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Chloroquine Blocks a Mutant Kir2.1 Channel Responsible for Short QT Syndrome and Normalizes Repolarization Properties in silicoLopez-Izquierdo A.1 · Ponce-Balbuena D.1 · Ferrer T.1 · Sachse F.B.2,3 · Tristani-Firouzi M.2,4 · Sánchez-Chapula J.A.1
1Centro Universitario de Investigaciones Biomedicas de la Universidad de Colima, Colima,2Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City,3Bioengineering Department and4Division of Pediatric Cardiology, University of Utah, Salt Lake City Corresponding Author
Pediatric Cardiology, Suite 1500 PCMC
University of Utah School of Medicine
100 N. Mario Capecchi Way, Salt Lake City, UT 84113 (USA)
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 μM 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.
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