# Mechanisms of Mechanical and Chemical Gating in Mechanosensitive Piezo1 Channels

> **NIH NIH R01** · WESTERN UNIVERSITY OF HEALTH SCIENCES · 2022 · $324,300

## Abstract

Abstract
Piezo1 and Piezo2 are mammalian cation-selective mechanosensitive ion channels homologs which open their
pore in response to various mechanical stimuli. Mechanotransduction signaling through Piezo channels plays a
central role in a bewildering variety of important physiological processes including red blood cell osmotic
homeostasis, somatic and visceral mechanosensation, proprioception, blood pressure regulation and
development and differentiation of many tissues and organ systems. Several human diseases including
xerocytosis and lymphedema have been directly linked to genetic mutations in Piezo channels and many studies
further indicate a role of Piezo-mediated signaling in allodynia and hyperalgesia and a possible role of Piezo
channels in sleep apnea. The development of drugs capable of selectively activating or inhibiting Piezo channels
represent a promising therapeutic opportunity for the treatment of some of these Piezo-related pathologies. To
date, Yoda1, a synthetic small molecule agonist capable of selectively activating Piezo1 with micromolar affinity,
represents the best small molecule candidate to expand the pharmacome of Piezo channels. Unfortunately, the
fundamental mechanisms by which Piezo channel sense mechanical forces and activates in the presence of
Yoda1 are still unknown. In this proposal we will address these two unsolved questions using a multidisciplinary
approach combining molecular dynamic (MD) stimulations and experimental assays. In our first aim, we will
identify rapid, force-induced structural rearrangements in Piezo1 by simulating the channel molecule in a
membrane under tension. On another hand, using force-clamp fluorimetry, we will probe local conformational
changes using spectroscopic measurements. This will be done by inserting conformational probes into strategic
positions of the channel expressed in cells while protein function is being monitored in real-time. This combination
of computations and experiments will allow us to capture structural dynamic information that happens in a
temporal window spanning several orders of magnitude, from microsecond to minutes. In our second Aim, we
will identify how Yoda1 interacts with and activates Piezo1. We have already identified a Yoda1 binding site
using a combination of predictive MD simulations and experimental validations. We will characterize structural
changes, changes in transition free energy, and modifications of allosteric residue-residue interactions that
happen upon Yoda1 binding. This aim will shed light on the mechanism of chemical activation of a Piezo channel
and will be invaluable to develop pharmacological agents with clinical value.

## Key facts

- **NIH application ID:** 10408005
- **Project number:** 5R01GM130834-04
- **Recipient organization:** WESTERN UNIVERSITY OF HEALTH SCIENCES
- **Principal Investigator:** Yun Lyna LUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $324,300
- **Award type:** 5
- **Project period:** 2019-09-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408005

## Citation

> US National Institutes of Health, RePORTER application 10408005, Mechanisms of Mechanical and Chemical Gating in Mechanosensitive Piezo1 Channels (5R01GM130834-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10408005. Licensed CC0.

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