The Mechanics of Piezo Ion Channels

压电离子通道的力学原理

• 批准号: 2051681
• 负责人: Christoph Haselwandter
• 金额: $ 42万
• 依托单位: University of Southern California
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2051681&HistoricalAwards=false
• 关键词: Mechanics; Piezo; Ion; Channels

Nontechnical summaryGoing back to antiquity, it has been recognized that touch, the ability to sense mechanical stimuli, is fundamental to life. However, the molecular mechanisms underlying mechanosensation in humans and other vertebrates have long remained elusive. Piezo ion channels have recently been found to provide the molecular basis for a wide range of seemingly unrelated forms of mechanosensation. This presents a unique opportunity to discover and describe general physical mechanisms and principles underlying vertebrate mechanosensation.The primary research objective of this project is to conceive a physical theory describing the mechanics, and mechanical activation, of Piezo ion channels. The research team supported by this project works closely with experimental groups to test and refine this theory of Piezo mechanics, with the aim of elucidating the physical basis for mechanosensation in vertebrates. The research component of this project is motivated by the prospect that a quantitative understanding of the physical principles underlying mechanosensation will yield new fundamental insights into life, and that a physical understanding of mechanosensation will also suggest novel approaches for the quantitative analysis and control of mechanosensation under normal physiological conditions and under disease conditions, such as in the case of chronic pain. The interdisciplinary research supported by this project will be closely integrated with interdisciplinary teaching activities at the interface of physics and biology, at the level of high school, undergraduate, and graduate education.Technical summaryIn common with other organisms, vertebrates possess a variety of senses that respond to mechanical stimuli. Despite intense efforts, the molecules and physical mechanisms responsible for vertebrate mechanosensation have long remained elusive. In 2010, Piezo proteins, a previously unknown class of mechanosensitive ion channels, were discovered, which has led to stunning progress in the elucidation of the molecular basis for vertebrate mechanosensation. Piezo has been found to underlie mechanosensation in many important physiological functions in vertebrates, such as cardiovascular mechanotransduction, mechanosensing in epithelial homeostasis, proprioception, sensing of touch, and mechanotransduction in the respiratory system.Several molecular structures of Piezo are now available, which presents a unique opportunity to arrive at a quantitative, physical understanding of how Piezo interacts with the surrounding membrane to sense mechanical stimuli. Based on approaches from condensed-matter theory and materials science, this project aims to develop a physical theory describing the mechanics of Piezo ion channels, and thus to elucidate the physical basis for Piezo gating in cell membranes: the project (1) develops physical models describing the dependence of Piezo gating and Piezo localization on local membrane composition, membrane shape, and force exertion on the membrane; (2) explores how Piezo interacts through the membrane with other proteins, and how this might give rise to cooperative gating responses of Piezo; and (3) develops physical models describing the shape and energetics of the observed Piezo vesicles and, on this basis, explores the protein mechanics of Piezo. The physical theory of Piezo mechanics developed through this project is directly motivated by experiments, and the research team supported by this project works closely with experimental groups to test and refine new models of membrane-Piezo interactions. Given the ubiquity of Piezo in vertebrate mechanosensation, this project raises the exciting prospect that simple physical mechanisms and principles underlie a diverse array of complex physiological functions, which may reveal new and unexpected links between seemingly unrelated biological phenomena.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

回顾古代，人们已经认识到触觉，即感知机械刺激的能力，是生命的基础。然而，人类和其他脊椎动物机械感觉的分子机制长期以来一直是难以捉摸的。压电离子通道最近被发现为许多看似无关的机械感觉形式提供了分子基础。这为发现和描述脊椎动物机械感觉的一般物理机制和原理提供了一个独特的机会。这个项目的主要研究目标是设想一个描述压电离子通道的力学和机械激活的物理理论。该项目支持的研究小组与实验组密切合作，以测试和完善压电力学理论，目的是阐明脊椎动物机械感觉的物理基础。对机械感觉的物理原理的定量理解将产生对生命的新的基本见解，对机械感觉的物理理解也将为在正常生理条件和疾病条件下（如慢性疼痛）的机械感觉的定量分析和控制提供新的方法，这一前景推动了该项目的研究部分。本项目支持的跨学科研究将与物理和生物交叉领域的跨学科教学活动紧密结合，在高中、本科和研究生教育的层面上进行。与其他生物一样，脊椎动物具有对机械刺激作出反应的各种感觉。尽管付出了巨大的努力，但脊椎动物机械感觉的分子和物理机制长期以来仍是难以捉摸的。2010年，一种以前未知的机械敏感离子通道压电蛋白被发现，这在阐明脊椎动物机械感觉的分子基础方面取得了惊人的进展。压电已被发现是脊椎动物许多重要生理功能的机械感觉基础，如心血管机械传导、上皮稳态机械传感、本体感觉、触觉传感和呼吸系统机械传导。压电陶瓷的几个分子结构现在是可用的，这提供了一个独特的机会来定量地，物理地理解压电陶瓷是如何与周围的膜相互作用来感知机械刺激的。基于凝聚态理论和材料科学的方法，本项目旨在建立描述压电离子通道力学的物理理论，从而阐明细胞膜中压电门控的物理基础：该项目(1)建立描述压电门控和压电定位对局部膜组成、膜形状和膜上施加的力的依赖的物理模型；(2)探讨了Piezo如何通过膜与其他蛋白质相互作用，以及这可能如何引起Piezo的合作门控反应；(3)建立描述所观察到的压电小泡的形状和能量学的物理模型，并在此基础上探索压电的蛋白质力学。通过该项目开发的压电力学物理理论直接受到实验的推动，该项目支持的研究团队与实验组密切合作，测试和完善膜-压电相互作用的新模型。鉴于压电在脊椎动物机械感觉中的普遍存在，该项目提出了一个令人兴奋的前景，即简单的物理机制和原理是多种复杂生理功能的基础，这可能揭示看似无关的生物现象之间新的和意想不到的联系。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Piezo1 as a force-through-membrane sensor in red blood cells.

红细胞中作为力穿透膜传感器的 Piezo1。

• DOI: 10.7554/elife.82621
• 发表时间: 2022-12-14
• 期刊: eLife
• 影响因子: 7.7
• 作者: Vaisey G;Banerjee P;North AJ;Haselwandter CA;MacKinnon R
• 通讯作者: MacKinnon R

Stochastic effects in bacterial communication mediated by extracellular vesicles

细胞外囊泡介导的细菌通讯的随机效应

• DOI: 10.1103/physreve.107.024409
• 发表时间: 2023
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Weaver, Brian P.;Haselwandter, Christoph A.;Boedicker, James Q.
• 通讯作者: Boedicker, James Q.

Dependence of protein-induced lipid bilayer deformations on protein shape

• DOI: 10.1103/physreve.107.024403
• 发表时间: 2023-02-06
• 期刊: PHYSICAL REVIEW E
• 影响因子: 2.4
• 作者: Alas，Carlos D.;Haselwandter，Christoph A.
• 通讯作者: Haselwandter，Christoph A.

Quantitative prediction and measurement of Piezo's membrane footprint.

• DOI: 10.1073/pnas.2208027119
• 发表时间: 2022-10-04
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Elastic properties and shape of the Piezo dome underlying its mechanosensory function.

• DOI: 10.1073/pnas.2208034119
• 发表时间: 2022-10-04
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Haselwandtera, Christoph A.;Guoc, Yusong R.;Fuc, Ziao;MacKinnon, Roderick
• 通讯作者: MacKinnon, Roderick