Skip to main content
SpringerLink
Log in
Book cover

Pharmacology of Ionic Channel Function: Activators and Inhibitors pp 347–362Cite as

Cardiac K+ Channels and Inherited Long QT Syndrome

  • Chapter

  • 332 Accesses

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 147))

Abstract

The hallmark of all long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram. LQTS have a drastically different prognosis whether or not they are congenital. Congenital Long QT syndrome is a rare cardiac disorder associating the occurrence of syncopes often triggered in adrenergic setting, like strenuous exercise or emotional stress (RODEN et al. 1996). Most of the times, syncopes result from polymorphic ventricular tachycardia, calledtorsades de pointes, that were described first by Dessertene who characterized their pause-dependency and their distinctive time-dependent change in electrical axis (DESSERTENNE 1966). They may degenerate into entricular fibrillation, possibly causing sudden death, and are remarkably prevented by ß-adrenergic antagonists. In fact, the clinical diagnosis of LQTS can be fairly difficult in the absence of typical rhythmic problems or if the QT interval remains within the normal limits (QTc<0.46s in women,or 0.45 s in men).

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   429.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   549.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   549.99
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

  • Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, Di DJ, Gintant GA, Liu DW (1991) Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res 69:1427-1449

    Article  PubMed  CAS  Google Scholar 

  • Antzelevitch C, Zhuo-Quian S, Zi-Qing Z, Gan-Xin Y (1996) Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and Torsade de Pointe. J Am Coll Cardiol 28:1836-1848

    Article  PubMed  CAS  Google Scholar 

  • Apkon M, Nerbonne JM (1991) Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes. J Gen Physiol 97:973-1011

    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 

  • Backx PH, Marban E (1993) Background potassium current active during the plateau of the action potential in Guinea-pig ventricular myocytes. Circ Res 72:890-900

    Article  PubMed  CAS  Google Scholar 

  • Barhanin J, Attali B, Lazdunski M (1998) IKS, a very slow and very intriguing cardiac K+ channel and its associated long QT diseases. Trends CardiovascMed 8:207-214

    Article  CAS  Google Scholar 

  • Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G (1996) K(v)LQT1 and IsK (minK) proteins associate to form theIK,cardiac potassium current. Nature 384:78-80

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Busch AE, Suessbrich H (1997b) Role of the ISK protein in the IminK channel complex. Trends Pharmacol Sci 18:26-29

    Article  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 

  • Choy AM, Lang CC, Chomsky DM, Rayos GH, Wilson JR, Roden DM (1997) Normalization of acquired QT prolongation in humans by intravenous potassium. Circulation 96:2149-2154

    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 

  • Davies MP, Doevendans P, An RH, Kubalak S, Chien KR, Kass RS (1996) Developmental changes in ionic channel activity in the embryonic murine heart. Circ Res 78:15-25

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Dessertenne F (1966) La tachycardie ventriculaire à deux foyers opposés variables. Arch Malcoeur 59:263-272

    CAS  Google Scholar 

  • Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P (1997) KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 96:2778-2781

    Article  PubMed  CAS  Google Scholar 

  • Doyle DA, Cabral JM, Pfuetzner RA, Kuo AL, 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 

  • Drici MD, Arrighi I, Chouabe C, Mann JR, Lazdunski M, Romey G, Barhanin J (1998) Involvment of IsK associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome. Circ Res 83:95-102

    Article  PubMed  CAS  Google Scholar 

  • Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL (1996) Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 94:1471-1474

    Article  PubMed  CAS  Google Scholar 

  • Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V, Beggs AH (1998) Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation 97:142-146

    Article  PubMed  CAS  Google Scholar 

  • Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M (1997) TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16:5464-5471

    Article  PubMed  CAS  Google Scholar 

  • Fiset C, Drolet B, Hamelin BA, Turgeon J (1997) Block ofIK, by the diuretic agent indapamide modulates cardiac electrophysiological effects of the class III antiarrhythmic drug dl-sotalol. J Pharmacol Exp Ther 283:148-156

    PubMed  CAS  Google Scholar 

  • Hauswirth O, Noble D, Tsien RW (1972) Separation of the pace-maker and plateau components of delayed rectification in cardiac Purkinje fibres. J Physiol 225:211-235

    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

    Article  PubMed  CAS  Google Scholar 

  • Hirao H, Shimizu W, Kurita T, Suyama K, Aihara N, Kamakura S, Shimomura K (1996) Frequency-dependent electrophysiologic properties of ventricular repolarization in patients with congenital long QT syndrome. J Am Coll Cardiol 28:1269-1277

    Article  PubMed  CAS  Google Scholar 

  • Honoré E, Attali B, Romey G, Heurteaux C, Ricard P, Lesage F, Lazdunski M, Barhanin J (1991) Cloning, expression, pharmacology and regulation of a delayed rectifier K' channel in mouse heart. EMBO J 10:2805-2811

    PubMed  Google Scholar 

  • Cast Investigators (1989) Preliminary report: effect of encainide and flecainide on mortality in a randomized trial arrhythmia suppression after myocardial infarction. N Engl J Med 321:406-412

    Article  Google Scholar 

  • Jervell A, Lange-Nielsen F (1957) Congenital deaf-mutism, functional heart disease with prolongation of Q-T interval and sudden death. Am Heart J 54:59-68

    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

    Article  PubMed  CAS  Google Scholar 

  • Kaczmarek LK, Blumenthal EM (1997) Properties and regulation of the minK potassium channel protein. Physiol Rev 77:627-641

    PubMed  CAS  Google Scholar 

  • Krahn AD, Klein GJ, Yee R (1997) Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome? Circulation 96:1551-1556

    Article  PubMed  CAS  Google Scholar 

  • Kupershmidt S, Sutherland M, King D, Magnuson MA, Roden DM (1996) Replacement by homologous recombination of the minK gene with LacZ reveals cell-specific minK expression (Abstract). Biophys J 72:A226

    Google Scholar 

  • Li GR, Feng JL, Yue LX, Carrier M, Nattel S (1996) Evidence for two components of delayed rectifier K' current in human ventricular myocytes. Circ Res 78:689-696

    Article  PubMed  CAS  Google Scholar 

  • Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH (1993) Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 270:2590-2597

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Nair LA, Grant AO (1997) Emerging class III antiarrhythmic agents: Mechanism of action and proarrhythmic potential. Cardiovasc Drug Therapy 11:149-167

    Article  CAS  Google Scholar 

  • Napolitano C, Priori S, Schwartz P, Cantù F, Paganini V, De Fusco M, Pinnavia A, Aquaro G, Casari G (1997) Identification of a long QT syndrome molecular defect in drug-induced torsade de pointes. Circulation 96:211 (Abstract)

    Google Scholar 

  • Napolitano C, Priori SG, Schwartz PJ (1994) Torsade de pointes. Mechanisms and management. Drugs 47:51-65

    Article  PubMed  CAS  Google Scholar 

  • Neyroud N, Denjoy I, Donger C, Villain E, Leenhardt A, Gary F, Coumel P, Schwartz K, Guicheney P (1998) A heterozygous mutation in the pore of the potassium channel gene KvLQT1 causes a benign phenotype in the long QT syndrome. Europ J Hum Genet 19(1):158-165

    CAS  Google Scholar 

  • Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P (1997) A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet 15:186-189

    Article  PubMed  CAS  Google Scholar 

  • Noble D,Tsien RW (1969) Outward membrane currents activated in the plateau range of potential in cardiac Purkinje fibers. J Physiol 200:205-231

    PubMed  CAS  Google Scholar 

  • Priori SG, Napolitano C, Paganini V, Cantu F, Schwartz PJ (1997) Molecular biology of the long QT syndrome: Impact on management. Pac Clin Electrophys 20:2052-2057

    Article  CAS  Google Scholar 

  • Roden D (1994) Risks and benefits of antiarrhythmic drug therapy. N Engl J Med 331:785-791

    Article  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

    Article  Google Scholar 

  • Romano C (1965) Congenital cardiac arrhythmia. (Letter) Lancet 1:658-659

    Article  CAS  Google Scholar 

  • Romey G, Attali B, Chouabe C, Abitbol I, Guillemare E, Barhanin J, Lazdunski M(1997) Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity. J Biol Chem 272:16713-16716

    Article  Google Scholar 

  • Rosen MR (1998) Antiarrhythmic drugs: Rethinking targets, development strategies, and evaluation tools. Am J Cardiol 81:D21-D23

    Article  Google Scholar 

  • Salata JJ, Brooks RR (1997a) Pharmacology of azimilide dihydrochloride (NE-10064), a class III antiarrhthmic agent. Cardiov Drug Rev 15:137-156

    Article  Google Scholar 

  • Salata JJ, Jurkiewicz NK, Jow B, Folander K, Guinosso PJ, Raynor B, Swanson R, Fermini B (1996) IK Of rabbit ventricle is composed of two currents: Evidence for I-Ks. Amer J Physiol 40:H2477-H2489

    Google Scholar 

  • Sanguinetti M, Keating M (1997a) Role ofdelayed rectifier potassium channels in cardiac repolarization and arrhythmias. NewPhysiol Sci 12:152-157

    Google Scholar 

  • Sanguinetti MC, Spector PS (1997b) Potassium channelopathies. Neuropharmacology 36:755-762

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT (1996b) Coassembly of K(v)LQTI and MinK (IsK) proteins to form cardiac IK, potassium channel. Nature 384:80-83

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sanguinetti MC, Jurkiewicz NK (1990) 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 

  • Satoh T, Zipes DP (1996) Rapid rates during bradycardia prolong ventricular refractoriness and facilitate ventricular tachycardia induction with cesium in dogs. Circulation 94:217-227

    Article  PubMed  CAS  Google Scholar 

  • Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, Donnelly P, Vergnaud G, Bachner L, Moisan JP (1995) Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet 57:1114-1122

    PubMed  CAS  Google Scholar 

  • Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y (1997) KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nature Genet 17:267-268

    Article  PubMed  CAS  Google Scholar 

  • Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, JenkinsWest T, Blanar MA (1997) Dominant-negative KVLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 96:1733-1736

    Article  PubMed  CAS  Google Scholar 

  • Splawski I, Timothy KW, Vincent GM, Atkinson DL, Keating MT (1997a) Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 336:1562-1567

    Article  Google Scholar 

  • Splawski I, Tristani-Firouzi M, Lehmannn MH, Sanguinetti MC, Keating MT (1997b) Mutations in hminK gene cause long-QT syndrome and suppressIK, function. Nature Genet 17:338-340

    Article  Google Scholar 

  • Takumi T, Moriyoshi K, Aramori I, Ishii T, Oiki S, Okada Y, Ohkubo H, Nakanishi S (1991) Alteration of Channel Activities and Gating by Mutations of Slow-IsK Potassium Channel. J Biol Chem 266:22192-22198

    PubMed  CAS  Google Scholar 

  • Turgeon J, Daleau P, Bennett PB, Wiggins SS, Selby L, Roden DM (1994) Block of IKs, the slow component of the delayed rectifier K' current, by the diuretic agent indapamide in guinea pig myocytes. Circ Res 75:879-886

    Article  PubMed  CAS  Google Scholar 

  • Tyson J, Tranebjærg L, Bellman S, Wren C, Taylor J, Bathen J, Aslaksen B, SO-land SJ, Lund O, Malcolm S, Pembrey M, Bhattacharya S, Bitner-Glindzicz M (1997) IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet 6:2179-2185

    Article  PubMed  CAS  Google Scholar 

  • Vetter DE, Mann JR, Wangemann P, Liu JZ, McLaughlin KJ, Lesage F, Marcus DC, Lazdunski M, Heinemann SF, Barhanin J (1996) Inner ear defects induced by null mutation of the IsK gene. Neuron 17:1251-1264

    Article  PubMed  CAS  Google Scholar 

  • Vincent G, Timothy K, Leppert M, Keating M (1992) The spectrum of symptoms and QT intervals in carriers of the gene for long QT syndrome. N Engl J Med 327:846-852

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Chen Q, Li H, Towbin JA (1997) Molecular genetics of long QT syndrome from genes to patients. Curr Opin Cardiol 12:310-320

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, Vanraay TJ, Shen J, Timothy KW, Vincent GM, Dejager T, Schwartz PJ, Towbin 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. Nature Genet 12:17-23

    Article  PubMed  Google Scholar 

  • Wang Q, Shen JX, Splawski I, Atkinson D, Li ZZ, Robinson JL, Moss AJ, Towbin JA, Keating MT (1995) SCN5 A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80:805-811

    Article  PubMed  CAS  Google Scholar 

  • Ward OC (1964) A new familial cardiac syndrome in children. J Irish Med Assoc 54:103-106

    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 USA 91:3438-3442

    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 

  • Woosley RL, Chen YW, Freiman JP, Gillis RA (1993) Mechanism of the cardiotoxic actions of terfenadine. JAMA 269:1532-1536

    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

    Article  PubMed  CAS  Google Scholar 

  • Zeng J, Rudy Y (1995a) Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 68:949-964

    Article  Google Scholar 

  • Zeng JL, Laurita KR, Rosenbaum DS, Rudy Y (1995b) Two components of the delayed rectifier K' current in ventricular myocytes of the guinea pig type — theoretical formation and their role in repolarization. Circ Res 77:140-152

    Article  Google Scholar 

Download references

Authors
  1. M.-D. Drici
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Barhanin
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Saitama Medical School, 38 Morohongo, Moroyama Iruma-Gun, Saitama, 350-0495, Japan

    Makato Endo M.D., Ph.D.

  2. Department of Pharmacology II Graduate School of Medicine and Faculty of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yoshihisa Kurachi

  3. Department of Molecular Neurobiology and Pharmacology School of Medicine, University of Tokyo, Hongo 7-3-1, Bukyo-ku, Tokyo, 113-0033, Japan

    Masayoshi Mishina

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Drici, MD., Barhanin, J. (2000). Cardiac K+ Channels and Inherited Long QT Syndrome. In: Endo, M., Kurachi, Y., Mishina, M. (eds) Pharmacology of Ionic Channel Function: Activators and Inhibitors. Handbook of Experimental Pharmacology, vol 147. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-57083-4_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-57083-4_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63030-9

  • Online ISBN: 978-3-642-57083-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation