title: Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets.
abstract: Atrial and ventricular tachyarrhythmias can be perpetuated by up-regulation of inward rectifier potassium channels. Thus, it may be beneficial to block inward rectifier channels under conditions in which their function becomes arrhythmogenic (e.g., inherited gain-of-function mutation channelopathies, ischemia, and chronic and vagally mediated atrial fibrillation). We hypothesize that the antimalarial quinoline chloroquine exerts potent antiarrhythmic effects by interacting with the cytoplasmic domains of Kir2.1 (I(K1)), Kir3.1 (I(KACh)), or Kir6.2 (I(KATP)) and reducing inward rectifier potassium currents. In isolated hearts of three different mammalian species, intracoronary chloroquine perfusion reduced fibrillatory frequency (atrial or ventricular), and effectively terminated the arrhythmia with resumption of sinus rhythm. In patch-clamp experiments chloroquine blocked I(K1), I(KACh), and I(KATP). Comparative molecular modeling and ligand docking of chloroquine in the intracellular domains of Kir2.1, Kir3.1, and Kir6.2 suggested that chloroquine blocks or reduces potassium flow by interacting with negatively charged amino acids facing the ion permeation vestibule of the channel in question. These results open a novel path toward discovering antiarrhythmic pharmacophores that target specific residues of the cytoplasmic domain of inward rectifier potassium channels.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48108, USA.
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer-Villada
authors.forename: Angelica
authors.initials: A
authors.lastname: López-Izquierdo
authors.forename: Sandeep
authors.initials: S
authors.lastname: Pandit
authors.forename: Conrado J
authors.initials: CJ
authors.lastname: Calvo
authors.forename: Krzysztof R
authors.initials: KR
authors.lastname: Grzeda
authors.forename: Omer
authors.initials: O
authors.lastname: Berenfeld
authors.forename: José A Sánchez
authors.initials: JA
authors.lastname: Chapula
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008958:Models, Molecular; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects; D011817:Rabbits; D054340:Receptors, KIR / Q000037:antagonists & inhibitors / Q000378:metabolism; D012756:Sheep; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000473:pathology; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000473:pathology
chemical_list: D000889:Anti-Arrhythmia Agents; D024661:Potassium Channels, Inwardly Rectifying; D054340:Receptors, KIR; D002738:Chloroquine