Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease
Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease
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DOI：
10.1038/s41598-019-46427-x
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发表时间：
2019-07-15
影响因子：
4.6
通讯作者：
Gyorke, Sandor
中科院分区：
文献类型：
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作者：
Bonilla, Ingrid M.;Belevych, Andriy E.;Gyorke, Sandor
钙池操纵的钙内流（SOCE）是非心肌细胞中的一种主要的钙信号传导机制，最近被认为是心肌细胞中钙信号传导的一个组成部分。尽管已经报道了它在心律失常中起作用并且在心脏疾病中上调，但对心脏SOCE的基本性质、其结构基础或效应靶点知之甚少。一个更大的问题是SOCE如何与典型的兴奋-收缩耦合（ECC）相互作用。我们进行了多尺度的结构和功能的调查SOCE在心肌细胞从健康小鼠（野生型; WT）和遗传性小鼠模型的心脏病（儿茶酚胺能室性心动过速; CPVT）。在这里，我们提供了第一个演示的本地，短暂的钙离子进入（LoCE）事件，其中包括心脏SOCE。虽然WT心肌细胞中不常见，但CPVT心肌细胞中LoCE的发生频率和幅度更高。CPVT心肌细胞在胆碱能应激下也表现出特征性的致炎性自发性Ca 2+波，SOCE抑制可有效地阻止这种自发性Ca 2+波。在一个令人惊讶的发现中，我们报告了LoCE及其潜在的蛋白质机制都集中在闰盘（ID）上。因此，心脏SOCE在ID隔室中的定位对于健康和疾病中的SOCE介导的信号传导、细胞生成和细胞间机械和电耦合具有重要意义。
Store-operated Ca2+ entry (SOCE), a major Ca2+ signaling mechanism in non-myocyte cells, has recently emerged as a component of Ca2+ signaling in cardiac myocytes. Though it has been reported to play a role in cardiac arrhythmias and to be upregulated in cardiac disease, little is known about the fundamental properties of cardiac SOCE, its structural underpinnings or effector targets. An even greater question is how SOCE interacts with canonical excitation-contraction coupling (ECC). We undertook a multiscale structural and functional investigation of SOCE in cardiac myocytes from healthy mice (wild type; WT) and from a genetic murine model of arrhythmic disease (catecholaminergic ventricular tachycardia; CPVT). Here we provide the first demonstration of local, transient Ca2+ entry (LoCE) events, which comprise cardiac SOCE. Although infrequent in WT myocytes, LoCEs occurred with greater frequency and amplitude in CPVT myocytes. CPVT myocytes also evidenced characteristic arrhythmogenic spontaneous Ca2+ waves under cholinergic stress, which were effectively prevented by SOCE inhibition. In a surprising finding, we report that both LoCEs and their underlying protein machinery are concentrated at the intercalated disk (ID). Therefore, localization of cardiac SOCE in the ID compartment has important implications for SOCE-mediated signaling, arrhythmogenesis and intercellular mechanical and electrical coupling in health and disease.