Institute of Biophysics, Johannes Kepler University Linz, A-4020, Linz, Austria.
Institute of Biophysics, Johannes Kepler University Linz, A-4020, Linz, Austria.
Cell Calcium. 2019 Jan;77:29-38. doi: 10.1016/j.ceca.2018.11.009. Epub 2018 Nov 30.
A primary calcium (Ca) entry pathway into non-excitable cells is through the store-operated Ca release activated Ca (CRAC) channel. Ca entry into cells is responsible for the initiation of diverse signalling cascades that affect essential cellular processes like gene regulation, cell growth and death, secretion and gene transcription. Upon depletion of intracellular Ca stores within the endoplasmic reticulum (ER), the CRAC channel opens to refill depleted stores. The two key limiting molecular players of the CRAC channel are the stromal interaction molecule (STIM1) embedded in the ER-membrane and Orai1, residing in the plasma membrane (PM), respectively. Together, they form a highly Ca selective ion channel complex. STIM1 senses the Ca content of the ER and confers Ca store-depletion into the opening of Orai1 channels in the PM for triggering Ca-dependent gene transcription, T-cell activation or mast cell degranulation. The interplay of Orai and STIM proteins in the CRAC channel signalling cascade has been the main focus of research for more than twelve years. This chapter focuses on current knowledge and main experimental advances in the understanding of Orai1 activation by STIM1, thereby portraying key mechanistic steps in the CRAC channel signalling cascade.
非兴奋细胞的主要钙 (Ca) 内流途径是通过钙库操纵的钙释放激活钙 (CRAC) 通道。Ca 进入细胞负责启动多种信号级联反应，影响基因调控、细胞生长和死亡、分泌和基因转录等基本细胞过程。内质网 (ER) 内细胞内 Ca 储存耗尽时，CRAC 通道打开以补充耗尽的储存。CRAC 通道的两个关键限制分子参与者是分别位于内质网膜中的基质相互作用分子 (STIM1) 和位于质膜 (PM) 中的 Orai1。它们共同形成高度 Ca 选择性离子通道复合物。STIM1 感知 ER 中的 Ca 含量，并将 Ca 储存耗竭转化为 PM 中 Orai1 通道的打开，以触发 Ca 依赖性基因转录、T 细胞激活或肥大细胞脱颗粒。十二年来，Orai 和 STIM 蛋白在 CRAC 通道信号级联中的相互作用一直是研究的主要重点。本章重点介绍了目前对 STIM1 激活 Orai1 的理解的最新知识和主要实验进展，从而描绘了 CRAC 通道信号级联中的关键机制步骤。
