Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment.

中文翻译：

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第六个跨膜片段是TMEM16A钙激活的氯离子通道的主要门控组件。

由TMEM16A或TMEM16B形成的钙激活的氯离子通道（CaCC）在神经系统，平滑肌，外分泌腺和其他组织中广泛表达。二聚体CaCC在每个单体中都有两个钙结合位点和一个孔，显示出电压依赖性钙敏感性。通道活性还取决于渗透性阴离子的身份。为了了解CaCC如何调节神经元信号传导以及CaCC是如何被神经元活动调节的，我们研究了CaCC门控的分子基础。在这里，我们报告说，TMEM16A-CaCC的电压调节涉及膜电场内钙和阴离子结合位点的电压依赖性占据以及通道蛋白固有的电压依赖性构象变化。这些选通方式都关键取决于第六个跨膜片段。