title: Kv1.5 open channel block by the antiarrhythmic drug disopyramide: molecular determinants of block.
abstract: Kv1.5 is considered to be a potential molecular target for treatment of atrial fibrillation or flutter. Disopyramide is widely used in the treatment of atrial flutter and/or atrial fibrillation. The present study was undertaken to characterize the effects of disopyramide on currents mediated by Kv1.5 channels and to determine the putative binding site involved in the inhibitory effects of disopyramide. Experiments were carried out on wild-type and site directed mutated hKv1.5 channels expressed on HEK 293 cells using the patch-clamp technique. Disopyramide acting from the cytoplasmic side of the membrane produced blocking effects on Kv1.5 that exhibited several features typical of an open channel blocker. Ala-scanning mutagenesis of the Kv1.5 pore domain combined with macroscopic current analysis suggested that disopyramide interacted only with the Val512 residue that faces to the central cavity of the channel. Mutation of this key residue to Ala caused marked change in the IC(50) of disopyramide (22-fold). The single interaction between disopyramide and Val512 in the PVP region is able to change the mechanism of channel closure, reproducing the "foot-in-the-door" phenomenon.
authors.affiliation: Unidad de Investigación Carlos Méndez, Centro de Investigaciones Biomédicas de la Universidad de Colima, Colima, México.
authors.forename: Iván A
authors.initials: IA
authors.lastname: Aréchiga
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Barrio-Echavarria
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rodríguez-Menchaca
authors.forename: Eloy G
authors.initials: EG
authors.lastname: Moreno-Galindo
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Chapula
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Navarro-Polanco
mesh_terms: D000409:Alanine / Q000235:genetics; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002460:Cell Line; D003627:Data Interpretation, Statistical; D004206:Disopyramide / Q000494:pharmacology*; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D016296:Mutagenesis / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers
chemical_list: D000889:Anti-Arrhythmia Agents; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D004206:Disopyramide; D000409:Alanine