The Mechanics of Piezo Ion Channels

Nontechnical summary

Going 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 summary

In 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.