%SCN5ANav1.5Na+ channel (INa)INa decrease—Rare (one family)GPD1-LGPD1-LRegulates intracellular Nav1.5 traffickingINa decrease—<1%SCN1Bβ1β-subunit Na+ channelINa decrease—<1%SCN3Bβ3β-subunit Na+ channelINa decrease—<1%KCNE3MiRP2β-subunit Ito,fast channelIto,fast increase—<8.5%CACNA1CCav1.2α-subunit Ca2+ channelICa,L decrease—<8.5%CACNB2Cavβ2β-subunit Ca2+ channelICa,L decreaseFamilial Atrial Fibrillation—One (small) familyKCNE3MiRP2β-subunit Ito,fast channelIto,fast increase—Three familiesKCNA5Kv1.5α-subunit IKur channelIKur increase—One familyKCNH2Kv11.1α-subunit IKr channelIKr increase—Two familiesKCNE2MiRP1β-subunit IKr channel (may modulate IKs channel)IKs increase—One familyKCNQ1Kv7.1α-subunit IKs channelIKs increase—One familyKCNJ2Kir2.1α-subunit IK1 channelIK1 increase Open table in a new tab Brugada syndrome is traditionally linked to mutations in SCN5A that reduce INa by different mechanisms (Figure 4). Brugada syndrome is characterized by prolonged conduction intervals, right precordial ST-segment elevation, and increased risk for ventricular tachyarrhythmia. Prolonged conduction intervals are attributed to conduction slowing due to INa reduction (Figure 5). ST-segment elevation is hypothesized to be due to preferential conduction slowing in the right ventricle and/or aggravation of transmural voltage gradients (AP shortening in epicardial but not endocardial myocytes).3Meregalli P.G. Wilde A.A. Tan H.L. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?.Cardiovasc Res. 2005; 67: 367-378Crossref PubMed Scopus (298) Google Scholar Recently, Brugada syndrome has also been linked to mutations in genes encoding Na+ channel β-subunits or a protein involved in intracellular Nav1.5 trafficking (Table 2).7Watanabe H. Koopmann T.T. Le Scouarnec S. et al.Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.J Clin Invest. 2008; 118: 2260-2268Crossref PubMed Scopus (395) Google Scholar, 8Hu D. Barajas–Martinez H. Burashnikov E. et al.A mutation in the β3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.Circ Cardiovasc Genet. 2009; 2: 270-278Crossref PubMed Scopus (215) Google Scholar, 9London B. Michalec M. Mehdi H. et al.Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.Circulation. 2007; 116: 2260-2268Crossref PubMed Scopus (372) Google Scholar Of note, use of Na+ channel blocking drugs may evoke or aggravate Brugada syndrome (see http://www.brugadadrugs.org) and is discouraged in patients (suspected of) having Brugada syndrome.Figure 4Common molecular mechanisms responsible for ion channel loss of function or gain of function in inherited and/or acquired cardiac diseases.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Brugada syndrome (BrS). A: Typical ECG abnormalities in Brugada syndrome. B: Brugada syndrome is often linked to INa loss of function, leading to slowed action potential depolarization.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Cardiac conduction disease is manifested by progressive conduction defects at the atrial, atrioventricular, and/or ventricular level and is commonly associated with SCN5A mutations that are also linked to Brugada syndrome. How a single mutation may cause different phenotypes or combinations thereof is often not known.3Meregalli P.G. Wilde A.A. Tan H.L. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?.Cardiovasc Res. 2005; 67: 367-378Crossref PubMed Scopus (298) Google Scholar Dilated cardiomyopathy is a familial disease with ventricular dilation and failure. The few reported cases with SCN5A mutation display atrial and/or ventricular arrhythmia. Dilated cardiomyopathy–linked SCN5A mutations cause divergent changes in gating, but how such changes evoke contractile dysfunction and arrhythmia is not understood.10Nguyen T.P. Wang D.W. Rhodes T.H. George Jr, A.L. Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia.Circ Res. 2008; 102: 364-371Crossref PubMed Scopus (68) Google Scholar Finally, mutations in SCN5A have occasionally been linked to sick sinus syndrome, which includes sinus bradycardia, sinus arrest, and/or sinoatrial block. SCN5A mutations may impair sinus node function by slowing AP depolarization or prolonging AP duration in SAN cells.11Smits J.P. Koopmann T.T. Wilders R. et al.A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families.J Mol Cell Cardiol. 2005; 38: 969-981Abstract Full Text Full Text PDF PubMed Scopus (163) Google ScholarAcquired diseasesINa reduction and/or INaL increase may contribute to arrhythmogenesis in acquired diseases. In atrial fibrillation (AF), chronic tachyarrhythmia alters expression levels of several ion channels in atrial myocytes, which may promote and maintain AF ("electrical remodeling"). Nav1.5 expression is reduced as part of this process, leading to INa reduction.12Nattel S. Maguy A. Le Bouter S. Yeh Y.H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.Physiol Rev. 2007; 87: 425-456Crossref PubMed Scopus (644) Google Scholar Moreover, AF (either familial or secondary to cardiac diseases [nonfamilial]) is linked to both SCN5A loss-of-function mutations and gain-of-function mutations.13Tsai C.T. Lai L.P. Hwang J.J. Lin J.L. Chiang F.T. Molecular genetics of atrial fibrillation.J Am Coll Cardiol. 2008; 52: 241-250Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar INa loss of function may provoke AF by slowing atrial electrical conduction, whereas gain of function may induce AF by enhancing spontaneous excitability of atrial myocytes.14Li Q. Huang H. Liu G. et al.Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing.Biochem Biophys Res Commun. 2009; 380: 132-137Crossref PubMed Scopus (86) Google Scholar In heart failure, peak INa is reduced, while INaL is increased. Decreased SCN5A expression may underlie peak INa reduction. INaL increase is attributed to increased phosphorylation of Na+ channels, when intracellular Ca2+ in heart failure rises.12Nattel S. Maguy A. Le Bouter S. Yeh Y.H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.Physiol Rev. 2007; 87: 425-456Crossref PubMed Scopus (644) Google Scholar In myocardial infarction, myocytes in the surviving border zone of the infarcted area exhibit decreased INa due to reduced Na+ channel expression and altered gating.12Nattel S. Maguy A. Le Bouter S. Yeh Y.H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.Physiol Rev. 2007; 87: 425-456Crossref PubMed Scopus (644) Google Scholar Moreover, Na+ channel blocking drugs increase the risk for sudden death in patients with ischemic heart disease, possibly by facilitating the initiation of reentrant excitation waves. Finally, INaL increases during myocardial ischemia, explaining why INaL inhibition may be an effective therapy for chronic stable angina.6Moss A.J. Zareba W. Schwarz K.Q. Rosero S. McNitt S. Robinson J.L. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome.J Cardiovasc Electrophysiol. 2008; 19: 1289-1293Crossref PubMed Scopus (216) Google ScholarTransient outward K+ current (Ito)Ito supports early repolarization during phase 1. The transient nature of Ito is secondary to its fast activation and inactivation upon depolarization. Ito displays two phenotypes. Ito,fast recovers rapidly from inactivation, and its α-subunit (Kv4.3) is encoded by KCND3. Ito,slow recovers slowly from inactivation; its α-subunit (Kv1.4) is encoded by KCNA4.1Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Crossref PubMed Scopus (735) Google Scholar Like other members of the voltage-gated K+ channel family (Kv family; Table 1), Kv4.3 and Kv1.4 contain one domain with six transmembrane segments (Figure 2B). Four subunits co-assemble to form one channel. Kv4.3 is abundantly expressed in the epicardium and is responsible for shorter AP duration there compared to endocardium, where Kv1.4 is expressed to a much lesser extent. This creates a transmural voltage gradient between epicardium and endocardium. Ito is blocked by 4-aminopyridine, whereas Ito,fast is selectively blocked by Heteropoda spider toxins.15Tamargo J. Caballero R. Gómez R. Valenzuela C. Delpón E. Pharmacology of cardiac potassium channels.Cardiovasc Res. 2004; 62: 9-33Crossref PubMed Scopus (373) Google Scholar Heterologous expression of KCND3 or KCNA4 does not fully recapitulate native Ito phenotypes unless co-expressed with their accessory proteins. For Kv1.4, four β-subunits have been identified (Table 1). For Kv4.3, gating properties are modulated by MiRP1 and MiRP2 (encoded by KCNE2 and KCNE3), intracellular Kv channel interacting proteins (KChIPs), and dipeptidyl-aminopeptidase-like protein-6 (DPP6; encoded by DPP6).15Tamargo J. Caballero R. Gómez R. Valenzuela C. Delpón E. Pharmacology of cardiac potassium channels.Cardiovasc Res. 2004; 62: 9-33Crossref PubMed Scopus (373) Google Scholar, 16Delpón E. Cordeiro J.M. Núñez L. et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.Circ Arrhythm Electrophysiol. 2008; 1: 209-218Crossref PubMed Scopus (281) Google ScholarInherited diseasesTo date, only mutations in KCNE3 are linked to inherited arrhythmia. An KCNE3 mutation was found in five related patients with Brugada syndrome. When expressed with Kv4.3, the mutation increased Ito,fast.16Delpón E. Cordeiro J.M. Núñez L. et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.Circ Arrhythm Electrophysiol. 2008; 1: 209-218Crossref PubMed Scopus (281) Google Scholar It was speculated that increased Ito,fast induces ST-segment elevation in Brugada syndrome by aggravating transmural voltage gradients. Another KCNE3 mutation was identified in one patient with familial AF.17Lundby A. Ravn L.S. Svendsen J.H. Hauns S. Olesen S.P. Schmitt N. KCNE3 mutation V17M identified in a patient with lone atrial fibrillation.Cell Physiol Biochem. 2008; 21: 47-54Crossref PubMed Scopus (72) Google Scholar The mutation was found to increase Ito,fast and postulated to cause AF by shortening AP duration and facilitating atrial reentrant excitation waves.Recently, a genome-wide haplotype-sharing study associated a haplotype on chromosome 7, harboring DPP6, with idiopathic ventricular fibrillation in three distantly related families. Risk-haplotype carriers had increased DPP6 mRNA levels.18Alders M. Koopmann T.T. Christiaans I. et al.Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.Am J Hum Genet. 2009; 84: 468-476Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Although, in vitro, DPP6 decreases Ito and modulates its gating,16Delpón E. Cordeiro J.M. Núñez L. et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.Circ Arrhythm Electrophysiol. 2008; 1: 209-218Crossref PubMed Scopus (281) Google Scholar how potential DPP6 overexpression causes ventricular fibrillation is unresolved.Acquired diseasesIto is reduced in AF, myocardial infarction, and heart failure.12Nattel S. Maguy A. Le Bouter S. Yeh Y.H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.Physiol Rev. 2007; 87: 425-456Crossref PubMed Scopus (644) Google Scholar In myocardial infarction, Ito is down-regulated by the increased activity of calcineurin, a phosphatase that regulates gene transcription by dephosphorylating transcription factors.2Mangoni M.E. Nargeot J. Genesis and regulation of the heart automaticity.Physiol Rev. 2005; 88: 919-982Crossref Scopus (417) Google Scholar, 12Nattel S. Maguy A. Le Bouter S. Yeh Y.H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.Physiol Rev. 2007; 87: 425-456Crossref PubMed Scopus (644) Google Scholar Sustained tachycardia in heart failure reduces Ito, probably through a similar mechanism.12Nattel S. Maguy A. Le Bouter S. Yeh Y.H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.Physiol Rev. 2007; 87: 425-456Crossref PubMed Scopus (644) Google Scholar However, Ito may be increased in the hypertrophic phase preceding heart failure. Accordingly, Kv4.3 mRNA and protein levels decrease during progression of hypertrophy to heart failure. Finally, Ito may be reduced and contribute to QT interval prolongation in diabetes. Importantly, with certain delay, insulin therapy partially restores Ito, maybe by enhancing Kv4.3 expression.15Tamargo J. Caballero R. Gómez R. Valenzuela C. Delpón E. Pharmacology of cardiac potassium channels.Cardiovasc Res. 2004; 62: 9-33Crossref PubMed Scopus (373) Google ScholarCardiac Ca2+ current (ICa) and intracellular Ca2+ transientsThe L-type (long-lasting) inward Ca2+ current (ICa,L) is largely responsible for the AP plateau. Ca2+ influx by ICa,L activates Ca2+ release channels (ryanodine receptor [RyR2]), located in the sarcoplasmic reticulum membrane. Sarcoplasmic reticulum Ca2+ release (Ca2+ transients) via RyR2 channels couples excitation to contraction in myocytes.1Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Cross
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