机械门控Piezo通道的离子通透与机械门控机制研究

The Piezo family of ion channels has been recently identified as the founding class of mechanosensitive cation channels in vertebrates. They have been shown to play critical roles in various mechanotransduction processes, including touch, proprioception and cardiovascular development. Mutations in Piezo genes have been linked to various genetic diseases in human, demonstrating their pathophysiological relevance and potential as valid drug targets. Given their physiological and pathophysiological importance and being the prototype of vertebrate mechanosensitive cation channels, exploring the molecular mechanisms of Piezo channels is of great significance, representing a hot research topic in the field of ion channels and receptors. Following the initial demonstration that Piezo proteins are the pore-forming subunits of mechanosensitive cation channels, we have recently determined the medium-resolution cryo-EM structure of the full-length mouse Piezo1 protein through collaboration, and uncovered the molecular bases that underlie its ion permeation and mechanotransduction properties. Based on these breakthroughs, we aim to systematically investigate the ion permeation and mechano-gating mechanisms of Piezo channels. The proposed studies will shed light on understanding the working principles of the vertebrate mechanosensitive cation channels, their physiological and pathophysiological relevance, and drug development.

机械门控Piezo离子通道是新近发现的一类具有重要生理病理功能且与人类疾病直接相关的全新复杂离子通道家族。鉴于其生理病理功能的重要性和作为脊椎动物机械门控阳离子通道的原型成员的新颖性，深入解析Piezo离子通道的结构功能关系代表“离子通道与受体”研究领域的一个重要科学前沿。本课题申请人继首次证实Piezo蛋白是机械门控阳离子通道的孔道蛋白之后，又于最近带领其课题组通过合作率先解析鼠源Piezo1离子通道的冷冻电镜三维结构，并进而揭示其离子通透与机械力传感的分子基础。本申请项目瞄准这一非立项领域的科学前沿，依托已取得的系列重要研究进展，致力于深入、系统性地解析Piezo通道的离子通透与机械力门控机制这两大离子通道研究领域的关键科学问题，从而帮助理解脊椎动物机械门控阳离子通道的工作原理、与生理／病理疾病发生的相关性，并为相关的药物设计与开发提供线索和理论依据。

围绕阐明机械门控Piezo通道的离子通透与机械门控的分子作用机制的项目研究目标，解析了Piezo通道家族多个成员的系列高分辨率冷冻电镜结构；鉴定了其离子通透路径以及关键机械传感位点；筛选发现了其小分子调控药物以及相互作用蛋白；系统性提出了其进行机械门控的功能区模块化作用机制假说、杠杆作用机制假说、双门控作用机制假说、门塞和闩锁作用机制假说、基于脂膜张力的曲率门控模型、基于Cadherin介导的细胞骨架拴的绳拉力门控模型，有力驱动了对Piezo通道这类全新离子通道家族的分子作用机制的深入理解。相关研究成果以通讯作者身份（含共同）发表在Nature、Neuron、Nature Communications、Annual Review of Pharmacology and Toxicology、Trends in Biological Sciences等期刊，并产生了重要的学术影响：1）5篇通讯作者论文被诺奖官网所引用(Nature 2015; Nature 2018; Nature 2019; eLife 2019; Trends in Biochemical Science 2021)，推动了Piezo通道的发现与研究工作被授予了2021年的诺贝尔生理学或医学奖；2）1篇通讯作者论文(Nature 2018)被收录进神经科学教科书：3）1篇通讯作者论文(Nature 2018)的研究成果被国家基金委生命科学学部选定为“鼓励探索、突出原创”典型案例；4）1篇论文（Nature 2019）被选定为国家“十三五”重点创新成果，并参选国家“十三五”科技创新成就展。