Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule.

ABSTRACT: The acetylcholine-activated inward rectifier potassium current ( I_KACh) is constitutively active in persistent atrial fibrillation (AF). We tested the hypothesis that the blocking of I_KACh with the small molecule chloroquine terminates persistent AF. We used a sheep model of tachypacing-induced, persistent AF, molecular modeling, electrophysiology, and structural biology approaches. The 50% inhibition/inhibitory concentration of I_KACh block with chloroquine, measured by patch clamp, was 1 μM. In optical mapping of sheep hearts with persistent AF, 1 μM chloroquine restored sinus rhythm. Molecular modeling suggested that chloroquine blocked the passage of a hydrated potassium ion through the intracellular domain of Kir3.1 (a molecular correlate of I_KACh<

SUBMITTER: Takemoto Y 

PROVIDER: S-EPMC5893172 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature