Calsequestrin in Ventricular Arrhythmia and Sudden Death

钙螯合素与室性心律失常和猝死 心脏钙螯合蛋白（CASQ 2）及其结合伙伴连接蛋白和三聚体蛋白-1（TRDN）是关键的 肌浆网（SR）钙储存和释放的调节剂。在人类中，CASQ 2突变 引起儿茶酚胺能多形性室性心动过速和突发性室性心动过速综合征 心源性死亡为了确定CASQ 2突变引起电生理学异常的机制， 不稳定但保留收缩功能，我们产生了Casq 2缺失（Casq 2 +/-）小鼠。我们 初步研究表明，尽管缺乏Casq 2蛋白，这些小鼠仍保持了近 正常SR Ca 2+储存，可能是SR体积膨胀和急剧减少的结果 在Casq 2结合蛋白triadin-1和junctin中。Casq 2-/-小鼠表型复制人CASQ 2- 通过输注儿茶酚胺形成多形性室性心动过速的连锁心律失常 或者锻炼。Casq 2 +/-肌细胞显示过早的自发性SR Ca 2+释放，导致后 宫缩和触发性搏动值得注意的是，常用的抗抑郁药物， 体外Ca 2 * 与CASQ 2的结合也与心脏骤停的发生率增加有关。 死亡，增加了Casq 2相关形式的药物诱导心律失常的可能性，类似于 与药物相关的长QT综合征根据这些人类遗传学、流行病学和 小鼠数据，我们假设Casq 2的破坏导致SR Ca 2+释放功能障碍 并导致心律失常和猝死。 为了验证我们的中心假设，我们将检查单细胞，整个心脏和体内 电生理、收缩功能、Ca 2 * 稳态、蛋白表达和SR超微结构 在Casq 2、Casq 2 + 1 ′、三聚体蛋白-1缺失（Trdn '7 ′）和选择性杂交动物中。我们的目标是测试 Casq 2和triadin-1对心律失常易感性单独贡献以及进一步阐明 导致室性心律失常的分子和细胞机制 遗传性和可能的药物诱导的Casq 2功能障碍。 这项研究的结果不仅将促进我们对糖尿病的病理生理学的理解， 遗传性心律失常综合征，但也有助于解开机制（S）负责突然 与数百万患者服用的抗抑郁药物有关的死亡。

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.