MISC

2006年5月

Molecular determinants of hERG channel block

MOLECULAR PHARMACOLOGY
  • K Kamiya
  • ,
  • R Niwa
  • ,
  • JS Mitcheson
  • ,
  • MC Sanguinetti

69
5
開始ページ
1709
終了ページ
1716
記述言語
英語
掲載種別
DOI
10.1124/mol.105.020990
出版者・発行元
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Drug-induced block of cardiac hERG K+ channels causes acquired long QT syndrome. Here, we characterized the molecular mechanism of hERG block by two low-potency drugs (Nifekalant and bepridil) and two high-potency drugs 1-[2-(6-methyl-2-pyridyl) ethyl]-4-(4-methylsulfonyl aminobenzoyl) piperidine (E-4031) and dofetilide). Channels were expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. All four drugs progressively reduced hERG current during a 20-s depolarization to 0 mV after a 10-min pulse-free period, consistent with the preferential block of open channels. Recovery from block in response to pulses to -160 mV was observed for D540K hERG channels but not for wild-type hERG channels, suggesting that all four drugs are trapped in the central cavity by closure of the activation gate. The molecular determinants of hERG channel block were defined by using a site-directed mutagenesis approach. Mutation to alanine of three residues near the pore helix (Thr623, Ser624, and Val625) and four residues in Ser6 (Gly648, Tyr652, Phe656, and Val659) reduced channel sensitivity to block by dofetilide and E-4031, effects identical with those reported previously for two other methanesulfonanilides, (+)N-[1'-(6-cyano- 1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride (MK-499) and ibutilide. The effect of nifekalant on mutant channels was similar, except that V659A retained normal sensitivity and I655A channels were less sensitive. Finally, mutation of the three residues near the pore helix and Phe656 in the Ser6 domain reduced channel block by bepridil. We conclude that the binding site is not identical for all drugs that preferentially block hERG in the open state.

Web of Science ® 被引用回数 : 139

リンク情報
DOI
https://doi.org/10.1124/mol.105.020990
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000236874100025&DestApp=WOS_CPL
ID情報
  • DOI : 10.1124/mol.105.020990
  • ISSN : 0026-895X
  • Web of Science ID : WOS:000236874100025

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