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Table of Contents
Vol. 24, No. 3-4, 2009
Issue release date: August 2009
Section title: Original Paper
Free Access
Cell Physiol Biochem 2009;24:153–160

Chloroquine Blocks a Mutant Kir2.1 Channel Responsible for Short QT Syndrome and Normalizes Repolarization Properties in silico

Lopez-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
email Corresponding Author

Martin Tristani-Firouzi

Pediatric Cardiology, Suite 1500 PCMC

University of Utah School of Medicine

100 N. Mario Capecchi Way, Salt Lake City, UT 84113 (USA)

E-Mail mfirouzi@cvrti.utah.edu

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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.

© 2009 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: June 12, 2009
Published online: August 03, 2009
Issue release date: August 2009

Number of Print Pages: 8
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

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