ABSTRACT

Ca²⁺-activated Cl⁻ channels (CaCCs) perform a multitude of functions including the control of cell excitability, regulation of cell volume and ionic homeostasis, exocrine and endocrine secretion, fertilization, amplification of olfactory sensory function, and control of smooth muscle cell contractility. CaCCs are the translated products of two members (ANO1 and ANO2, also known as TMEM16A and TMEM16B) of the Anoctamin family of genes comprising ten paralogs. This review focuses on recent progress in understanding the molecular mechanisms involved in the regulation of ANO1 by cytoplasmic Ca²⁺, post-translational modifications, and how the channel protein interacts with membrane lipids and protein partners. After first reviewing the basic properties of native CaCCs, we then present a brief historical perspective highlighting controversies about their molecular identity in native cells. This is followed by a summary of the fundamental biophysical and structural properties of ANO1. We specifically address whether the channel is directly activated by internal Ca²⁺ or indirectly through the intervention of the Ca²⁺-binding protein Calmodulin (CaM), and the structural domains responsible for Ca²⁺- and voltage-dependent gating. We then review the regulation of ANO1 by internal ATP, Calmodulin-dependent protein kinase II-(CaMKII)-mediated phosphorylation and phosphatase activity, membrane lipids such as the phospholipid phosphatidyl-(4,5)-bisphosphate (PIP₂), free fatty acids and cholesterol, and the cytoskeleton. The article ends with a survey of physical and functional interactions of ANO1 with other membrane proteins such as CLCA1/2, inositol trisphosphate and ryanodine receptors in the endoplasmic reticulum, several members of the TRP channel family, and the ancillary Κ⁺ channel β subunits KCNE1/5.

摘要

Ca ²⁺激活的 Cl ^-通道 (CaCC) 执行多种功能，包括控制细胞兴奋性、调节细胞体积和离子稳态、外分泌和内分泌分泌、受精、放大嗅觉感觉功能以及控制平滑肌细胞收缩性。CaCC 是包含十个旁系同源物的 Anoctamin 基因家族的两个成员（ANO1 和 ANO2，也称为 TMEM16A 和 TMEM16B）的翻译产物。本综述重点关注细胞质 Ca ²⁺调节 ANO1 的分子机制、翻译后修饰以及通道蛋白如何与膜脂和蛋白伴侣相互作用的最新进展。在首先回顾了天然 CaCC 的基本特性后，我们提出了一个简短的历史观点，强调了它们在天然细胞中分子身份的争议。接下来总结了 ANO1 的基本生物物理和结构特性。我们特别讨论了该通道是由内部 Ca ^{2+直接激活还是通过 Ca 2+}结合蛋白钙调蛋白 (CaM)的干预间接激活，以及负责 Ca ²⁺和电压依赖性门控的结构域。然后，我们回顾了内部 ATP、钙调蛋白依赖性蛋白激酶 II-(CaMKII) 介导的磷酸化和磷酸酶活性、膜脂（例如磷脂酰磷脂酰-(4,5)-二磷酸 (PIP2) _）、游离脂肪对 ANO1 的调节。酸和胆固醇，以及细胞骨架。本文最后调查了 ANO1 与其他膜蛋白（例如内质网中的 CLCA1/2、三磷酸肌醇和兰尼碱受体、TRP 通道家族的几个成员以及辅助 κ + 通道 β 亚基 KCNE1）的物理和功能^相互作用。 /5。