title: Molecular determinants of hERG channel block by terfenadine and cisapride.
abstract: 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.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. kamiya@riem.nagoya-u.ac.jp
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.forename: Ryoko
authors.initials: R
authors.lastname: Niwa
authors.forename: Mikio
authors.initials: M
authors.lastname: Morishima
authors.forename: Haruo
authors.initials: H
authors.lastname: Honjo
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D000818:Animals; D001665:Binding Sites; D020117:Cisapride / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology; D018014:Gene Transfer Techniques; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials; D016296:Mutagenesis; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D016593:Terfenadine / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents; D039563:Histamine H1 Antagonists, Non-Sedating; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D016593:Terfenadine; D020117:Cisapride