title: Chloroquine blocks a mutant Kir2.1 channel responsible for short QT syndrome and normalizes repolarization properties in silico.
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.
authors.affiliation: Centro Universitario de Investigaciones Biomedicas de la Universidad de Colima, Colima.
authors.forename: Angelica
authors.initials: A
authors.lastname: Lopez-Izquierdo
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Frank B
authors.initials: FB
authors.lastname: Sachse
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: Jose A
authors.initials: JA
authors.lastname: Sanchez-Chapula
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000962:Antimalarials / Q000494:pharmacology*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D007668:Kidney / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015233:Models, Statistical; D009154:Mutation / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
chemical_list: D000962:Antimalarials; C489461:Kir2.1 channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D002738:Chloroquine