IKr: The hERG Channel

Abstract G.-N. Tseng. IKr: The hERG Channel. Journal of Molecular and Cellular Cardiology (2001) 33, 835–849. The rapid delayed rectifier (IKr) channel is important for cardiac action potential repolarization. Suppressing IKrfunction, due to either genetic defects in its pore-forming subunit (hERG) or adverse drug effects, can lead to long-QT (LQT) syndrome that carries increased risk of life-threatening arrhythmias. The implication of IKrin cardiac arrhythmias and in anti-arrhythmic/pro-arrhythmic actions of drugs has driven intensive research interests in its structure–function relationship, the linkage between LQT-associated mutations and changes in channel function, and the mechanism of drug actions. This review will cover the following topics: (1) heterogeneous contribution of IKrto action potential repolarization in the heart, (2) structure–function relationship of IKr/hERG channels, (3) role of regulatory β subunits in IKr/hERG channel function, (4) structural basis for the unique pharmacological properties of IKr/hERG channels, and (5) IKr/hERG channel modulation by changes in cellular milieu under physiological and pathological conditions of the heart. It is anticipated that further advances in our understanding of IKr/hERG, particularly in the areas of roles of different (α and β) subunits in native IKrfunction, alterations in IKrfunction in diseased hearts, and the 3-dimensional structure of the IKr/hERG pore based on homology modeling using the KcsA model, will help us better define the role of IKrin arrhythmias and design therapeutic agents that can increase IKrand are useful for LQT syndrome.

[1]  J. Balser,et al.  Probing the Interaction Between Inactivation Gating and d-Sotalol Block of HERG , 2000, Circulation research.

[2]  D. Papazian,et al.  Mg2+ Modulates Voltage-Dependent Activation in Ether-à-Go-Go Potassium Channels by Binding between Transmembrane Segments S2 and S3 , 2000, The Journal of general physiology.

[3]  Jun Chen,et al.  A structural basis for drug-induced long QT syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Hancox,et al.  Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current , 2000, Clinical and experimental pharmacology & physiology.

[5]  C. Cabo,et al.  Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle. , 2000, Cardiovascular research.

[6]  D M Roden,et al.  A common polymorphism associated with antibiotic-induced cardiac arrhythmia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A J Moss,et al.  Spectrum of Mutations in Long-QT Syndrome Genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 , 2000, Circulation.

[8]  J. Nerbonne.  Molecular basis of functional voltage‐gated K+ channel diversity in the mammalian myocardium , 2000, The Journal of physiology.

[9]  Glenn I. Fishman,et al.  Cyclic AMP regulates the HERG K+ channel by dual pathways , 2000, Current Biology.

[10]  Gail A. Robertson,et al.  Dynamic Control of Deactivation Gating by a Soluble Amino-Terminal Domain in HERG K+ Channels , 2000, The Journal of general physiology.

[11]  Jeffrey R. Balser,et al.  A sensitive mechanism for cation modulation of potassium current , 2000, Nature Neuroscience.

[12]  G. Gintant.  Characterization and functional consequences of delayed rectifier current transient in ventricular repolarization. , 2000, American journal of physiology. Heart and circulatory physiology.

[13]  John S. Mitcheson,et al.  Trapping of a Methanesulfonanilide by Closure of the Herg Potassium Channel Activation Gate , 2000, The Journal of general physiology.

[14]  J. Nerbonne,et al.  Expression of Distinct ERG Proteins in Rat, Mouse, and Human Heart , 2000, The Journal of Biological Chemistry.

[15]  E. Carmeliet,et al.  The effect of external pH on the delayed rectifying K+ current in cardiac ventricular myocytes , 2000, Pflügers Archiv.

[16]  H. Duff,et al.  Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. , 2000, Molecular pharmacology.

[17]  J. Sánchez-Chapula,et al.  Developmental differences in delayed rectifying outward current in feline ventricular myocytes. , 2000, American journal of physiology. Heart and circulatory physiology.

[18]  Yi Liu,et al.  Blocker protection in the pore of a voltage-gated K+ channel and its structural implications , 2000, Nature.

[19]  S. Waldegger,et al.  A constitutively open potassium channel formed by KCNQ1 and KCNE3 , 2000, Nature.

[20]  H. Wellens,et al.  Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. , 1999, Circulation.

[21]  J. Tytgat,et al.  Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. , 1999, Cardiovascular research.

[22]  M. Jiang,et al.  Use-dependent 'agonist' effect of azimilide on the HERG channel. , 1999, The Journal of pharmacology and experimental therapeutics.

[23]  Allosteric effects of mutations in the extracellular S5-P loop on the gating and ion permeation properties of the hERG potassium channel , 1999, Pflügers Archiv.

[24]  D. Roden,et al.  A plethora of mechanisms in the HERG-related long QT syndrome. Genetics meets electrophysiology. , 1999, Cardiovascular research.

[25]  C. January,et al.  Correction of Defective Protein Trafficking of a Mutant HERG Potassium Channel in Human Long QT Syndrome , 1999, The Journal of Biological Chemistry.

[26]  J. Hancox,et al.  An investigation of the role played by the E-4031-sensitive (rapid delayed rectifier) potassium current in isolated rabbit atrioventricular nodal and ventricular myocytes , 1999, Pflügers Archiv.

[27]  M. Sanguinetti,et al.  Biophysical Properties and Molecular Basis of Cardiac Rapid and Slow Delayed Rectifier Potassium Channels , 1999, Cellular Physiology and Biochemistry.

[28]  M. Jiang,et al.  Mechanism for the effects of extracellular acidification on HERG-channel function. , 1999, American journal of physiology. Heart and circulatory physiology.

[29]  W. Kübler,et al.  Deletion of Protein Kinase A Phosphorylation Sites in the HERG Potassium Channel Inhibits Activation Shift by Protein Kinase A* , 1999, The Journal of Biological Chemistry.

[30]  Hui-zhen Wang,et al.  Inactivation gating determines nicotine blockade of human HERG channels. , 1999, American journal of physiology. Heart and circulatory physiology.

[31]  P. Daleau,et al.  Modulation of HERG potassium channel properties by external pH , 1999, Pflügers Archiv.

[32]  J. Jalife,et al.  Proton and zinc effects on HERG currents. , 1999, Biophysical journal.

[33]  K. Kamiya,et al.  Heterogeneous distribution of the two components of delayed rectifier K+ current: a potential mechanism of the proarrhythmic effects of methanesulfonanilideclass III agents. , 1999, Cardiovascular research.

[34]  M. Jiang,et al.  Effects of outer mouth mutations on hERG channel function: a comparison with similar mutations in the Shaker channel. , 1999, Biophysical journal.

[35]  C. January,et al.  Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. , 1999, Circulation research.

[36]  P. Boyden,et al.  Electrical remodeling in ischemia and infarction. , 1999, Cardiovascular research.

[37]  G. Tomaselli,et al.  Electrophysiological remodeling in hypertrophy and heart failure. , 1999, Cardiovascular research.

[38]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[39]  M. Sanguinetti,et al.  Long QT Syndrome-associated Mutations in the Per-Arnt-Sim (PAS) Domain of HERG Potassium Channels Accelerate Channel Deactivation* , 1999, The Journal of Biological Chemistry.

[40]  M. Sanguinetti.  Dysfunction of Delayed Rectifier Potassium Channels in an Inherited Cardiac Arrhythmia , 1999, Annals of the New York Academy of Sciences.

[41]  S. H. Lee,et al.  Blockade of HERG channels expressed in Xenopus laevis oocytes by external divalent cations. , 1999, Biophysical journal.

[42]  S. Nattel,et al.  Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes. , 1999, The Journal of pharmacology and experimental therapeutics.

[43]  P. Bennett,et al.  Human Ether-à-go-go–related Gene K+ Channel Gating Probed with Extracellular Ca2+ , 1999, The Journal of general physiology.

[44]  D. Roden,et al.  Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. , 1999, Circulation research.

[45]  R. Hauer,et al.  Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management , 2022 .

[46]  M. Sanguinetti,et al.  Mutations of the S4‐S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes , 1999, The Journal of physiology.

[47]  R. Hauer,et al.  Genetic and molecular basis of cardiac arrhythmias : Impact on clinical management , 1999 .

[48]  Steven L. Cohen,et al.  DEPARTMENT OF PHYSIOLOGY: 2016/2017 LT/LE ORGANIZATION CHART , 2016 .

[49]  M. Jiang,et al.  Stabilization of a channel’s open state by a hydrophobic residue in the sixth membrane-spanning segment (S6) of rKv1.4 , 1998, Pflügers Archiv.

[50]  G. Hart,et al.  Regional differences in action potential characteristics and membrane currents of guinea‐pig left ventricular myocytes , 1998, Experimental physiology.

[51]  M. Trudeau,et al.  Regulation of Deactivation by an Amino Terminal Domain in Human Ether-à-go-go –related Gene Potassium Channels , 1998, The Journal of general physiology.

[52]  D. Roden,et al.  A K+ Channel Splice Variant Common in Human Heart Lacks a C-terminal Domain Required for Expression of Rapidly Activating Delayed Rectifier Current* , 1998, The Journal of Biological Chemistry.

[53]  Harry J. Witchel,et al.  Time course and voltage dependence of expressed HERG current compared with native ”rapid” delayed rectifier K current during the cardiac ventricular action potential , 1998, Pflügers Archiv.

[54]  W. Kübler,et al.  HERG Potassium Channel Activation Is Shifted by Phorbol Esters via Protein Kinase A-dependent Pathways* , 1998, The Journal of Biological Chemistry.

[55]  T. Colatsky,et al.  Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice. , 1998, Circulation research.

[56]  S Nattel,et al.  Ionic mechanisms of regional action potential heterogeneity in the canine right atrium. , 1998, Circulation research.

[57]  G. Yellen,et al.  The Activation Gate of a Voltage-Gated K+ Channel Can Be Trapped in the Open State by an Intersubunit Metal Bridge , 1998, Neuron.

[58]  C. January,et al.  HERG Channel Dysfunction in Human Long QT Syndrome , 1998, The Journal of Biological Chemistry.

[59]  G. Robertson,et al.  Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E‐4031 from HERG to M‐eag channels , 1998, The Journal of physiology.

[60]  W. Giles,et al.  Repolarizing K+ currents in rabbit heart Purkinje cells , 1998, The Journal of physiology.

[61]  M. Sanguinetti,et al.  A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation , 1998, The Journal of physiology.

[62]  B. Chait,et al.  The structure of the potassium channel: molecular basis of K+ conduction and selectivity. , 1998, Science.

[63]  P. Boyden,et al.  Reduced Inward Rectifying and Increased E‐4031‐Sensitive K+ Current Density in Arrhythmogenic Subendocardial Purkinje Myocytes from the Infarcted Heart , 1998, Journal of cardiovascular electrophysiology.

[64]  A. Brown,et al.  Molecular determinants of dofetilide block of HERG K+ channels. , 1998, Circulation research.

[65]  L. Kiss,et al.  The Interaction of Na+ and K+ in Voltage-gated Potassium Channels , 1998, The Journal of general physiology.

[66]  C. January,et al.  Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. , 1998, Biophysical journal.

[67]  H. Strauss,et al.  Modulation of HERG affinity for E‐4031 by [K+]o and C‐type inactivation , 1997, FEBS letters.

[68]  N. Copeland,et al.  Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current. , 1997, Circulation research.

[69]  L. Wang,et al.  Electrophysiological characterization of an alternatively processed ERG K+ channel in mouse and human hearts. , 1997, Circulation research.

[70]  Stefan H. Heinemann,et al.  Ion Conduction through C-Type Inactivated Shaker Channels , 1997, The Journal of general physiology.

[71]  D M Roden,et al.  Structure and function of cardiac sodium and potassium channels. , 1997, The American journal of physiology.

[72]  Glenn I. Fishman,et al.  A minK–HERG complex regulates the cardiac potassium current IKr , 1997, Nature.

[73]  H. Strauss,et al.  Regional localization of ERG, the channel protein responsible for the rapid component of the delayed rectifier, K+ current in the ferret heart. , 1997, Circulation research.

[74]  H. Strauss,et al.  A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes , 1997, The Journal of physiology.

[75]  D M Roden,et al.  Rapid inactivation determines the rectification and [K+]o dependence of the rapid component of the delayed rectifier K+ current in cardiac cells. , 1997, Circulation research.

[76]  K. Klemic,et al.  Role of Transmembrane Segment S5 on Gating of Voltage-dependent K+ Channels , 1997, The Journal of general physiology.

[77]  M. Sanguinetti,et al.  Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes. , 1997, The American journal of physiology.

[78]  B Attali,et al.  The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes , 1997, British journal of pharmacology.

[79]  G. Gintant,et al.  Tissue and species distribution of mRNA for the IKr-like K+ channel, erg. , 1997, Circulation research.

[80]  B. Fermini,et al.  IK of rabbit ventricle is composed of two currents: evidence for IKs. , 1996, The American journal of physiology.

[81]  A. Brown,et al.  Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. , 1996, Circulation.

[82]  A. Brown,et al.  HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. , 1996, Circulation.

[83]  H. Duff,et al.  Developmental changes in the delayed rectifier K+ channels in mouse heart. , 1996, Circulation research.

[84]  S. Heinemann,et al.  Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. , 1996, The Journal of physiology.

[85]  D. Snyders,et al.  High affinity open channel block by dofetilide of HERG expressed in a human cell line. , 1996, Molecular pharmacology.

[86]  H. Strauss,et al.  Activation and inactivation kinetics of an E-4031-sensitive current from single ferret atrial myocytes. , 1996, Biophysical journal.

[87]  M. Sanguinetti,et al.  Fast inactivation causes rectification of the IKr channel , 1996, The Journal of general physiology.

[88]  F. Lang,et al.  Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole , 1996, FEBS letters.

[89]  S Nattel,et al.  Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. , 1996, Circulation research.

[90]  M. Sanguinetti,et al.  Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. , 1996, Circulation research.

[91]  Gary Yellen,et al.  The inward rectification mechanism of the HERG cardiac potassium channel , 1996, Nature.

[92]  G. Yellen,et al.  Use-Dependent Blockers and Exit Rate of the Last Ion from the Multi-Ion Pore of a K+ Channel , 1996, Science.

[93]  P. Doevendans,et al.  Developmental changes in ionic channel activity in the embryonic murine heart. , 1996, Circulation research.

[94]  G. Gintant,et al.  Two components of delayed rectifier current in canine atrium and ventricle. Does IKs play a role in the reverse rate dependence of class III agents? , 1996, Circulation research.

[95]  D. Roden,et al.  Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K+ current. , 1995, Circulation Research.

[96]  R. Aldrich,et al.  Cooperative subunit interactions in C-type inactivation of K channels. , 1995, Biophysical journal.

[97]  J. R. Clay,et al.  A quantitative description of the E-4031-sensitive repolarization current in rabbit ventricular myocytes. , 1995, Biophysical journal.

[98]  G. Yellen,et al.  Modulation of K+ current by frequency and external [K+]: A tale of two inactivation mechanisms , 1995, Neuron.

[99]  C. Deutsch,et al.  C-type inactivation of a voltage-gated K+ channel occurs by a cooperative mechanism. , 1995, Biophysical journal.

[100]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

[101]  C. Antzelevitch,et al.  Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. , 1995, Circulation research.

[102]  R. Latorre,et al.  Molecular determinants of ion conduction and inactivation in K+ channels. , 1995, The American journal of physiology.

[103]  H. Guy,et al.  Structural models of Na+, Ca2+, and K+ channels. , 1995, Society of General Physiologists series.

[104]  B. Fermini,et al.  Rapid and slow components of delayed rectifier current in human atrial myocytes. , 1994, Cardiovascular research.

[105]  R. MacKinnon,et al.  Mutations in the K+ channel signature sequence. , 1994, Biophysical journal.

[106]  D Sodickson,et al.  An engineered cysteine in the external mouth of a K+ channel allows inactivation to be modulated by metal binding. , 1994, Biophysical journal.

[107]  E. Carmeliet.  Use-dependent block and use-dependent unblock of the delayed rectifier K+ current by almokalant in rabbit ventricular myocytes. , 1993, Circulation research.

[108]  A. V. van Ginneken,et al.  Single delayed rectifier channels in the membrane of rabbit ventricular myocytes. , 1993, Circulation research.

[109]  M. Sanguinetti,et al.  Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. , 1993, Circulation research.

[110]  E. Carmeliet.  Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. , 1992, The Journal of pharmacology and experimental therapeutics.

[111]  R. Myerburg,et al.  Potassium rectifier currents differ in myocytes of endocardial and epicardial origin. , 1992, Circulation research.

[112]  Richard W. Aldrich,et al.  Two types of inactivation in Shaker K+ channels: Effects of alterations in the carboxy-terminal region , 1991, Neuron.

[113]  M. Sanguinetti,et al.  Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells. , 1991, The American journal of physiology.

[114]  M. Sanguinetti,et al.  Isoproterenol antagonizes prolongation of refractory period by the class III antiarrhythmic agent E-4031 in guinea pig myocytes. Mechanism of action. , 1991, Circulation research.

[115]  T. Colatsky,et al.  Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. , 1990, Circulation.

[116]  M. Sanguinetti,et al.  Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents , 1990, The Journal of general physiology.

[117]  E. Carmeliet,et al.  Delayed K+ current and external K+ in single cardiac Purkinje cells. , 1989, The American journal of physiology.

[118]  S. Houser,et al.  Outward currents in normal and hypertrophied feline ventricular myocytes. , 1989, The American journal of physiology.

[119]  T. Shibasaki,et al.  Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. , 1987, The Journal of physiology.

[120]  E. W. Miles.  Modification of histidyl residues in proteins by diethylpyrocarbonate. , 1977, Methods in enzymology.