Calsequestrin in Ventricular Arrhythmia and Sudden Death

钙黄体酮在室性心律失常和猝死中的应用 心脏钙调蛋白(CASQ2)及其结合蛋白连接素和三聚氰胺-1(TRDN)是关键 肌浆网(SR)钙储存和释放的调节器。在人类中，CASQ2突变 导致儿茶酚胺能多形性室性心动过速和猝发综合征 心源性死亡。为了确定CASQ2突变导致电生理的机制 不稳定但保留收缩功能，我们产生了Casq2缺失(Casq2‘/~)小鼠。我们的 初步研究表明，尽管缺乏Casq2蛋白，但这些小鼠保持在 正常的肌质网钙离子存储，可能是由于肌质网体积扩大和急剧减少所致 在Casq2结合蛋白Triadin-1和Junctin中。Casq2~/~小鼠复制人类CASQ2- 儿茶酚胺注射诱发多形性室性心动过速所致的连锁心律失常 或者锻炼身体。Casq2‘/“心肌细胞过早地自发释放肌浆网钙离子，导致后- 宫缩和触发的心跳。值得注意的是，常用的抗抑郁药物扰乱了 在体外，CA2*与CASQ2的结合也与心脏病突发发生率的增加有关 死亡，增加了Casq2相关形式的药物引起的心律失常的可能性，类似于 药物相关的长QT间期综合征。基于这些人类遗传、流行病学和 小鼠数据，我们假设Casq2的中断导致SR钙释放功能障碍 并导致心律失常易感性和猝死。 为了验证我们的中心假设，我们将检查单个细胞、整个心脏和活体 电生理、收缩功能、钙稳态、蛋白质表达和肌浆网超微结构 在Casq2中，Casq2+L‘、Triadin-1缺失(TrdN’7‘)和选择性杂交动物。我们的目标是测试 Casq2和Triadin-1在心律失常易感性中的个体作用及进一步阐明 心肌梗死致室性心律失常的分子和细胞机制(S) 遗传性的，可能是药物引起的Casq2功能障碍。 这项研究的结果不仅将促进我们对心绞痛的病理生理学的理解 遗传性心律失常综合征，也有助于揭开突发心律失常的发病机制(S) 数百万患者服用抗抑郁药物导致死亡。

Calsequestrin in ventricular arrhythmia and sudden death Cardiac calsequestrin (CASQ2), and its binding partners junctin and triadin-1 (TRDN), are key regulators of sarcoplasmic reticulum (SR) Ca2+ storage and release. In humans, CASQ2 mutations cause a syndrome of catecholaminergic polymorphic ventricular tachycardia and sudden cardiac death. To determine the mechanisms whereby CASQ2 mutations cause electrophysiologic instability but preserve contractile function, we have generated Casq2 null (Casq2'/~) mice. Our preliminary studies demonstrate that despite a lack of Casq2 protein, these mice maintain near normal SR Ca2+ storage, possibly as a result of an expansion of SR volume and drastic reductions in the Casq2 binding proteins triadin-1 and junctin. Casq2~/~ mice phenocopy the human CASQ2- linked arrhythmias by developing polymorphic ventricular tachycardia with catecholamine infusion or exercise. Casq2'/" myocytes display premature spontaneous SR Ca2* releases resulting in after- contractions and triggered beats. Significantly, commonly-used antidepressant drugs which disrupt Ca2* binding to CASQ2 in vitro have also been linked to an increased incidence in sudden cardiac death, raising the possibility of a Casq2-linked form of drug-induced arrhythmias, analogous to the drug-associated long QT syndrome. Based on these human genetic, epidemiological, and mouse data, we hypothesize that disruption ofCasq2 causes dysfunctional SR Ca2+ release and contributes to arrhythmia susceptibility andsudden death. To test our central hypothesis, we will examine single cell, whole heart and in vivo electrophysiology, contractile function, Ca2* homeostasis, protein expression and SR ultrastructure in Casq2 , Casq2+l', triadin-1 null (Trdn'7') and selectively cross-bred animals. Our goals are to test the individual contribution of Casq2 and triadin-1 to arrhythmia susceptibility and further elucidate the molecular and cellular mechanism(s) that lead to ventricular arrhythmias in response to inherited and possibly drug-induced Casq2 dysfunction. The outcome of this research willnot only advance our understanding of the pathophysiology of inheritedarrhythmia syndromes, but also help unravel the mechanism(s) responsible for sudden deaths linked to antidepressant medications taken by millions of patients.