MISC

2008年11月

Molecular Determinants of hERG Channel Block by Terfenadine and Cisapride

JOURNAL OF PHARMACOLOGICAL SCIENCES
  • Kaichiro Kamiya
  • ,
  • Ryoko Niwa
  • ,
  • Mikio Morishima
  • ,
  • Haruo Honjo
  • ,
  • Michael C. Sanguinetti

108
3
開始ページ
301
終了ページ
307
記述言語
英語
掲載種別
DOI
10.1254/jphs.08102FP
出版者・発行元
JAPANESE PHARMACOLOGICAL SOC

Block of cardiac hERG K(+) channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160-3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.

Web of Science ® 被引用回数 : 72

リンク情報
DOI
https://doi.org/10.1254/jphs.08102FP
CiNii Articles
http://ci.nii.ac.jp/naid/10024593080
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000261353400009&DestApp=WOS_CPL
ID情報
  • DOI : 10.1254/jphs.08102FP
  • ISSN : 1347-8613
  • CiNii Articles ID : 10024593080
  • Web of Science ID : WOS:000261353400009

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