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• W2155409176 abstract "HomeCirculation ResearchVol. 86, No. 5LQT2 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBLQT2 Amplitude Reduction and Loss of Selectivity in the Tail That Wags the HERG Channel Gail A. Robertson Gail A. RobertsonGail A. Robertson From the Department of Physiology and Cardiovascular Research Center, University of Wisconsin – Madison Medical School, Madison, Wis. Search for more papers by this author Originally published17 Mar 2000https://doi.org/10.1161/01.RES.86.5.492Circulation Research. 2000;86:492–493Without the ion selectivity of voltage-gated ion channels, excitable cells could not generate more than a few millivolts of resting potential, much less produce action potentials. Even when the loss of selectivity occurs in just one type of K+ channel in the heart, the outcome may be catastrophic, suggests a report in this issue of Circulation Research.1 A defect in K+ selectivity caused by a mutation near the “signature sequence” in the pore of HERG channel subunits may contribute as a new mechanism to the prolongation of the action potential and the associated susceptibility to life-threatening torsades de pointes arrhythmias.Since chromosome 7-linked long-QT syndrome (LQT2) was first mapped to HERG,2 a relative of the Drosophila and mammalian eag genes,3 we have learned much about the pathology of the disease and the underlying physiological mechanisms that have gone awry. In heterologous expression systems, the subunits encoded by the wild-type HERG gene assemble to form channels with the functional properties of IKr,45 an unusual repolarizing current first identified by its sensitivity to the antiarrhythmic agent E-4031.6 Our understanding of how IKr participates in repolarization has emerged largely from voltage-clamp analyses of the remarkable tail currents dominating the HERG current profile. At the positive voltages typically reached at the peak or plateau of the ventricular action potential, much of the current is suppressed by a rapid inactivation mechanism.4578910 As repolarization ensues, HERG channels recover from inactivation and linger in a highly stable open state before closing.11 The result is a “resurgent current,” a term coined for Na+ current in cerebellar Purkinje neurons arising from an analogous gating process.12HERG mutations causing long-QT syndrome generally reduce the magnitude of this resurgent current by altering channel properties131415 or as a consequence of trafficking defects.1617Add to the mounting list of familial HERG mutations N629D,18 situated conspicuously in a guilty-by-association position adjacent to three residues thought to single-handedly ensure high rates of K+ conduction through the pore while excluding Na+ entry.19 Whereas most K+ channels exhibit the signature gly-tyr-gly (GYG),20 HERG and other Eag-related channels have GFG at the corresponding site,3 with a phenylalanine substituting for tyrosine. Mutations at the adjacent residue in Shaker channels (GYGD) are not well tolerated,20 but when engineered into heteromeric dimers, they reduce the degree of selectivity for K+ over Na+ and alter the rate of C-type inactivation.21 As Duff and colleagues1 show, a disease mutation at the corresponding site in HERG (GFGN to D) eliminates selectivity of K+ over Na+ and disrupts C-type inactivation as well, underscoring the influence of residues at this site in the closely related processes of selectivity and C-type inactivation.2223It may seem surprising that a mutation that removes inactivation, which would increase the relative amplitude of HERG currents during the peak and plateau phases of the action potential, could prolong the QT interval. However, in the absence of an inactivated state from which to recover, the resurgent current is eliminated and thus cannot contribute to terminal repolarization.8910 What is left is a small, rapid tail current unable to exert much of a physiological effect. If that were not enough, the authors observe, the tail currents of the selectivity-impaired N629D mutant are inward and may be surprisingly effective at further delaying repolarization and contributing to arrhythmogenesis. That even a small inward current could be proarrhythmic is supported by the modeling study of Clancy and Rudy,24 who show that the persistent inward current through mutant Na+ channels associated with LQT325 is capable of prolonging the QT interval, even though it is a mere 2% of its normal peak amplitude. Whether the inward Na+ current tail in the HERG mutant N629D prolongs the QT interval over and above the simple loss of the resurgent current could be put to the test using the same model.As fascinating as the biophysical defects in channel properties are, one must ask whether long QT in families carrying the N629D mutation might actually be due to a HERG protein trafficking defect. The data indicate that the mutant N629D RNA does not express as well as wild type in oocytes, with one example showing mutant current amplitudes less than 10% of those of wild type, despite the injection of twice as much RNA. It would not be the first case in which biophysical defects in channel properties were of secondary importance to failed transport of channels to the plasma membrane in accounting for the disease process.17 Furthermore, trafficking defects can be exacerbated at physiological temperatures,2627 potentially limiting the inferences about disease mechanisms that can be drawn from experiments conducted in Xenopus oocytes at room temperature. Given the growing importance of trafficking defects in LQT2, the burden of proof is on the investigator to eliminate this possibility before the disease process can be attributed solely to a defect in channel properties, however compelling the biophysical phenotype may be.An interesting and paradoxical result of the present study is that an aspartate adjacent to the signature sequence can sabotage selectivity in HERG channels whereas it may serve as part of the normal selectivity filter in Shaker.21 However, no such K+ binding site can be inferred from the superimposed electron density and rubidium difference maps reported for the KcsA bacterial channel structure, which bears the GYGD sequence.19 More information should come to light in the next generation of K+ channel structures, which, with luck, will include a view of HERG at atomic resolution. Whether its curious GFGN signature translates into three-dimensional differences compared with its K+ channel brethren remains to be seen.This study by Duff and colleagues1 is emblematic of the explosive synergy of basic and clinical research over little more than a single decade, punctuated in this case by such milestones as the cloning of the Shaker28 and eag29 channel genes from Drosophila, the mapping of disease loci on the human chromosome,2 the structural resolution of a K+ channel pore,19 and innumerable structure-function studies along the way. No less significant are the emerging models30 that will soon encompass every element of excitability in different regions of the heart, revealing the mechanistic underpinnings of the long-QT syndromes at the molecular, cellular, and systems levels.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Gail Robertson, Department of Physiology, University of Wisconsin – Madison Medical School, 1300 University Ave, Madison, WI 53706. E-mail [email protected] References 1 Lees-Miller JP, Duan Y, Teng GQ, Thorstad K, Duff HJ. Novel gain-of-function mechanism in K+ channel–related long-QT syndrome: altered gating and selectivity in the HERG1 N629D mutant. Circ Res.2000; 86:507–513.CrossrefMedlineGoogle Scholar2 Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell.1995; 80:795–803.CrossrefMedlineGoogle Scholar3 Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A.1994; 91:3438–3442.CrossrefMedlineGoogle Scholar4 Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell.1995; 81:299–307.CrossrefMedlineGoogle Scholar5 Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science.1995; 269:92–95.CrossrefMedlineGoogle Scholar6 Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol.1990; 96:195–215.CrossrefMedlineGoogle Scholar7 Spector PS, Curran ME, Zou A, Keating MT, Sanguinetti MC. Fast inactivation causes rectification of the IKr channel. J Gen Physiol.1996; 107:611–619.CrossrefMedlineGoogle Scholar8 Schonherr R, Heinemann SH. Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. J Physiol (Lond).1996; 493:635–642.CrossrefGoogle Scholar9 Smith PL, Baukrowitz T, Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature.1996; 379:833–836.CrossrefMedlineGoogle Scholar10 Herzberg IM, Trudeau MC, Robertson GA. Transfer of rapid inactivation and E-4031 sensitivity from HERG to M-EAG Channels. J Physiol (Lond).1998; 511:3–14.CrossrefGoogle Scholar11 Wang J, Trudeau MC, Zappia AM, Robertson GA. Regulation of deactivation by an amino terminal domain in human ether-a-go-go-related gene potassium channels [published erratum appears in J Gen Physiol.1999; 113:359]. J Gen Physiol. 1998;112:637–647.CrossrefGoogle Scholar12 Raman IM, Bean BP. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J Neurosci.1997; 17:4517–4526.CrossrefMedlineGoogle Scholar13 Sanguinetti MC, Curran ME, Spector PS, Keating MT. Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia [published erratum appears in Proc Natl Acad Sci U S A.1996; 93:8796]. Proc Natl Acad Sci U S A. 1996;93:2208–2212.CrossrefGoogle Scholar14 Nakajima T, Furukawa T, Tanaka T, Katayama Y, Nagai R, Nakamura Y, Hiraoka M. Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circ Res.1998; 83:415–422.CrossrefMedlineGoogle Scholar15 Chen J, Zou A, Splawski I, Keating MT, Sanguinetti MC. Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation. J Biol Chem.1999; 274:10113–10118.CrossrefMedlineGoogle Scholar16 Zhou Z, Gong Q, Epstein ML, January CT. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem.1998; 273:21061–21066.CrossrefMedlineGoogle Scholar17 Furutani M, Trudeau MC, Hagiwara N, Seki A, Gong Q, Zhou Z, Imamura S, Nagashima H, Kasanuki H, Takao A, Momma K, January CT, Robertson GA, Matsuoka R. Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation.1999; 99:2290–2294.CrossrefMedlineGoogle Scholar18 Satler CA, Vesely MR, Duggal P, Ginsburg GS, Beggs AH. Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome. Hum Genet.1998; 102:265–272.CrossrefMedlineGoogle Scholar19 Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science.1998; 280:69–77.CrossrefMedlineGoogle Scholar20 Heginbotham L, Lu Z, Abramson T, MacKinnon R. Mutations in the K+ channel signature sequence. Biophys J.1994; 66:1061–1067.CrossrefMedlineGoogle Scholar21 Kirsch GE, Pascual JM, Shieh CC. Functional role of a conserved aspartate in the external mouth of voltage-gated potassium channels. Biophys J.1995; 68:1804–1813.CrossrefMedlineGoogle Scholar22 Starkus JG, Kuschel L, Rayner MD, Heinemann SH. Ion conduction through C-type inactivated Shaker channels. J Gen Physiol.1997; 110:539–550.CrossrefMedlineGoogle Scholar23 Kiss L, LoTurco J, Korn SJ. Contribution of the selectivity filter to inactivation in potassium channels. Biophys J.1999; 76:253–263.CrossrefMedlineGoogle Scholar24 Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature.1999; 400:566–569.CrossrefMedlineGoogle Scholar25 Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature.1995; 376:683–685.CrossrefMedlineGoogle Scholar26 Zhou Z, Gong Q, January CT. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem.1999; 274:31123–31126.CrossrefMedlineGoogle Scholar27 Ficker EK, Thomas D, Viswanathan P, Rudy Y, Brown AM. Rescue of a misprocessed mutant HERG channel linked to hereditary long QT syndrome. Biophys J.2000; 78:342A. Abstract.Google Scholar28 Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan LY. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science.1987; 237:749–753.CrossrefMedlineGoogle Scholar29 Warmke J, Drysdale R, Ganetzky B. A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Science.1991; 252:1560–1562.CrossrefMedlineGoogle Scholar30 Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential, I: simulations of ionic currents and concentration changes. Circ Res.1994; 74:1071–1096.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Chen W, Gan L and Wang Y (2019) Characteristics of hERG and hNav1.5 channel blockade by sulcardine sulfate, a novel anti-arrhythmic compound, European Journal of Pharmacology, 10.1016/j.ejphar.2018.12.009, 844, (130-138), Online publication date: 1-Feb-2019. Vandenberg J, Perry M, Perrin M, Mann S, Ke Y and Hill A (2012) hERG K + Channels: Structure, Function, and Clinical Significance , Physiological Reviews, 10.1152/physrev.00036.2011, 92:3, (1393-1478), Online publication date: 1-Jul-2012. Chen W, Wang W, Zhang J, Yang D and Wang Y (2010) State-dependent blockade of human ether-a-go-go-related gene (hERG) K+ channels by changrolin in stably transfected HEK293 cells, Acta Pharmacologica Sinica, 10.1038/aps.2010.84, 31:8, (915-922), Online publication date: 1-Aug-2010. Lagrutta A and Salata J (2009) Safety Pharmacology and Regulatory Issues in the Development of Antiarrhythmic Medications Novel Therapeutic Targets for Antiarrhythmic Drugs, 10.1002/9780470561416.ch8, (233-269), Online publication date: 16-Dec-2009. Perrin M, Subbiah R, Vandenberg J and Hill A (2008) Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction, Progress in Biophysics and Molecular Biology, 10.1016/j.pbiomolbio.2008.10.006, 98:2-3, (137-148), Online publication date: 1-Oct-2008. McPate M, Duncan R, Hancox J and Witchel H (2009) Pharmacology of the short QT syndrome N588K-hERG K + channel mutation: differential impact on selected class I and class III antiarrhythmic drugs , British Journal of Pharmacology, 10.1038/bjp.2008.325, 155:6, (957-966), Online publication date: 1-Nov-2008. Wehrens X Structural Determinants of Potassium Channel Blockade and Drug-Induced Arrhythmias Basis and Treatment of Cardiac Arrhythmias, 10.1007/3-540-29715-4_5, (123-157) McPate M, Duncan R, Milnes J, Witchel H and Hancox J (2005) The N588K-HERG K+ channel mutation in the ‘short QT syndrome’: Mechanism of gain-in-function determined at 37°C, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2005.06.112, 334:2, (441-449), Online publication date: 1-Aug-2005. Roti E, Myers C, Ayers R, Boatman D, Delfosse S, Chan E, Ackerman M, January C and Robertson G (2002) Interaction with GM130 during HERG Ion Channel Trafficking, Journal of Biological Chemistry, 10.1074/jbc.M206638200, 277:49, (47779-47785), Online publication date: 1-Dec-2002. Witchel H, Milnes J, Mitcheson J and Hancox J (2002) Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes, Journal of Pharmacological and Toxicological Methods, 10.1016/S1056-8719(03)00041-8, 48:2, (65-80), Online publication date: 1-Sep-2002. March 17, 2000Vol 86, Issue 5 Advertisement Article InformationMetrics © 2000 American Heart Association, Inc.https://doi.org/10.1161/01.RES.86.5.492 Originally publishedMarch 17, 2000 KeywordsselectivityHERGK+ channelsLQT2PDF download Advertisement" @default.
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