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首页> 外文期刊>Cellular Physiology and Biochemistry >Modulation of human ether a gogo related channels by CASQ2 contributes to etiology of catecholaminergic polymorphic ventricular tachycardia (CPVT)
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Modulation of human ether a gogo related channels by CASQ2 contributes to etiology of catecholaminergic polymorphic ventricular tachycardia (CPVT)

机译：CASQ2调节gogo相关通道对人乙醚的作用有助于儿茶酚胺能性多形性室性心动过速（CPVT）的病因

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Rationale - The plateau phase of the ventricular action potential is the result of balanced Ca~(2+) influx and K~+ efflux. The action potential is terminated by repolarizing K~+ currents. Under β-adrenergic stimulation, both the Ca~(2+)-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 Ca~(2+) influx. Intracellularly, a Calsequestrin2 (CASQ2)-ryanodine receptor complex serves as the most effective Ca~(2+) reservoir/release system to aid the control of intracellular Ca~(2+) levels. Currently, it is unclear if disease-associated CASQ2 gene variants alter intracellular free Ca~(2+) concentrations and if cardiac ion channels are affected by it. Objective - The goal of this study is to test if CASQ2 determines intracellular free Ca~(2+) 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 Ca~(2+) measurements and molecular dynamics simulations imply alterations in Ca~(2+) 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 Ca~(2+) and hERG channels which may contribute to the etiology of CPVT.
机译：原理-心室动作电位的平稳期是Ca〜（2+）内流和K〜+外排平衡的结果。动作电位通过重新极化K〜+电流而终止。在β-肾上腺素能刺激下，Ca〜（2+）流入和整流器K〜+延迟电流I_K均被刺激，以调节心脏动作电位的持续时间以提高心率，并确定净Ca〜（2）的适当增加。 +）涌入。在细胞内，Calsequestrin2（CASQ2）-ryanodine受体复合物是最有效的Ca〜（2+）储库/释放系统，有助于控制细胞内Ca〜（2+）的水平。目前，尚不清楚疾病相关的CASQ2基因变异是否会改变细胞内游离Ca〜（2+）的浓度，以及心脏离子通道是否受其影响。目的-这项研究的目的是测试CASQ2是否确定细胞内游离Ca〜（2+）的浓度，并确定受其影响的心脏离子通道。此外，我们旨在在这种情况下研究与疾病相关的CASQ2基因变异。方法和结果-在这里，我们使用两个电极电压钳研究位于高度保守区域的CASQ2突变R33Q，F189L和D307H对非洲爪蟾卵母细胞心脏钾通道功能的影响。结果，CASQ2野生型和CASQ2突变体调节的hERG功能不同。免费的Ca〜（2+）测量和分子动力学模拟表明，与CASQ2野生型相比，CAS〜2突变体的动态行为发生了变化，Ca〜（2+）缓冲能力发生了变化。结论-这些体外和计算机模拟数据表明CASQ2对胞质Ca〜（2+）和hERG通道的调节作用，可能有助于CPVT的病因。

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