Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria.
Int J Mol Sci. 2021 Jan 5;22(1):471. doi: 10.3390/ijms22010471.
The calcium-release-activated calcium (CRAC) channel, activated by the release of Ca from the endoplasmic reticulum (ER), is critical for Ca homeostasis and active signal transduction in a plethora of cell types. Spurred by the long-sought decryption of the molecular nature of the CRAC channel, considerable scientific effort has been devoted to gaining insights into functional and structural mechanisms underlying this signalling cascade. Key players in CRAC channel function are the Stromal interaction molecule 1 (STIM1) and Orai1. STIM1 proteins span through the membrane of the ER, are competent in sensing luminal Ca concentration, and in turn, are responsible for relaying the signal of Ca store-depletion to pore-forming Orai1 proteins in the plasma membrane. A direct interaction of STIM1 and Orai1 allows for the re-entry of Ca from the extracellular space. Although much is already known about the structure, function, and interaction of STIM1 and Orai1, there is growing evidence that CRAC under physiological conditions is dependent on additional proteins to function properly. Several auxiliary proteins have been shown to regulate CRAC channel activity by means of direct interactions with STIM1 and/or Orai1, promoting or hindering Ca influx in a mechanistically diverse manner. Various proteins have also been identified to exert a modulatory role on the CRAC signalling cascade although inherently lacking an affinity for both STIM1 and Orai1. Apart from ubiquitously expressed representatives, a subset of such regulatory mechanisms seems to allow for a cell-type-specific control of CRAC channel function, considering the rather restricted expression patterns of the specific proteins. Given the high functional and clinical relevance of both generic and cell-type-specific interacting networks, the following review shall provide a comprehensive summary of regulators of the multilayered CRAC channel signalling cascade. It also includes proteins expressed in a narrow spectrum of cells and tissues that are often disregarded in other reviews of similar topics.
钙释放激活钙 (CRAC) 通道，由内质网 (ER) 中 Ca 的释放激活，对多种细胞类型的 Ca 稳态和活性信号转导至关重要。由于长期以来一直寻求解密 CRAC 通道的分子性质，因此大量科学努力致力于深入了解该信号级联的功能和结构机制。CRAC 通道功能的关键参与者是基质相互作用分子 1 (STIM1) 和 Orai1。STIM1 蛋白跨越 ER 的膜，能够感知腔内腔 Ca 浓度，并反过来负责将 Ca 储存耗竭的信号传递到质膜中的孔形成 Orai1 蛋白。STIM1 和 Orai1 的直接相互作用允许 Ca 从细胞外空间重新进入。尽管已经了解了 STIM1 和 Orai1 的结构、功能和相互作用，但越来越多的证据表明，CRAC 在生理条件下依赖于其他蛋白质才能正常发挥作用。已经证明几种辅助蛋白通过与 STIM1 和/或 Orai1 的直接相互作用来调节 CRAC 通道活性，以机械多样化的方式促进或阻碍 Ca 流入。虽然固有地缺乏对 STIM1 和 Orai1 的亲和力，但各种蛋白质也被确定对 CRAC 信号级联具有调节作用。除了普遍表达的代表外，这种调节机制的子集似乎允许对 CRAC 通道功能进行细胞类型特异性控制，考虑到特定蛋白质的表达模式相当受限。鉴于通用和细胞类型特异性相互作用网络的高功能和临床相关性，以下综述将全面总结 CRAC 通道信号级联的调节剂。它还包括在狭窄细胞和组织谱中表达的蛋白质，这些蛋白质在其他类似主题的综述中经常被忽略。
