# Permeation and Gating Mechanisms of Mechanosensitive PIEZO channels

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $122,986

## Abstract

Project Summary
Many cardiovascular and neurological disorders result from changes in cell mechanics.
Assessment of human pathophysiology in this context reveals that these diseases share a root
cause: abnormal mechanotransduction – the process by which cells respond to physical stress
and forces. Mechanosensitive ion channels convert external forces into electrical response and
are emerging targets of interest for understanding biological processes and therapeutic
development. The PIEZO family (PIEZO1 and PIEZO2) was discovered in 2010 as the first
excitatory mechanosensitive ion channels in vertebrates. PIEZO channels are critical sensors of
touch and pain (somatosensation), volume regulation (osmosensation), shear stress
(cardiovascular tone), baroreception, proprioception and respiratory physiology, and may have
other important functions. PIEZO dysfunction has been linked to diverse pathologies including
hypertension, lymphatic disease and anemias, somatosensory and neurological disorders, cancer
and metastasis, amongst others.
Despite their biological and medical relevance, the mechanism behind PIEZO-dependent
mechanotransduction remains elusive. Our lab’s goal is to understand how physical forces
such as pressure and membrane tension control PIEZO1 function. The parent research proposal
focuses on ion permeation and force-dependent gating mechanisms of PIEZO1 channels in cells
and reconstituted lipid bilayer systems. We will employ biochemical and biophysical techniques
to understand how lipid bilayers control the gating of PIEZO1 and subsequent ion conduction
across the membrane. Moreover, we have identified robust expression and protein purification
protocols to examine the function of PIEZO1 channels. Droplet lipid bilayers will be used to study
the single channel conductance and open probability of the purified protein in biologically relevant
lipid compositions. Structurally and functionally identified pore domain of PIEZO1 will be used as
a template to understand the pressure sensitivity and voltage-dependent inactivation, hallmarks
of PIEZO channels. To study global effect of PIEZO in cellular context, calcium flux assay will be
used. The preliminary data is striking and shows the droplet bilayer approach coupled with
traditional cellular patch clamp assays are ideally suited to study mammalian PIEZO1 channel
function. Our unique proposal represents the application of single molecule investigation of
PIEZOs. Completion of this proposal will provide a path to development of effective therapeutics
targeting neuropathic pain, brain ischemia and gliomas, amongst others.

## Key facts

- **NIH application ID:** 11098965
- **Project number:** 3R01GM142024-04S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** RUHMA SYEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $122,986
- **Award type:** 3
- **Project period:** 2021-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11098965

## Citation

> US National Institutes of Health, RePORTER application 11098965, Permeation and Gating Mechanisms of Mechanosensitive PIEZO channels (3R01GM142024-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11098965. Licensed CC0.

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