The molecular physiology of CRAC channels.
The molecular physiology of CRAC channels.
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DOI：
10.1111/j.1600-065x.2009.00820.x
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发表时间：
2009-09
影响因子：
8.7
通讯作者：
Prakriya M
中科院分区：
文献类型：
--
作者：
Prakriya M
钙离子释放激活的钙通道(CRAC)是一种高选择性的存储操作通道，表达于T细胞、肥大细胞等多种组织中。CRAC通道调节关键的细胞过程，如基因表达、运动性和炎性介质的分泌。CRAC通道孔的关键亚单位Orai1和内质网(ER)钙离子感受器STIM1的发现为阐明CRAC通道的调控机制和孔特性提供了工具。最近的证据表明，CRAC通道的激活涉及一系列协调的步骤，包括STIM1和Orai1的重新分布，这些蛋白质之间的直接物理相互作用，以及Orai1的构象变化，最终导致通道激活。更多的研究表明，CRAC通道对钙的高选择性来自于孔内钙结合部位的存在，该结合部位的性质被精细地磨练，以阻止更普遍的Na+的渗透。结构-功能研究已经确定了钙离子潜在的孔结合部位，为理解CRAC通道的选择性和门控机制提供了坚实的框架。本文综述了近几年来对CRAC通道激活、孔道特性和调控机制的研究进展。
The Ca2+release-activated Ca2+ (CRAC) channel is a highly Ca2+-selective store-operated channel expressed in T cells, mast cells, and various other tissues. CRAC channels regulate critical cellular processes such as gene expression, motility, and the secretion of inflammatory mediators. The identification of Orai1, a key subunit of the CRAC channel pore, and STIM1, the endoplasmic reticulum (ER) Ca2+ sensor, have provided the tools to illuminate the mechanisms of regulation and the pore properties of CRAC channels. Recent evidence indicates that the activation of CRAC channels by store depletion involves a coordinated series of steps, which include the redistributions of STIM1 and Orai1, direct physical interactions between these proteins, and conformational changes in Orai1, culminating in channel activation. Additional studies have revealed that the high Ca2+ selectivity of CRAC channels arises from the presence of an intrapore Ca2+ binding site, the properties of which are finely honed to occlude the permeation of the much more prevalent Na+. Structure-function studies have led to the identification of the potential pore-binding sites for Ca2+, providing a firm framework for understanding the mechanisms of selectivity and gating of the CRAC channel. This review summarizes recent progress in understanding the mechanisms of CRAC channel activation, pore properties, and modulation.