RT Journal Article
SR Electronic
T1 Molecular Mechanisms of Chloroquine Inhibition of Heterologously Expressed Kir6.2/SUR2A Channels.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.079152
DO 10.1124/mol.112.079152
A1 Daniela Ponce-Balbuena
A1 Aldo A Rodriguez-Menchaca
A1 Angelica Lopez-Izquierdo
A1 Tania Ferrer
A1 Harley T Kurata
A1 Colin G Nichols
A1 Jose A Sanchez-Chapula
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/07/31/mol.112.079152.abstract
AB 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 IKATP is anti-fibrillatory in rabbit ventricle, we investigated the mechanism of chloroquine inihibition of cardiac KATP channels (Kir6.2/SUR2A) expressed in HEK293 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, likely reflecting direct channel block resulting from the drug entering the channel pore from the cytoplasmic side. Conversely, a slow-onset, voltage-independent inhibition of KATP currents is regulated by chloroquine interaction with a different site, and likely involves disruption of interactions between Kir6.2/SUR2A and PIP2. Our findings reveal multiple mechanisms of KATP channel inhibition by chloroquine, highlighting the numerous convergent regulatory mechanisms of these ligand-dependent ion channels.