Modulation of Human Ether A Gogo Related Channels by CASQ2 Contributes to Etiology of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Rationale - The plateau phase of the ventricular action potential is the result of balanced Ca2+ influx and K+ efflux. The action potential is terminated by repolarizing K+ currents. Under beta-adrenergic stimulation, both the Ca2+-influx and the delayed rectifier K+ currents I-K are stimulated to adjust the cardiac action potential duration to the enhanced heart rate and to ascertain adequate increase in net Ca2+ influx. Intracellularly, a Calsequestrin2 (CASQ2)-ryanodine receptor complex serves as the most effective Ca2+ reservoir/release system to aid the control of intracellular Ca2+ levels. Currently, it is unclear if disease-associated CASQ2 gene variants alter intracellular free Ca2+ concentrations and if cardiac ion channels are affected by it. Objective - The goal of this study is to test if CASQ2 determines intracellular free Ca2+ concentrations and to identify cardiac ion channels that are affected by it. Further, we aim to study disease-associated CASQ2 gene variants in this context. Methods and Results - Here, we study the effects of the CASQ2 mutations R33Q, F189L, and D307H, located in highly conserved regions, on the functions of cardiac potassium channels in Xenopus oocytes using two electrode voltage clamp. As a result, CASQ2 wild type and CASQ2-mutants modulated hERG functions differently. Free Ca2+ measurements and molecular dynamics simulations imply alterations in Ca2+ buffer capacity paralled by changes in the dynamic behavior of the CASQ2-mutants compared to CASQ2 wild type. Conclusions - These in vitro and in silico data suggest a regulatory role of CASQ2 on cytosolic Ca2+ and hERG channels which may contribute to the etiology of CPVT. Copyright (C) 2010 S. Karger AG, Basel