title: Molecular mechanisms of chloroquine inhibition of heterologously expressed Kir6.2/SUR2A channels.
abstract: Chloroquine and related compounds can inhibit inwardly rectifying potassium channels by multiple potential mechanisms, including pore block and allosteric effects on channel gating. Motivated by reports that chloroquine inhibition of cardiac ATP-sensitive inward rectifier K(+) current (I(KATP)) is antifibrillatory in rabbit ventricle, we investigated the mechanism of chloroquine inhibition of ATP-sensitive potassium (K(ATP)) channels (Kir6.2/SUR2A) expressed in human embryonic kidney 293 cells, using inside-out patch-clamp recordings. We found that chloroquine inhibits the Kir6.2/SUR2A channel by interacting with at least two different sites and by two mechanisms of action. A fast-onset effect is observed at depolarized membrane voltages and enhanced by the N160D mutation in the central cavity, probably reflecting direct channel block resulting from the drug entering the channel pore from the cytoplasmic side. Conversely, a slow-onset, voltage-independent inhibition of I(KATP) is regulated by chloroquine interaction with a different site and probably involves disruption of interactions between Kir6.2/SUR2A and phosphatidylinositol 4,5-bisphosphate. Our findings reveal multiple mechanisms of K(ATP) channel inhibition by chloroquine, highlighting the numerous convergent regulatory mechanisms of these ligand-dependent ion channels.
authors.affiliation: Unidad de Investigación Carlos Méndez del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rodríguez-Menchaca
authors.forename: Angélica
authors.initials: A
authors.lastname: López-Izquierdo
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Harley T
authors.initials: HT
authors.lastname: Kurata
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Chapula
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001665:Binding Sites; D002738:Chloroquine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000235:genetics; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D013096:Spermine / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D014162:Transfection; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D002738:Chloroquine; D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013096:Spermine; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577510:ABCC9 protein, human; C577511:Abcc9 protein, mouse