Referenced in: none

Automatically associated channels: Kir2.1

Title: Chloroquine blocks a mutant Kir2.1 channel responsible for short QT syndrome and normalizes repolarization properties in silico.

Authors: Angélica López-Izquierdo, Daniela Ponce-Balbuena, Tania Ferrer, Frank B Sachse, Martin Tristani-Firouzi, José A Sánchez-Chapula

Journal, date & volume: Cell. Physiol. Biochem., 2009 , 24, 153-60

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19710529

Abstract
Short QT Syndrome (SQTS) is a novel clinical entity characterized by markedly rapid cardiac repolarization and lethal arrhythmias. A mutation in the Kir2.1 inward rectifier K+ channel (D172N) causes one form of SQTS (SQT3). Pharmacologic block of Kir2.1 channels may hold promise as potential therapy for SQT3. We recently reported that the anti-malarial drug chloroquine blocks Kir2.1 channels by plugging the cytoplasmic pore domain. In this study, we tested whether chloroquine blocks D172N Kir2.1 channels in a heterologous expression system and if chloroquine normalizes repolarization properties using a mathematical model of a human ventricular myocyte. Chloroquine caused a dose- and voltage-dependent reduction in wild-type (WT), D172N and WT-D172N heteromeric Kir2.1 current. The potency and kinetics of chloroquine block of D172N and WT-D172N Kir2.1 current were similar to WT. In silico modeling of the heterozygous WT-D172N Kir2.1 condition predicted that 3 microM chloroquine normalized inward rectifier K+ current magnitude, action potential duration and effective refractory period. Our results suggest that therapeutic concentrations of chloroquine might lengthen cardiac repolarization in SQT3.