Skip to main content
SpringerLink
Log in
Book cover

Basis and Treatment of Cardiac Arrhythmias pp 123–157Cite as

Structural Determinants of Potassium Channel Blockade and Drug-Induced Arrhythmias

  • Chapter

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 171))

Abstract

Cardiac K+ channels play an important role in the regulation of the shape and duration of the action potential. They have been recognized as targets for the actions of neurotransmitters, hormones, and anti-arrhythmic drugs that prolong the action potential duration (APD) and increase refractoriness. However, pharmacological therapy, often for the purpose of treating syndromes unrelated to cardiac disease, can also increase the vulnerability of some patients to life-threatening rhythm disturbances. This may be due to an underlying propensity stemming from inherited mutations or polymorphisms, or structural abnormalities that provide a substrate allowing for the initiation of arrhythmic triggers. A number of pharmacological agents that have proved useful in the treatment of allergic reactions, gastrointestinal disorders, and psychotic disorders, among others, have been shown to reduce repolarizing K+ currents and prolong the Q-T interval on the electrocardiogram. Understanding the structural determinants of K+ channel blockade might provide new insights into the mechanism and rate-dependent effects of drugs on cellular physiology. Drug-induced disruption of cellular repolarization underlies electrocardiographic abnormalities that are diagnostic indicators of arrhythmia susceptibility.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   389.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   499.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abbott GW, Goldstein SA (2001) Potassium channel subunits encoded by the KCNE gene family: physiology and pathophysiology of the MinK-related peptides (MiRPs). Mol Interv 1:95–107

    PubMed  CAS  Google Scholar 

  • Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175–187

    Article  PubMed  CAS  Google Scholar 

  • Abitbol I, Peretz A, Lerche C, Busch AE, Attali B (1999) Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants. EMBO J 18:4137–4148

    Article  PubMed  CAS  Google Scholar 

  • Anderson ME, Al-Khatib SM, Roden DM, Califf RM (2002) Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 144:769–781

    Article  PubMed  CAS  Google Scholar 

  • Anson BD, Ackerman MJ, Tester DJ, Will ML, Delisle BP, Anderson CL, January CT (2004) Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Am J Physiol Heart Circ Physiol 286:H2434–H2441

    Article  PubMed  CAS  Google Scholar 

  • Antzelevitch C, Fish J (2001) Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 96:517–527

    Article  PubMed  CAS  Google Scholar 

  • Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX (1996) Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 28:1836–1848

    Article  PubMed  CAS  Google Scholar 

  • Attali B, Guillemare E, Lesage F, Honore E, Romey G, Lazdunski M, Barhanin J (1993) The protein IsK is a dual activator of K+ and Cl- channels. Nature 365:850–852

    Article  PubMed  CAS  Google Scholar 

  • Axelsson R, Aspenstrom G (1982) Electrocardiographic changes and serum concentrations in thioridazine-treated patients. J Clin Psychiatry 43:332–335

    PubMed  CAS  Google Scholar 

  • Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G (1996) K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 384:78–80

    Article  PubMed  CAS  Google Scholar 

  • Barros F, Gomez-Varela D, Viloria CG, Palomero T, Giraldez T, de la Pena P(1998)Modulation of human erg K+ channel gating by activation of a G protein-coupled receptor and protein kinase C. J Physiol 511:333–346

    CAS  Google Scholar 

  • Barry DM, Nerbonne JM (1996) Myocardial potassium channels: electrophysiological and molecular diversity. Annu Rev Physiol 58:363–394

    Article  PubMed  CAS  Google Scholar 

  • Baukrowitz T, Yellen G (1995) Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms. Neuron 15:951–960

    Article  PubMed  CAS  Google Scholar 

  • Belardinelli L, Antzelevitch C, Vos MA (2003) Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci 24:619–625

    Article  PubMed  CAS  Google Scholar 

  • Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA (2004) Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109:2394–2397

    Article  PubMed  Google Scholar 

  • Berube J, Chahine M, Daleau P (1999) Modulation of HERG potassium channel properties by external pH. Pflugers Arch 438:419–422

    Article  PubMed  CAS  Google Scholar 

  • Beuckelmann DJ, Nabauer M, Erdmann E (1993) Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73:379–385

    PubMed  CAS  Google Scholar 

  • Bezzina CR, Verkerk AO, Busjahn A, Jeron A, Erdmann J, Koopmann TT, Bhuiyan ZA, Wilders R, Mannens MM, Tan HL, Luft FC, Schunkert H, Wilde AA (2003) A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 59:27–36

    Article  PubMed  CAS  Google Scholar 

  • Bian JS, Kagan A, McDonald TV (2004) Molecular analysis of phosphatidyl inositol 4,5-bisphosphate regulation of HERG/IKr. Am J Physiol Heart Circ Physiol 287:H2154–H2163

    Article  PubMed  CAS  Google Scholar 

  • Bianchi L, Shen Z, Dennis AT, Priori SG, Napolitano C, Ronchetti E, Bryskin R, Schwartz PJ, Brown AM (1999) Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome. Hum Mol Genet 8:1499–1507

    Article  PubMed  CAS  Google Scholar 

  • Bosch RF, Gaspo R, Busch AE, Lang HJ, Li GR, Nattel S (1998) Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res 38:441–450

    Article  PubMed  CAS  Google Scholar 

  • Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C (2004) Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 109:30–35

    Article  PubMed  CAS  Google Scholar 

  • Busch AE, Suessbrich H, Waldegger S, Sailer E, Greger R, Lang H, Lang F, Gibson KJ, Maylie JG (1996) Inhibition of IKs in guinea pig cardiac myocytes and guinea pig IsK channels by the chromanol 293B. Pflugers Arch 432:1094–1096

    Article  PubMed  CAS  Google Scholar 

  • Busch AE, Busch GL, Ford E, Suessbrich H, Lang HJ, Greger R, Kunzelmann K, Attali B, Stuhmer W (1997) The role of the IsK protein in the specific pharmacological properties of the IKs channel complex. Br J Pharmacol 122:187–189

    Article  PubMed  CAS  Google Scholar 

  • Caballero R, Moreno I, Gonzalez T, Arias C, Valenzuela C, Delpon E, Tamargo J (2003) Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels. Circulation 107:889–895

    Article  PubMed  Google Scholar 

  • Chen H, Kim LA, Rajan S, Xu S, Goldstein SA (2003) Charybdotoxin binding in the I(Ks) pore demonstrates two MinK subunits in each channel complex. Neuron 40:15–23

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Seebohm G, Sanguinetti MC (2002a) Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proc Natl Acad Sci U S A 99:12461–12466

    Article  PubMed  CAS  Google Scholar 

  • Chen Q, Zhang D, Gingell RL, Moss AJ, Napolitano C, Priori SG, Schwartz PJ, Kehoe E, Robinson JL, Schulze-Bahr E, Wang Q, Towbin JA (1999) Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. Circulation 99:1344–1347

    PubMed  CAS  Google Scholar 

  • Chen X, Piacentino V 3rd, Furukawa S, Goldman B, Margulies KB, Houser SR (2002b) L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices. Circ Res 91:517–524

    Article  PubMed  CAS  Google Scholar 

  • Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J (1997) Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J 16:5472–5479

    Article  PubMed  CAS  Google Scholar 

  • Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, Drici MD, Guicheney P, Barhanin J (2000) Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. Cardiovasc Res 45:971–980

    Article  PubMed  CAS  Google Scholar 

  • Clancy CE, Rudy Y (2001) Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Cardiovasc Res 50:301–313

    Article  PubMed  CAS  Google Scholar 

  • Clancy CE, Kurokawa J, Tateyama M, Wehrens XH, Kass RS (2003) K+ channel structure activity relationships and mechanisms of drug-induced QT prolongation. Annu Rev Pharmacol Toxicol 43:441–461

    Article  PubMed  CAS  Google Scholar 

  • Coumel P, Krikler D, Rosen MR, Wellens HJ, Zipes DP (1978) Newer antiarrhythmic drugs. Pacing Clin Electrophysiol 1:521–528

    PubMed  CAS  Google Scholar 

  • Crumb WJ Jr (2000) Loratadine blockade of K(+) channels in human heart: comparison with terfenadine under physiological conditions. J Pharmacol Exp Ther 292:261–264

    PubMed  CAS  Google Scholar 

  • Cui J, Melman Y, Palma E, Fishman GI, McDonald TV (2000) Cyclic AMP regulates the HERG K(+) channel by dual pathways. Curr Biol 10:671–674

    Article  PubMed  CAS  Google Scholar 

  • Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803

    Article  PubMed  CAS  Google Scholar 

  • De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N (2002) Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 25:263–286

    Article  PubMed  Google Scholar 

  • Deal KK, England SK, Tamkun MM (1996) Molecular physiology of cardiac potassium channels. Physiol Rev 76:49–67

    PubMed  CAS  Google Scholar 

  • del Camino D, Holmgren M, Liu Y, Yellen G (2000) Blocker protection in the pore of a voltage-gated K+ channel and its structural implications. Nature 403:321–325

    Article  PubMed  CAS  Google Scholar 

  • Demolombe S, Baro I, Pereon Y, Bliek J, Mohammad-Panah R, Pollard H, Morid S, Mannens M, Wilde A, Barhanin J, Charpentier F, Escande D (1998) A dominant negative isoform of the long QT syndrome 1 gene product. J Biol Chem 273:6837–6843

    Article  PubMed  CAS  Google Scholar 

  • Demolombe S, Lande G, Charpentier F, van Roon MA, van den Hoff MJ, Toumaniantz G, Baro I, Guihard G, Le Berre N, Corbier A, de Bakker J, Opthof T, Wilde A, Moorman AF, Escande D (2001) Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I. Phenotypic characterisation. Cardiovasc Res 50:314–327

    Article  PubMed  CAS  Google Scholar 

  • Di Diego JM, Belardinelli L, Antzelevitch C (2003) Cisapride-induced transmural dispersion of repolarization and torsade de pointes in the canine left ventricular wedge preparation during epicardial stimulation. Circulation 108:1027–1033

    Article  PubMed  Google Scholar 

  • Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77

    Article  PubMed  CAS  Google Scholar 

  • Ebert SN, Liu XK, Woosley RL (1998) Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 7:547–557

    Article  PubMed  CAS  Google Scholar 

  • Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW (2003) A new oral therapy for long QT syndrome: long-termoral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol 42:1777–1782

    Article  PubMed  CAS  Google Scholar 

  • Faber GM, Rudy Y (2000) Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. Biophys J 78:2392–2404

    PubMed  CAS  Google Scholar 

  • Ficker E, Jarolimek W, Kiehn J, Baumann A, Brown AM (1998) Molecular determinants of dofetilide block of HERG K+ channels. Circ Res 82:386–395

    PubMed  CAS  Google Scholar 

  • Ficker E, Jarolimek W, Brown AM (2001) Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels. Mol Pharmacol 60:1343–1348

    PubMed  CAS  Google Scholar 

  • Folander K, Smith JS, Antanavage J, Bennett C, Stein RB, Swanson R (1990) Cloning and expression of the delayed-rectifier IsK channel from neonatal rat heart and diethylstilbestrol-primed rat uterus. Proc Natl Acad Sci U S A 87:2975–2979

    PubMed  CAS  Google Scholar 

  • Follmer CH, Colatsky TJ (1990) Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. Circulation 82:289–293

    PubMed  CAS  Google Scholar 

  • Franqueza L, Lin M, Shen J, Splawski I, Keating MT, Sanguinetti MC (1999) Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits. J Biol Chem 274:21063–21070

    Article  PubMed  CAS  Google Scholar 

  • Furukawa T, Myerburg RJ, Furukawa N, Kimura S, Bassett AL (1994) Metabolic inhibition of ICa, L and IK differs in feline left ventricular hypertrophy. Am J Physiol 266:H1121–H1131

    PubMed  CAS  Google Scholar 

  • Gaita F, Giustetto C, Bianchi F, Schimpf R, Haissaguerre M, Calo L, Brugada R, Antzelevitch C, Borggrefe M, Wolpert C (2004) Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 43:1494–1499

    Article  PubMed  CAS  Google Scholar 

  • Gima K, Rudy Y (2002) Ionic current basis of electrocardiographic waveforms: a model study. Circ Res 90:889–896

    Article  PubMed  CAS  Google Scholar 

  • Gogelein H, Bruggemann A, Gerlach U, Brendel J, Busch AE (2000) Inhibition of IKs channels by HMR 1556. Naunyn Schmiedebergs Arch Pharmacol 362:480–488

    Article  PubMed  CAS  Google Scholar 

  • Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P (2000) Idiopathic short QT interval: a new clinical syndrome? Cardiology 94:99–102

    Article  PubMed  CAS  Google Scholar 

  • Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham DE, Covarriubias M, Desir GV, Furuichi K, Ganetzky B, Garcia ML, Grissmer S, Jan LY, Karschin A, Kim D, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage F, Lester HA, McKinnon D, Nichols CG, O’Kelly I, Robbins J, Robertson GA, Rudy B, Sanguinetti M, Seino S, Stuehmer W, Tamkun MM, Vandenberg CA, Wei A, Wulff H, Wymore RS (2003) International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: potassium channels. Pharmacol Rev 55:583–586

    Article  PubMed  CAS  Google Scholar 

  • Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R (2000) The potential for QT prolongation and proarrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Cardiovasc Res 47:219–233

    Article  PubMed  CAS  Google Scholar 

  • Heginbotham L, Lu Z, Abramson T, MacKinnon R (1994) Mutations in the K+ channel signature sequence. Biophys J 66:1061–1067

    PubMed  CAS  Google Scholar 

  • Hondeghem LM, Carlsson L, Duker G (2001a) Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 103:2004–2013

    PubMed  CAS  Google Scholar 

  • Hondeghem LM, Dujardin K, De Clerck F (2001b) Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia. Cardiovasc Res 50:345–353

    Article  PubMed  CAS  Google Scholar 

  • Janse MJ (2004) Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 61:208–217

    Article  PubMed  CAS  Google Scholar 

  • Jiang M, Dun W, Tseng GN (1999) Mechanism for the effects of extracellular acidification on HERG-channel function. Am J Physiol 277:H1283–H1292

    PubMed  CAS  Google Scholar 

  • Jiang M, Zhang M, Tang DG, Clemo HF, Liu J, Holwitt D, Kasirajan V, Pond AL, Wettwer E, Tseng GN (2004) KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation 109:1783–1788

    Article  PubMed  CAS  Google Scholar 

  • Jones EM, Roti Roti EC, Wang J, Delfosse SA, Robertson GA (2004) Cardiac IKr channels minimally comprise hERG1a and 1b subunits. J Biol Chem 279:44690–44694

    Article  PubMed  CAS  Google Scholar 

  • Jurkiewicz NK, Sanguinetti MC (1993) 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. Circ Res 72:75–83

    PubMed  CAS  Google Scholar 

  • Kaab S, Nuss HB, Chiamvimonvat N, O’Rourke B, Pak PH, Kass DA, Marban E, Tomaselli GF (1996) Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 78:262–273

    PubMed  CAS  Google Scholar 

  • Kaab S, Dixon J, Duc J, Ashen D, Nabauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, Tomaselli GF (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98:1383–1393

    PubMed  CAS  Google Scholar 

  • Kagan A, Yu Z, Fishman GI, McDonald TV (2000) The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. J Biol Chem 275:11241–11248

    Article  PubMed  CAS  Google Scholar 

  • Kass RS (1997) Genetically induced reduction in small currents has major impact. Circulation 96:1720–1721

    PubMed  CAS  Google Scholar 

  • Kass RS, Davies MP, Freeman LC (1996) Functional differences between native and recombinant forms of IKs. In: Endoh H, Morad M, Scholz H, Iijima T (eds) Molecular and cellular mechanisms of cardiovascular regulation. Springer, New York, pp 33–46

    Google Scholar 

  • Keating MT, Sanguinetti MC (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569–580

    Article  PubMed  CAS  Google Scholar 

  • Kiehn J (2000) Regulation of the cardiac repolarizing HERG potassium channel by protein kinase A. Trends Cardiovasc Med 10:205–209

    Article  PubMed  CAS  Google Scholar 

  • Kiehn J, Lacerda AE, Wible B, Brown AM (1996a) Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. Circulation 94:2572–2579

    PubMed  CAS  Google Scholar 

  • Kiehn J, Wible B, Lacerda AE, Brown AM (1996b) Mapping the block of a cloned human inward rectifier potassium channel by dofetilide. Mol Pharmacol 50:380–387

    PubMed  CAS  Google Scholar 

  • Kiehn J, Lacerda AE, Brown AM (1999) Pathways of HERG inactivation. Am J Physiol 277:H199–210

    PubMed  CAS  Google Scholar 

  • Kleiman RB, Houser SR (1989) Outward currents in normal and hypertrophied feline ventricular myocytes. Am J Physiol 256:H1450–H1461

    PubMed  CAS  Google Scholar 

  • Kupershmidt S, Snyders DJ, Raes A, Roden DM (1998) A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current. J Biol Chem 273:27231–27235

    Article  PubMed  CAS  Google Scholar 

  • Kupershmidt S, Yang T, Anderson ME, Wessels A, Niswender KD, Magnuson MA, Roden DM (1999) Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. Circ Res 84:146–152

    PubMed  CAS  Google Scholar 

  • Kurokawa J, Abriel H, Kass RS (2001a) Molecular basis of the delayed rectifier current I(ks) in heart. J Mol Cell Cardiol 33:873–882

    Article  PubMed  CAS  Google Scholar 

  • Kurokawa J, Motoike HK, Kass RS (2001b) TEA(+)-sensitive KCNQ1 constructs reveal pore independent access to KCNE1 in assembled I(Ks) channels. J Gen Physiol 117:43–52

    Article  PubMed  CAS  Google Scholar 

  • Kurokawa J, Chen L, Kass RS (2003) Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc Natl Acad Sci U S A 100:2122–2127

    Article  PubMed  CAS  Google Scholar 

  • Laitinen P, Fodstad H, Piippo K, Swan H, Toivonen L, Viitasalo M, Kaprio J, Kontula K (2000) Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects. Hum Mutat 15:580–581

    Article  PubMed  CAS  Google Scholar 

  • Larsen LA, Andersen PS, Kanters J, Svendsen IH, Jacobsen JR, Vuust J, Wettrell G, Tranebjaerg L, Bathen J, Christiansen M (2001) Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome. Clin Chem 47:1390–1395

    PubMed  CAS  Google Scholar 

  • Lees-Miller JP, Kondo C, Wang L, Duff HJ (1997) Electrophysiological characterization of an alternatively processed ERG K+ channel in mouse and human hearts. Circ Res 81:719–726

    PubMed  CAS  Google Scholar 

  • Lehmann MH, Hardy S, Archibald D, quart B, MacNeil DJ (1996) Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 94:2535–2541

    PubMed  CAS  Google Scholar 

  • Lei M, Brown HF, Terrar DA (2000) Modulation of delayed rectifier potassium current, iK, by isoprenaline in rabbit isolated pacemaker cells. Exp Physiol 85:27–35

    Article  PubMed  CAS  Google Scholar 

  • Li GR, Lau CP, Ducharme A, Tardif JC, Nattel S (2002) Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283:H1031–H1041

    PubMed  CAS  Google Scholar 

  • Liu DW, Antzelevitch C (1995) 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. Circ Res 76:351–365

    PubMed  CAS  Google Scholar 

  • London B, Trudeau MC, Newton KP, Beyer AK, Copeland NG, Gilbert DJ, Jenkins NA, Satler CA, Robertson GA (1997) 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. Circ Res 81:870–878

    PubMed  CAS  Google Scholar 

  • Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, Kass RS (2002)Requirementof a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295:496–499

    Article  PubMed  CAS  Google Scholar 

  • Mazhari R, Greenstein JL, Winslow RL, Marban E, Nuss HB (2001) Molecular interactions between two long-QT syndrome gene products, HERG and KCNE2, rationalized by in vitro and in silico analysis. Circ Res 89:33–38

    PubMed  CAS  Google Scholar 

  • McDonald TV, Yu Z, Ming Z, Palma E, Meyers MB, Wang KW, Goldstein SA, Fishman GI (1997) A minK-HERG complex regulates the cardiac potassium current I(Kr). Nature 388:289–292

    Article  PubMed  CAS  Google Scholar 

  • Miles EW (1977) Modification of histidyl residues in proteins by diethylpyrocarbonate. Methods Enzymol 47:431–442

    PubMed  CAS  Google Scholar 

  • Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003) Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. Br J Pharmacol 139:887–898

    Article  PubMed  CAS  Google Scholar 

  • Mitcheson JS (2003) Drug binding to HERG channels: evidence for a ‘non-aromatic’ binding site for fluvoxamine. Br J Pharmacol 139:883–884

    Article  PubMed  CAS  Google Scholar 

  • Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC (2000a) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A 97:12329–12333

    Article  PubMed  CAS  Google Scholar 

  • Mitcheson JS, Chen J, Sanguinetti MC (2000b) Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J Gen Physiol 115:229–240

    Article  PubMed  CAS  Google Scholar 

  • Mohammad-Panah R, Demolombe S, Neyroud N, Guicheney P, Kyndt F, van den Hoff M, Baro I, Escande D (1999) Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias. Am J Hum Genet 64:1015–1023

    Article  PubMed  CAS  Google Scholar 

  • Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, Mackinnon R (1998) Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95:649–655

    Article  PubMed  CAS  Google Scholar 

  • Murai T, Kakizuka A, Takumi T, Ohkubo H, Nakanishi S (1989) Molecular cloning and sequence analysis of human genomic DNA encoding a novel membrane protein which exhibits a slowly activating potassium channel activity. Biochem Biophys Res Commun 161:176–181

    Article  PubMed  CAS  Google Scholar 

  • Nabauer M, Kaab S (1998) Potassium channel down-regulation in heart failure. Cardiovasc Res 37:324–334

    Article  PubMed  CAS  Google Scholar 

  • Nattel S (2000) Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders. Cardiovasc Res 48:188–190

    Article  PubMed  CAS  Google Scholar 

  • Numaguchi H, Johnson JP Jr, Petersen CI, Balser JR (2000) A sensitive mechanism for cation modulation of potassium current. Nat Neurosci 3:429–430

    Article  PubMed  CAS  Google Scholar 

  • Paavonen KJ, Swan H, Piippo K, Hokkanen L, Laitinen P, Viitasalo M, Toivonen L, Kontula K (2001) Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome. Heart 86:39–44

    Article  PubMed  CAS  Google Scholar 

  • Paavonen KJ, Chapman H, Laitinen PJ, Fodstad H, Piippo K, Swan H, Toivonen L, Viitasalo M, Kontula K, Pasternack M (2003) Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG). Cardiovasc Res 59:603–611

    Article  PubMed  CAS  Google Scholar 

  • Pak PH, Nuss HB, Tunin RS, Kaab S, Tomaselli GF, Marban E, Kass DA (1997) Repolarization abnormalities, arrhythmia and sudden death in canine tachycardia-induced cardiomyopathy. J Am Coll Cardiol 30:576–584

    Article  PubMed  CAS  Google Scholar 

  • Petrecca K, Atanasiu R, Akhavan A, Shrier A (1999) N-linked glycosylation sites determine HERG channel surface membrane expression. J Physiol 515:41–48

    Article  PubMed  CAS  Google Scholar 

  • Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, Kontula K (2001) A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. J Am Coll Cardiol 37:562–568

    Article  PubMed  CAS  Google Scholar 

  • Pond AL, Scheve BK, Benedict AT, Petrecca K, Van Wagoner DR, Shrier A, Nerbonne JM (2000) Expression of distinct ERG proteins in rat, mouse, and human heart. Relation to functional I(Kr) channels. J Biol Chem 275:5997–6006

    Article  PubMed  CAS  Google Scholar 

  • Priori SG (2000) Long QT and Brugada syndromes: from genetics to clinical management. J Cardiovasc Electrophysiol 11:1174–1178

    PubMed  CAS  Google Scholar 

  • Robertson GA (2000) LQT2: amplitude reduction and loss of selectivity in the tail that wags the HERG channel. Circ Res 86:492–493

    PubMed  CAS  Google Scholar 

  • Roden DM (1998) Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes. Pacing Clin Electrophysiol 21:1029–1034

    PubMed  CAS  Google Scholar 

  • Roden DM (2000) Acquired long QT syndromes and the risk of proarrhythmia. J Cardiovasc Electrophysiol 11:938–940

    PubMed  CAS  Google Scholar 

  • Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM (1996) Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation 94:1996–2012

    PubMed  CAS  Google Scholar 

  • Roden DM, Balser JR, George AL Jr, Anderson ME (2002) Cardiac ion channels. Annu Rev Physiol 64:431–475

    Article  PubMed  CAS  Google Scholar 

  • Rozanski GJ, Xu Z, Whitney RT, Murakami H, Zucker IH (1997) Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing. J Mol Cell Cardiol 29:721–732

    Article  PubMed  CAS  Google Scholar 

  • Russell MW, Dick M 2nd, Collins FS, Brody LC (1996) KVLQT1 mutations in three families with familial or sporadic long QT syndrome. Hum Mol Genet 5:1319–1324

    Article  PubMed  CAS  Google Scholar 

  • Salata JJ, Jurkiewicz NK, Wang J, Evans BE, Orme HT, Sanguinetti MC (1998) A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol Pharmacol 54:220–230

    PubMed  CAS  Google Scholar 

  • Sanchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, Sanguinetti MC (2002) Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. J Biol Chem 277:23587–23595

    Article  PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Jurkiewicz NK (1990a) Lanthanum blocks a specific component of IK and screens membrane surface change in cardiac cells. Am J Physiol 259:H1881–H1889

    PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Jurkiewicz NK (1990b) Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96:195–215

    Article  PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Xu QP (1999) Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. J Physiol 514:667–675

    Article  PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the Ikr potassium channel. Cell 81:299–307

    Article  PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Curran ME, Spector PS, Keating MT (1996a) Spectrum of HERGK+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci U S A 93:2208–2212

    Article  PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT (1996b) Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 384:80–83

    Article  PubMed  CAS  Google Scholar 

  • Scherer CR, Lerche C, Decher N, Dennis AT, Maier P, Ficker E, Busch AE, Wollnik B, Steinmeyer K (2002) The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. Br J Pharmacol 137:892–900

    Article  PubMed  CAS  Google Scholar 

  • Schonherr R, Heinemann SH (1996) Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. J Physiol 493:635–642

    PubMed  Google Scholar 

  • Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403:196–199

    Article  PubMed  CAS  Google Scholar 

  • Seebohm G, Chen J, Strutz N, Culberson C, Lerche C, Sanguinetti MC (2003) Molecular determinants of KCNQ1 channel block by a benzodiazepine. Mol Pharmacol 64:70–77

    Article  PubMed  CAS  Google Scholar 

  • Selnick HG, Liverton NJ, Baldwin JJ, Butcher JW, Claremon DA, Elliott JM, Freidinger RM, King SA, Libby BE, McIntyre CJ, Pribush DA, Remy DC, Smith GR, Tebben AJ, Jurkiewicz NK, Lynch JJ, Salata JJ, Sanguinetti MC, Siegl PK, Slaughter DE, Vyas K (1997) Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current IKs by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2, 3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide. J Med Chem 40:3865–3868

    Article  PubMed  CAS  Google Scholar 

  • Sesti F, Tai KK, Goldstein SA (2000) MinK endows the I(Ks) potassium channel pore with sensitivity to internal tetraethylammonium. Biophys J 79:1369–1378

    Article  PubMed  CAS  Google Scholar 

  • Shah RR (2004) Drug-induced QT interval prolongation: regulatory perspectives and drug development. Ann Med 36 Suppl 1:47–52

    Article  CAS  Google Scholar 

  • Shibasaki T (1987) Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol 387:227–250

    PubMed  CAS  Google Scholar 

  • Shimizu W, Antzelevitch C (1998) Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 98:2314–2322

    PubMed  CAS  Google Scholar 

  • Smith PL, Baukrowitz T, Yellen G (1996) The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379:833–836

    Article  PubMed  CAS  Google Scholar 

  • Snyders DJ (1999) Structure and function of cardiac potassium channels. Cardiovasc Res 42:377–390

    Article  PubMed  CAS  Google Scholar 

  • Snyders DJ, Chaudhary A (1996) High affinity open channel block by dofetilide of HERG expressed in a human cell line. Mol Pharmacol 49:949–955

    PubMed  CAS  Google Scholar 

  • Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996a) Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. Circ Res 78:499–503

    PubMed  CAS  Google Scholar 

  • Spector PS, Curran ME, Zou A, Keating MT, Sanguinetti MC (1996b) Fast inactivation causes rectification of the IKr channel. J Gen Physiol 107:611–619

    Article  PubMed  CAS  Google Scholar 

  • Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT (1997) Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 17:338–340

    PubMed  CAS  Google Scholar 

  • Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102:1178–1185

    PubMed  CAS  Google Scholar 

  • Splawski I, Timothy KW, Tateyama M, Clancy CE, Malhotra A, Beggs AH, Cappuccio FP, Sagnella GA, Kass RS, Keating MT (2002) Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 297:1333–1336

    Article  PubMed  CAS  Google Scholar 

  • Stengl M, Volders PG, Thomsen MB, Spatjens RL, Sipido KR, Vos MA (2003) Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol 551:777–786

    Article  PubMed  CAS  Google Scholar 

  • Tai KK, Goldstein SA (1998) The conduction pore of a cardiac potassium channel. Nature 391:605–608

    Article  PubMed  CAS  Google Scholar 

  • Tamargo J (2000) Drug-induced torsade de pointes: from molecular biology to bedside. Jpn J Pharmacol 83:1–19

    Article  PubMed  CAS  Google Scholar 

  • Tamargo J, Caballero R, Gomez R, Valenzuela C, Delpon E (2004) Pharmacology of cardiac potassium channels. Cardiovasc Res 62:9–33

    Article  PubMed  CAS  Google Scholar 

  • Tapper AR, George AL Jr (2000) MinK subdomains that mediate modulation of and association with KvLQT1. J Gen Physiol 116:379–390

    Article  PubMed  CAS  Google Scholar 

  • Tapper AR, George AL Jr (2001) Location and orientation of minK within the I(Ks)potassium channel complex. J Biol Chem 276:38249–38254

    PubMed  CAS  Google Scholar 

  • Thomas D, Zhang W, Wu K, Wimmer AB, Gut B, Wendt-Nordahl G, Kathofer S, Kreye VA, Katus HA, Schoels W, Kiehn J, Karle CA (2003) Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein. Cardiovasc Res 59:14–26

    Article  PubMed  CAS  Google Scholar 

  • Tohse N, Kameyama M, Irisawa H (1987) Intracellular Ca2+ and protein kinase C modulate K+ current in guinea pig heart cells. Am J Physiol 253:H1321–H1324

    PubMed  CAS  Google Scholar 

  • Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42:270–283

    Article  PubMed  CAS  Google Scholar 

  • Tristani-Firouzi M, Sanguinetti MC (2003) Structural determinants and biophysical properties of HERG and KCNQ1 channel gating. J Mol Cell Cardiol 35:27–35

    Article  PubMed  CAS  Google Scholar 

  • Trudeau MC, Warmke JW, Ganetzky B, Robertson GA (1995) HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269:92–95

    PubMed  CAS  Google Scholar 

  • Tseng GN (2001) I(Kr): the hERG channel. J Mol Cell Cardiol 33:835–849

    Article  PubMed  CAS  Google Scholar 

  • Tsuji Y, Opthof T, Kamiya K, Yasui K, Liu W, Lu Z, Kodama I (2000) Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle. Cardiovasc Res 48:300–309

    Article  PubMed  CAS  Google Scholar 

  • Tsuji Y, Opthof T, Yasui K, Inden Y, Takemura H, Niwa N, Lu Z, Lee JK, Honjo H, Kamiya K, Kodama I (2002) Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block. Circulation 106:2012–2018

    Article  PubMed  Google Scholar 

  • Varnum MD, Busch AE, Bond CT, Maylie J, Adelman JP (1993) The min K channel underlies the cardiac potassium current IKs and mediates species-specific responses to protein kinase C. Proc Natl Acad Sci U S A 90:11528–11532

    PubMed  CAS  Google Scholar 

  • Varro A, Balati B, Iost N, Takacs J, Virag L, Lathrop DA, Csaba L, Talosi L, Papp JG (2000) The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization. J Physiol 523:67–81

    Article  PubMed  CAS  Google Scholar 

  • Vaughan Williams EM (1984) A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 24:129–147

    PubMed  CAS  Google Scholar 

  • Vereecke J, Carmeliet E (2000) The effect of external pH on the delayed rectifying K+ current in cardiac ventricular myocytes. Pflugers Arch 439:739–751

    Article  PubMed  CAS  Google Scholar 

  • Viswanathan PC, Shaw RM, Rudy Y (1999) Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 99:2466–2474

    PubMed  CAS  Google Scholar 

  • Volders PG, Sipido KR, Carmeliet E, Spatjens RL, Wellens HJ, Vos MA (1999a) Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation 99:206–210

    PubMed  CAS  Google Scholar 

  • Volders PG, Sipido KR, Vos MA, Spatjens RL, Leunissen JD, Carmeliet E, Wellens HJ (1999b) Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. Circulation 100:2455–2461

    PubMed  CAS  Google Scholar 

  • Walker AM, Szneke P, Weatherby LB, Dicker LW, Lanza LL, Loughlin JE, Yee CL, Dreyer NA (1999) The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada. Am J Med 107:356–362

    Article  PubMed  CAS  Google Scholar 

  • Walsh KB, Kass RS (1988) Regulation of a heart potassium channel by protein kinase A and C. Science 242:67–69

    PubMed  CAS  Google Scholar 

  • Walsh KB, Kass RS (1991) Distinct voltage-dependent regulation of a heart-delayed IK by protein kinases A and C. Am J Physiol 261:C1081–C1090

    PubMed  CAS  Google Scholar 

  • Wang HS, Brown BS, McKinnon D, Cohen IS (2000a) Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991. Mol Pharmacol 57:1218–1223

    PubMed  CAS  Google Scholar 

  • Wang J, Trudeau MC, Zappia AM, Robertson GA (1998a) Regulation of deactivation by an amino terminal domain in human ether-a-go-go-related gene potassium channels. J Gen Physiol 112:637–647

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Myers CD, Robertson GA (2000b) Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels. J Gen Physiol 115:749–758

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12:17–23

    Article  PubMed  Google Scholar 

  • Wang S, Liu S, Morales MJ, Strauss HC, Rasmusson RL (1997) A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J Physiol 502:45–60

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Xia J, Kass RS (1998b) MinK-KvLQT1 fusion proteins, evidence for multiple stoichiometries of the assembled IsK channel. J Biol Chem 273:34069–34074

    Article  PubMed  CAS  Google Scholar 

  • Warmke JW, Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A 91:3438–3442

    PubMed  CAS  Google Scholar 

  • Washizuka T, Horie M, Watanuki M, Sasayama S (1997) Endothelin-1 inhibits the slow component of cardiac delayed rectifier K+ currents via a pertussis toxin-sensitive mechanism. Circ Res 81:211–218

    PubMed  CAS  Google Scholar 

  • Weerapura M, Nattel S, Chartier D, Caballero R, Hebert TE (2002) A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? J Physiol 540:15–27

    Article  PubMed  CAS  Google Scholar 

  • Wehrens XH, Marks AR (2003) Altered function and regulation of cardiac ryanodine receptors in cardiac disease. Trends Biochem Sci 28:671–678

    Article  PubMed  CAS  Google Scholar 

  • Wehrens XH, Vos MA, Doevendans PA, Wellens HJ (2002) Novel insights in the congenital long QT syndrome. Ann Intern Med 137:981–992

    PubMed  CAS  Google Scholar 

  • Witchel HJ, Dempsey CE, Sessions RB, Perry M, Milnes JT, Hancox JC, Mitcheson JS (2004) The low potency, voltage-dependent HERG blocker propafenone—molecular determinants and drug trapping. Mol Pharmacol 66:1201–1212

    Article  PubMed  CAS  Google Scholar 

  • Wollnik B, Schroeder BC, Kubisch C, Esperer HD, Wieacker P, Jentsch TJ (1997) Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias. Hum Mol Genet 6:1943–1949

    Article  PubMed  CAS  Google Scholar 

  • Wysowski DK, Bacsanyi J (1996) Cisapride and fatal arrhythmia. N Engl J Med 335:290–291

    Article  PubMed  CAS  Google Scholar 

  • Yang IC, Scherz MW, Bahinski A, Bennett PB, Murray KT (2000) Stereoselective interactions of the enantiomers of chromanol 293B with human voltage-gated potassium channels. J Pharmacol Exp Ther 294:955–962

    PubMed  CAS  Google Scholar 

  • Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM (2002) Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 105:1943–1948

    Article  PubMed  CAS  Google Scholar 

  • Yang T, Kupershmidt S, Roden DM (1995) Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K+ current. Circ Res 77:1246–1253

    PubMed  CAS  Google Scholar 

  • Yang T, Kanki H, Roden DM (2003) Phosphorylation of the IKs channel complex inhibits drug block: novel mechanism underlying variable antiarrhythmic drug actions. Circulation 108:132–134

    Article  PubMed  CAS  Google Scholar 

  • Yang ZK, Boyett MR, Janvier NC, McMorn SO, Shui Z, Karim F (1996) Regional differences in the negative inotropic effect of acetylcholine within the canine ventricle. J Physiol 492:789–806

    PubMed  CAS  Google Scholar 

  • Zabel M, Hohnloser SH, Behrens S, Woosley RL, Franz MR (1997) Differential effects of D-sotalol, quinidine, and amiodarone on dispersion of ventricular repolarization in the isolated rabbit heart. J Cardiovasc Electrophysiol 8:1239–1245

    PubMed  CAS  Google Scholar 

  • Zeng J, Laurita KR, Rosenbaum DS, Rudy Y (1995) Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization. Circ Res 77:140–152

    PubMed  CAS  Google Scholar 

  • Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, January CT (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J 74:230–241

    PubMed  CAS  Google Scholar 

  • Zipes DP, Wellens HJ (1998) Sudden cardiac death. Circulation 98:2334–2351

    PubMed  CAS  Google Scholar 

  • Zou A, Curran ME, Keating MT, Sanguinetti MC (1997) Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes. Am J Physiol 272:H1309–H1314

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Molecular Cardiology, Dept. of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, 630West 168th Street, P&S 9-401, New York, NY, 10032, USA

    X.H.T. Wehrens

Authors
  1. X.H.T. Wehrens
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Wehrens, X. (2006). Structural Determinants of Potassium Channel Blockade and Drug-Induced Arrhythmias. In: Basis and Treatment of Cardiac Arrhythmias. Handbook of Experimental Pharmacology, vol 171. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29715-4_5

Download citation

Publish with us

Policies and ethics

Search

Navigation