# Permeation and Gating Mechanisms of Mechanosensitive PIEZO channels

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $410,000

## Abstract

Project Summary
Many cardiovascular and neurological disorders, and oncogenesis result from changes in cell mechanics.
Assessment of human pathophysiology in this context reveals that these diseases share a common root cause:
abnormal mechanotransduction – the process by which cells respond to physical stress and forces.
Mechanosensitive ion channels, the molecular machines by which cells convert external forces into electrical
response, are therefore emerging targets of interest, for understanding biological processes and for therapeutic
development.
Piezo family (Piezo1 and Piezo2) was discovered in 2010 as the first excitatory mechanosensitive ion channels
in vertebrates. Piezo channels are now known to be 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 yet to be discovered. Substantial efforts are made in the last
decade to identify Piezo related diseases and incidents within the United State population. So far, Piezo
dysfunction is 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. Therefore,
our lab’s goal is to understand how physical forces such as pressure and membrane tension control Piezo1
function in health and diseased state.
This research proposal focuses on ion permeation and force-dependent gating mechanisms of Piezo1 channels,
in cells, as well as in reconstituted lipid bilayer systems. We will employ biochemical and biophysical techniques
in efforts to understand how lipid bilayer 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 identified pore domain of
Piezo1 will be used as a template to understand the pressure sensitivity and voltage-dependent inactivation -
hallmark of Piezo channels - by constructing various deletion mutants- heterologous expression in HEK cells.
The preliminary data is striking, and shows that the droplet bilayer approach coupled with traditional cellular
patch clamp assays are ideally suited to study mammalian Piezo1 channel function. We are convinced that a
comprehensive understanding of Piezo’s function is a timely contribution to the field of mammalian
mechanotransduction. Our unique proposal represents the application of single molecule investigation of Piezos.
Completion of this proposal will provide a path to dissect and kick-start the development of effective thera...

## Key facts

- **NIH application ID:** 10364203
- **Project number:** 1R01GM142024-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** RUHMA SYEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2021-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364203

## Citation

> US National Institutes of Health, RePORTER application 10364203, Permeation and Gating Mechanisms of Mechanosensitive PIEZO channels (1R01GM142024-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10364203. Licensed CC0.

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