Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA.
Cell Calcium. 2019 Jun;80:112-116. doi: 10.1016/j.ceca.2019.03.004. Epub 2019 Mar 11.
Ca release-activated Ca (CRAC) channels are intimately linked with health and disease. The gene encoding the CRAC channel, ORAI1, was discovered in part by genetic analysis of patients with abolished CRAC channel function. And patients with autosomal recessive loss-of-function (LOF) mutations in ORAI1 and its activator stromal interaction molecule 1 (STIM1) that abolish CRAC channel function and store-operated Ca entry (SOCE) define essential functions of CRAC channels in health and disease. Conversely, gain-of-function (GOF) mutations in ORAI1 and STIM1 are associated with tubular aggregate myopathy (TAM) and Stormorken syndrome due to constitutive CRAC channel activation. In addition, genetically engineered animal models of ORAI and STIM function have provided important insights into the physiological and pathophysiological roles of CRAC channels in cell types and organs beyond those affected in human patients. The picture emerging from this body of work shows CRAC channels as important regulators of cell function in many tissues, and as potential drug targets for the treatment of autoimmune and inflammatory disorders.
钙释放激活钙 (CRAC) 通道与健康和疾病密切相关。CRAC 通道的编码基因 ORAI1 部分是通过对 CRAC 通道功能丧失的患者进行遗传分析发现的。常染色体隐性失活 (LOF) 突变的患者 ORAI1 及其激活剂基质相互作用分子 1 (STIM1) 丧失 CRAC 通道功能和储存操纵钙进入 (SOCE)，定义了 CRAC 通道在健康和疾病中的基本功能。相反，ORAI1 和 STIM1 的获得功能 (GOF) 突变与管状聚集性肌病 (TAM) 和 Stormorken 综合征有关，原因是 CRAC 通道持续激活。此外，ORAI 和 STIM 功能的基因工程动物模型为 CRAC 通道在人类患者受影响以外的细胞类型和器官中的生理和病理生理作用提供了重要的见解。从这一系列工作中得出的结论表明，CRAC 通道是许多组织中细胞功能的重要调节剂，并且是治疗自身免疫和炎症性疾病的潜在药物靶点。
