Molecular Determinants of hERG Channel Block by Terfenadine and Cisapride

DOI Web Site PubMed 被引用文献6件 参考文献63件 オープンアクセス
  • Kamiya Kaichiro
    Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan
  • Niwa Ryoko
    Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan
  • Morishima Mikio
    Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan
  • Honjo Haruo
    Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan
  • Sanguinetti Michael C.
    Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute, University of Utah, USA

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説明

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.<br>

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