# Regulation of mechanosensitive ion channels by membrane lipids

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $326,800

## Abstract

Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. Piezo channels mediate mechanoelectrical transduction to regulate crucial physiological processes, including vascular architecture and remodeling, cell migration, erythrocyte volume, touch, vibration, and proprioception. Piezo1 and Piezo2 are essential proteins in mice, as global knockouts are embryonic lethal and cell-specific
knockouts result in animals with severe defects. In humans, Piezo channels gain- and loss-of-function mutations
have been associated with hereditary human pathophysiologies. Mutations in Piezo1 are associated with dehydrated hereditary stomatocytosis, a hemolytic anemia characterized by increased cation permeability and dehydrated erythrocytes. Hence, it is essential to determine the proteins and lipids that regulate Piezo channels gating
mechanisms. It has been shown that phosphoinositides and phosphatidylserine translocation regulate Piezo
channels activity. However, it remains largely unknown how dietary fatty acids-containing phospholipids modulate Piezo1 and Piezo2 mechanical gating. Our long-term goal is to determine the mechanisms underpinning
how bioactive lipids modulate mechanosensitive ion channels. In this proposal, the overall objective is to establish the molecular basis underlying Piezo channels modulation by dietary fatty acids. The central hypothesis is
that Piezo channels activation and inactivation are regulated by the mechanical properties of the membrane via
lipid remodeling. The rationale for the proposed research plan is that once the precise mechanisms are determined whereby fatty acids modulate Piezo channels function, it will be possible to use fatty acids to control
vascular function and ameliorate the effects of hereditary disorders. The hypothesis will be tested by pursuing
three Specific Aims: 1) Determine how fatty acid composition modulates Piezo1 activity through changes in
membrane stiffness; 2) Determine the effect of dietary fatty acids on Piezo1 mutations causing red blood cell
disorders; and 3) Test the hypothesis that saturated fatty acids decrease Piezo2 activation. We will leverage
functional, biochemical, and biophysical approaches to uncover the contribution of bioactive lipids to mechanosensation. The research plan is innovative because it exploits the use of dietary fatty acids to control Piezo
channels mechanical response. The proposed research is significant because it is expected to have broad translational impact in targeting Piezo channels, involved in vascular and neuronal function.

## Key facts

- **NIH application ID:** 10200845
- **Project number:** 5R01GM133845-03
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Valeria Vasquez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $326,800
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200845

## Citation

> US National Institutes of Health, RePORTER application 10200845, Regulation of mechanosensitive ion channels by membrane lipids (5R01GM133845-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200845. Licensed CC0.

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