Action potential clamp and mefloquine sensitivity of recombinant IKs' channels incorporating the V307L KCNQ1 mutation

• Autorzy: El Harchi A. , Mcpate M.J. , Zhang Y.H. , Zhang H. , Hancox J.C.
• Języki publikacji: EN

Abstrakty

EN

The slow delayed rectifier potassium current, 'IKs', contributes to repolarisation of cardiac ventricular action potentials and thereby to the duration of the QT interval of the electrocardiogram. Mutations to IKs channel subunits occur in clinically significant cardiac repolarisation disorders. The short QT syndrome (SQTS) is associated with accelerated ventricular repolarisation and with an increased risk of arrhythmia and sudden death. The SQT2 variant of the SQTS has been linked to a gain-of-function amino-acid substitution (V307L) in the KCNQ1-encoded IKs channel -subunit. This study reports the first action potential (AP) voltage-clamp comparison between wild-type (WT) and V307L KCNQ1 (co-expressed with KCNE1 to recapitulate IKs) and identifies an effective pharmacological inhibitor of recombinant 'IKs' channels incorporating the V307L KCNQ1 mutation. Perforated-patch voltage-clamp recordings at 37°C of whole-cell current carried by co-expressed KCNQ1 and KCNE1 showed a marked (-36 mV) shift in half-maximal activation for V307L compared to WT KCNQ1; a significant slowing of current deactivation was also observed. Under AP clamp, peak repolarising current was significantly augmented for V307L KCNQ1 compared to WT KCNQ1 for both ventricular and atrial AP commands, consistent with an ability of the V307L mutation to increase repolarising IKs in both regions. The quinoline agent mefloquine inhibited WT KCNQ1+KCNE1 with an IC50 of 3.4 µM compared to 3.3 µM for V307L KCNQ1+KCNE1 (P >0.05). This establishes mefloquine as an effective inhibitor of recombinant 'IKs' channels incorporating this SQT2 KCNQ1 mutation.

Słowa kluczowe

EN

action potential; arrhythmia; cardiac arrhythmia; cardiac repolarization; heart disease; mefloquine; patient; potassium current; repolarization; short QT syndrome; sudden death

• Wydawca: -
• Czasopismo: Journal of Physiology and Pharmacology
• Rocznik: 2010
• Tom: 61
• Numer: 2
• Opis fizyczny: p.123-131,fig.,ref.

Twórcy

autor

El Harchi A.

• University of Bristol, Bristol, BS8 1TD, U.K.

autor

Mcpate M.J.

autor

Zhang Y.H.

autor

Zhang H.

autor

Hancox J.C.

Bibliografia

• Tamargo J, Caballero R, Gomez R, Valenzuela C, Delpon E. Pharmacology of cardiac potassium channels. Cardiovasc Res 2004; 62: 9-33.
• Mitcheson JS, Sanguinetti MC. Biophysical properties and molecular basis of cardiac rapid and slow delayed rectifier K channels. Cell Physiol Biochem 1999; 9: 201-216.
• Stengl M, Volders PG, Thomsen MB, Spatjens RL, Sipido KR, Vos MA. Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. J Physiol 2003; 551: 777-786.
• Volders PG, Stengl M, van Opstal JM, et al. Probing the contribution of IKs to canine ventricular repolarisation: key role for beta-adrenergic receptor stimulation. Circulation 2003; 107: 2753-2760.
• Jost N, Virag L, Bitay M, et al. Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation 2005; 112: 1392-1399.
• Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 1013-1022.
• Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium current. Nature 1996; 384: 78-80.
• Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 1996; 384: 80-83.
• Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med 2006; 8(3): 143-155.
• Maury P, Extramiana F, Sbragia P, et al. Short QT syndrome. Update on a recent entity. Arch Cardiovasc Dis 2008; 101: 779-786.
• Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome. Cardiovasc Res 2005; 67: 357-366.
• Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109: 30-35.
• Hong K, Bjeerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardivasc Electophysiol 2005; 16: 394-396.
• Hong K, Piper DR, az-Valdecantos A, et al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res 2005; 68: 433-440.
• Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109: 2394-2397.
• Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96: 800-807.
• Zhang H, Kharche S, Holden AV, Hancox JC. Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation a simulation study. Prog Biophys Mol Biol 2008; 96: 112-131.
• Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R. Modulation of IKr inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome. Cardiovas Res 2005; 67: 498-509.
• McPate MJ, Zhang H, Ideniran I, Cordeiro JM, Witchel HJ, Hancox JC. Comparative effects of the short QT N588K mutation at 37°C on hERG K+ channel current during ventricular, Purkinje fibre and atrial action potentials: an action potential clamp study. J Physiol Pharmacol 2009; 60: 23-41.
• McPate MJ, Duncan RS, Milnes JT, Witchel HJ, Hancox JC. The N588K-HERG K+ channel mutation in the 'short QT syndrome': mechanism of gain-in-function determined at 37°C. Biochem Biophys Res Commun 2005; 334: 441-449.
• El Harchi A, McPate MJ, Zhang YH, Zhang H, Hancox JC. Action potential clamp and chloroquine sensitivity of mutant Kir2.1 channels responsible for variant 3 short QT syndrome. J Mol Cell Cardiol 2009; 47: 743-747.
• Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electophysiol 2005; 16: 54-58.
• McPate MJ, Duncan RS, Witchel HJ, Hancox JC. Disopyramide is an effective inhibitor of mutant HERG K+ channels involved in variant 1 short QT syndrome. J Mol Cell Cardiol 2006; 41: 563-566.
• McPate MJ, Duncan RS, Hancox JC, Witchel HJ. Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs. Br J Pharmacol 2008; 155: 957-966.
• Lai LP, Deng CL, Moss AJ, Kass RS, Liang CS. Polymorphism of the gene encoding a human minimal potassium ion channel (minK). Gene 1994; 151: 339-340.
• Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc 2003; 78: 1479-1487.
• ten Tusscher KH, Noble D, Noble PJ, Panfilov AV. A model for human ventricular tissue. Am J Physiol 2004; 286: H1573-H1589.
• Courtemanche M, Ramirez RJ, Nattel S. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol 1998; 275: H301-H321.
• Hancox JC, Levi AJ, Witchel HJ. Time course and voltage dependence of expressed HERG current compared with native 'rapid' delayed rectifier K current during the cardiac ventricular action potential. Pflugers Archiv 1998; 436: 843-853.
• Lerche C, Bruhova I, Lerche H, et al. Chromanol 293B binding in KCNQ1 (Kv7.1) channels involves electrostatic interactions with a potassium ion in the selectivity filter. Mol Pharmacol 2007; 71: 1503-1511.
• Kang J, Chen XL, Wang L, Rampe D. Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQT1/minK and HERG. J Pharmacol Exp Ther 2001; 299: 290-296.
• Viswanathan PC, Shaw RM, Rudy Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 1999; 99: 2466-2474.
• Noble D, Varghese A, Kohl P, Noble P. Improved guinea-pig ventricular cell model incorporating a diadic space, IKr and IKs, and length- and tension-dependent processes. Can J Cardiol 1998; 14: 123-134.
• Wang Z, Fermini B, Nattel S. Rapid and slow components of delayed rectifier current in human atrial myocytes. Cardiovas Res 1994; 28: 1540-1546.
• Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003; 299: 251-254.
• Restier L, Cheng L, Sanguinetti MC. Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels. J Physiol 2008; 586: 4179-4191.
• Abraham RL, Yang T, Blair M, Roden DM, Darbar D. Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation. J Mol Cell Cardiol 2010; 48: 181-190.
• Tsai CT, Lai LP, Hwang JJ, Lin JL, Chiang FT. Molecular genetics of atrial fibrillation. J Am Coll Cardiol 2008; 52: 241-250.
• Nygren A, Fiset C, Firek L, et al. Mathematical model of an adult human atrial cell: the role of K+ currents in repolarisation. Circ Res 1998; 82: 63-81.
• Maleckar MM, Greenstein JL, Giles WR, Trayanova NA. K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. Am J Physiol Heart Circ Physiol 2009; 297(4): H1398-H1410.
• Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery. J Cardiovasc Electrophysiol 2003; 14: 1273- 1277.
• Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004; 43: 1494-1499.
• Bjeerregaard P, Jahangir A, Gussak I. Targeted therapy for short QT syndrome. Expert Opin Ther Targets 2006; 10: 393-400.
• Jaspers CA, Hopperus Buma AP, van Thiel PP, van Hulst RA, Kager PA. Tolerance of mefloquine chemoprophylaxis in Dutch military personnel. Am J Trop Med Hyg 1996; 55: 230-234.
• Hancox JC, McPate MJ, El Harchi A, Zhang YH. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther 2008; 119: 118-132.
• Toovey S. Mefloquine neurotoxicity: a literature review. Travel Med Infect Dis 2009; 7(1): 2-6.
• AlKadi HO. Antimalarial drug toxicity: a review. Chemotherapy 2007; 53: 385-391.