第六跨膜段是 TMEM16A 钙激活氯离子通道的主要门控组成部分。
The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel.
机构信息
Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
出版信息
Neuron. 2018 Mar 7;97(5):1063-1077.e4. doi: 10.1016/j.neuron.2018.01.048. Epub 2018 Feb 22.
Abstract
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.
摘要
钙激活氯离子通道（CaCCs）由 TMEM16A 或 TMEM16B 组成，广泛表达于神经系统、平滑肌、外分泌腺和其他组织中。每个单体具有两个钙结合位点和一个孔，二聚体 CaCC 表现出电压依赖性钙敏感性。通道活性还取决于可渗透阴离子的身份。为了了解 CaCC 如何调节神经元信号以及 CaCC 如何反过来被神经元活动调节，我们研究了 CaCC 门控的分子基础。在这里，我们报告 TMEM16A-CaCC 的电压调制涉及膜电场中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。这些门控模态都严重依赖于第六跨膜段。
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