Abstract
Aim:
The objectives of this study were to investigate the inhibitory action of verapamil on wild-type(WT) and mutation HERG K+ channel current (IHERG), and to determine whether mutations in the S6 region are important for the inhibition of IHERG by verapamil.
Methods:
HERG channels (WT, Y652A, and F656A) were expressed in oocytes of Xenopus laevis and studied using the 2-electrode voltage-clamp technique.
Results:
WT HERG is blocked in a concentration-dependent manner by verapamil (half-maximal inhibition concentration [IC50]=5.1 μmol/L), and the steady state activation and inactivation parameters are shifted to more negative values. However, mutation to Ala of Y652 and F656 located on the S6 domain produced 16-fold and 20-fold increases in IC50 for IHERG blockade, respectively. Simultaneously, the steady state activation and inactivation parameters for Y652A are also shifted to more negative values in the presence of the blockers.
Conclusion:
Verapamil preferentially binds to and blocks open HERG channels. Tyr-652 and Phe-656, 2 aromatic amino-acid residues in the inner (S6) helix, are critical in the verapamil-binding site.
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References
Warmke JW, Ganetzky B . A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci USA 1994; 91: 3438–42.
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.
Roden DM . Current status of class III antiarrhythmic drug therapy. Am J Cardiol 1993; 72: 44B–9.
Cavero I, Mestre M, Guillon JM, Crumb W . Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias. Exp Opin Pharmacother 2000; 1: 947–73.
De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N . Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes. Drug Safety 2002; 25: 263–86.
January CT, Gong Q, Zhou Z . Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2. J Cardiovasc Electrophysiol 2000; 11: 1413–8.
Tseng GN . I (Kr): the hERG channel. J Mol Cell Cardiol 2001; 33: 835–49.
Mitcheson JS, Perry MD . Molecular determinants of high-affinity drug binding to hERG channels. Curr Opin Drug Discov Dev 2003; 6: 667–74.
Chouabe C, Drici MD, Romey G, Barhanin J, Lazdunski M . HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers. Mol Pharm 1998; 54: 695–703.
Zhang S, Zhou ZF, Gong QM, Makielski JC, Craig T . Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ Res 1999; 84: 989–98.
Waldegger G, Niemeyer K, Mörike CA, Wagner H, Suessbrich AE, Busch F, et al. Effect of verapamil enantiomers and metabolites on cardiac K+ channels expressed in Xenopus oocytes. Cell Physiol Biochem 1999; 9: 81–9.
Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC . A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 2000; 97: 12329–33.
Su Z, Martin RL, Cox BF, Gintant GA . Ziprasidone: an open channel blocker of human ether-a-go-go-related gene K+ channel. J Mol Cell Cardiol 2004; 36: 151–60.
Sanchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, Sanguinetti MC . Molecular determinants of voltage dependent human ether-a-go-go related gene (HERG) K+ channel block. J Biol Chem 2002; 277: 23587–95.
Lees-Miller JP, Duan Y, Teng GQ, Duff HJ . Molecular determinant of high-affinity dofetilide binding to HERG expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol 2000; 57: 367–74.
Amiya K, Mitcheson JS, Yasui K, Kodama I, Sanguinetti MC . Open channel block of HERG K+ channels by vesnarinone. Mol Pharmacol 2001; 60: 244–53.
Sanchez-Chapula JA, Ferrer T, Navarro-Polanco RA, Sanguinetti MC . Voltage-dependent profile of human ethera-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol 2003; 63: 1051–8.
Wang S, Morales MJ, Liu S, Strauss HC, Rasmusson RL . Modulation of HERG affinity for E-4031 by [K+]0 and C-type inactivation, FEBS Lett 1997; 417: 43–7.
Sanguinetti MC, Mitcheson JS . Predicting drug-HERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci 2005; 26: 119–24.
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 2003; 58: 32–45.
Hosey MM, Lazdunski M . Calcium channels: molecular pharmacology, structure and regulation. J Membr Biol 1988; 104: 81–105.
Scholz EP, Zitron E, Kiesecker C, Lueck S, Kathofer S, Thomas D, et al. Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired long QT syndrome by antiparkinsonian drug budipine. Naunyn Schmiedebergs Arch Pharmacol 2003; 368: 404–14.
Cavalli A, Poluzzi E, De Ponti F, Recanatini M . Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K+ channel blockers. J Med Chem 2002; 45: 3844–53.
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This work was supported by the National Natural Science Foundation of China (No 30470711).
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Duan, Jj., Ma, Jh., Zhang, Ph. et al. Verapamil blocks HERG channel by the helix residue Y652 and F656 in the S6 transmembrane domain. Acta Pharmacol Sin 28, 959–967 (2007). https://doi.org/10.1111/j.1745-7254.2007.00562.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00562.x
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