离子通道结构-功能关系的研究一直是当代生理学中最具挑战性的目标之一。离子通道的三维(3D)结构的揭示促进了我们对离子通道内部许多亚分子机制的理解,例如选择性渗透性,电压依赖性,激动剂结合,和亚基间多聚化。识别离子通道的结构-功能关系在临床上也很重要,因为只有这样的知识才能使潜在的治疗方法具有实际的可能性。在某种意义上,由于人类TRPC通道具有钙渗透性,因此对瞬时受体电位规范(TRPC)通道的结构关系的理解的最新进展看起来很有希望,在许多组织中表达的非选择性阳离子通道,例如胃肠道(GI),肾,心,脉管系统,和大脑。已知TRPC通道调节GI收缩性和运动性,肺动脉高压,右心室肥厚,足细胞损伤,癫痫发作,恐惧,类似焦虑的行为,和许多其他人。在这篇文章中,我们试图阐述基于Cryo-EM(低温电子显微镜)的TRPC4和5通道的结构信息以及通道的特定域功能的最新发现,如G蛋白介导的激活机制,通道的细胞外修饰,同/杂四聚化,和药理门控机制。
The study of the structure-function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such as selective permeability, voltage dependency, agonist binding, and inter-subunit multimerization. Identifying the structure-function relationship of the ion channels is clinically important as well since only such knowledge can imbue potential therapeutics with practical possibilities. In a sense, recent advances in the understanding of the structure-relationship of transient receptor potential canonical (TRPC) channels look promising since human TRPC channels are calcium-permeable, non-selective cation channels expressed in many tissues such as the gastrointestinal (GI) tract, kidney, heart, vasculature, and brain. TRPC channels are known to regulate GI contractility and motility, pulmonary hypertension, right ventricular hypertrophy, podocyte injury, seizure, fear, anxiety-like behavior, and many others. In this article, we tried to elaborate recent findings of Cryo-EM (cryogenic-electron microscopy) based structural information of TRPC 4 and 5 channels and domain-specific functions of the channel, such as G-protein mediated activation mechanism, extracellular modification of the channel, homo/hetero-tetramerization, and pharmacological gating mechanisms.