Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Int J Mol Sci. 2022 Jan 29;23(3):1580. doi: 10.3390/ijms23031580.
The TMEM16A/anoctamin-1 calcium-activated chloride channel (CaCC) contributes to a range of vital functions, such as the control of vascular tone and epithelial ion transport. The channel is a founding member of a family of 10 proteins (TMEM16x) with varied functions; some members (i.e., TMEM16A and TMEM16B) serve as CaCCs, while others are lipid scramblases, combine channel and scramblase function, or perform additional cellular roles. TMEM16x proteins are typically activated by agonist-induced Ca release evoked by G-protein-coupled receptor (GPCR) activation; thus, TMEM16x proteins link Ca-signalling with cell electrical activity and/or lipid transport. Recent studies demonstrate that a range of other cellular factors-including plasmalemmal lipids, pH, hypoxia, ATP and auxiliary proteins-also control the activity of the TMEM16A channel and its paralogues, suggesting that the TMEM16x proteins are effectively polymodal sensors of cellular homeostasis. Here, we review the molecular pathophysiology, structural biology, and mechanisms of regulation of TMEM16x proteins by multiple cellular factors.
TMEM16A/anoctamin-1 钙激活氯离子通道（CaCC）参与了一系列重要的生理功能，如血管张力的控制和上皮离子转运。该通道是一个由 10 种蛋白（TMEM16x）组成的家族的创始成员，具有不同的功能；其中一些成员（如 TMEM16A 和 TMEM16B）作为 CaCC，而其他成员则是脂质翻转酶，兼具通道和翻转酶的功能，或执行其他细胞功能。TMEM16x 蛋白通常通过 G 蛋白偶联受体（GPCR）激活引起的激动剂诱导的 Ca 释放而被激活；因此，TMEM16x 蛋白将 Ca 信号与细胞电活动和/或脂质转运联系起来。最近的研究表明，一系列其他细胞因子，包括质膜脂质、pH 值、缺氧、ATP 和辅助蛋白，也控制着 TMEM16A 通道及其同源物的活性，这表明 TMEM16x 蛋白实际上是细胞内稳态的多模式传感器。在这里，我们综述了 TMEM16x 蛋白的分子病理生理学、结构生物学以及多种细胞因子对其调节的机制。
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