# The Molecular Basis of PIEZO Ion Channel Function

> **NIH NIH K99** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $125,000

## Abstract

PROJECT SUMMARY
PIEZO1 and PIEZO2 are mechanosensitive ion channels that convert force into chemoelectric signals. PIEZOs
play diverse roles in physiological processes such as touch, proprioception, breathing, and vascular
development. Pathogenic mutations in PIEZOs can cause extensive sensory defects and debilitating
neurological diseases such as distal arthrogryposis. Despite recent advances in elucidating the physiological
roles of PIEZO ion channels, the underlying structural correlates of function are largely unknown. PIEZOs are
homotrimeric ion channels with extensive blades of transmembrane domains that are thought to be the principal
transducers of mechanical force, but static structural snapshots and in vitro studies are poorly equipped to
describe which structural rearrangements underlie channel gating. To address these fundamental gaps in
knowledge, this proposal will use fluorescence nanoscopy to determine the structural mechanics of PIEZO ion
channels in a cell at single molecule resolution. These structural mechanics will then be correlated with the
functional output of the channel using electrophysiology. Aim 1 will determine which unique structural mechanics
underlie the functional differences between PIEZO1 and PIEZO2. This will be accomplished by examining how
the cellular environment and intrinsic structural mechanics shape the functional output of each channel. Aim 2
will define how the interplay between the protein and the plasma membrane shapes the activity of PIEZOs,
especially in the context of pathogenic gain-of-function mutations that cause distal arthrogryposis. This will be
accomplished by manipulating the lipid composition of the plasma membrane and by assessing how diverse
modulators shape the structure of the channel. This proposal will ultimately provide fundamental insight into how
PIEZO ion channels function inside of a cell and provide a foundation for the study of other sensory ion channels.

## Key facts

- **NIH application ID:** 10948369
- **Project number:** 1K99GM155547-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Eric Michael Mulhall
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,000
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948369

## Citation

> US National Institutes of Health, RePORTER application 10948369, The Molecular Basis of PIEZO Ion Channel Function (1K99GM155547-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10948369. Licensed CC0.

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