Molecular Determinants of hERG Channel Block by Terfenadine and Cisapride

Journal of Pharmacological Sciences

Michael C. Sanguinetti²  Ryoko Niwa¹  Mikio Morishima¹  Haruo Honjo¹  Kaichiro Kamiya¹ 

[1] Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan;Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute, University of Utah, USA

关键词: hERG;    long QT syndrome;    oocyte;    voltage clamp;   

DOI  :  10.1254/jphs.08102FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(34)Cited-By(35)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.

【 授权许可】

Unknown