San Diego State Heart Institute, San Diego State University, San Diego, CA 92182, USA.
J Cell Sci. 2012 Jan 15;125(Pt 2):287-94. doi: 10.1242/jcs.090464. Epub 2012 Feb 2.
Mutations in the store-operated Ca²⁺ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss of the calcineurin-associated protein calsarcin from the z-discs. Furthermore, we found mechanosignal transduction was affected in Orai1-depleted hearts, indicating an essential role for ORAI1 in establishing the cardiac signaling transduction machinery at the z-disc. Our findings identify ORAI1 as an important regulator of cardiac and skeletal muscle function and provide evidence linking ORAI1-mediated calcium signaling to sarcomere integrity and cardiomyocyte function.
已报道，储存操作的 Ca²⁺进入孔蛋白 ORAI1 的突变会导致人类患者发生肌病，但其中涉及的机制尚不清楚。心肌细胞表达 ORAI1，但它在心脏功能中的作用也不清楚。通过在斑马鱼中使用反向遗传学，我们证明了高度保守的 ORAI1 斑马鱼同源物的失活导致严重的心力衰竭、心室收缩功能降低、心动过缓和骨骼肌无力。Orai1 缺陷型肌细胞的电子显微镜检查显示骨骼肌不稳定进行性进展，肌纤维完整性丧失，骨骼肌和心肌的 z 盘出现超微结构异常。分离的 Orai1 缺陷型心肌细胞显示来自 z 盘的钙调神经磷酸酶相关蛋白 calsarcin 的丢失。此外，我们发现 Orai1 耗尽的心脏中的机械信号转导受到影响，表明 ORAI1 在建立 z 盘处的心脏信号转导机制中起重要作用。我们的研究结果确定 ORAI1 是心脏和骨骼肌功能的重要调节剂，并提供证据将 ORAI1 介导的钙信号与肌节完整性和心肌细胞功能联系起来。
