# Regulation of mechanically activated Piezo2 ion channels by membrane lipids

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $329,551

## Abstract

ABSTRACT
Piezo2 is a non-selective Ca2+-permeable cation channel activated by mechanical force. It is expressed in
peripheral sensory neurons of the dorsal root ganglia (DRG) and it plays important roles in gentle touch and
injury-induced mechanical pain. Piezos are large proteins, with 38 transmembrane domains and their membrane
footprint is larger than that of any other known ion channels. This suggests that membrane lipids could
significantly impact the behavior of these channels, but exploration of the effects of membrane lipids on Piezo
function is in its early stages. The goal of this proposal is to gain insights into how lipids regulate Piezo channels,
building upon our recent identification of membrane lipids that specifically inhibit Piezo2 activity while not
affecting Piezo1. The proposal is based on our recent finding that the TMEM120A protein robustly inhibits Piezo2,
but not Piezo1 channels. Structural studies of TMEM120A indicate that this protein shows similarity to a lipid
modifying enzyme ELOVL7, with a CoA molecule bound to each monomer. We hypothesized that TMEM120A
inhibits Piezo2 by modifying cellular lipid composition. Our preliminary data show that expressing TMEM120A
increases levels of lipids in the Kennedy pathway of triglyceride synthesis, with the most robust changes in
phosphatidic acid (PA) and lysophosphatidic acid (LPA) with saturated acyl chains. Intracellular PA delivery
through the whole cell patch pipette inhibited Piezo2, but not Piezo1 activity. Generating endogenous PA in the
plasma membrane by optogenetic activation of phospholipase D inhibited Piezo2, but not Piezo1 activity.
Intracellular delivery of LPA, as well as incubation with carbacyclic PA (ccPA), a non-metabolizable analogue of
PA and LPA inhibited Piezo2 channels. Our data identify PA and LPA as endogenous inhibitors of Piezo2
channels. In our proposal we aim to identify the molecular determinants of the effects of PA and LPA (Aim1),
investigate their roles in regulation of Piezo2 activity by signaling pathways (Aim 2), and tests in vivo
effectiveness of this lipid regulation on Piezo2 mediated sensory processes (Aim 3).
Overall, we identified novel lipid regulators of Piezo2 channels, that do not affect Piezo1. Our data will provide
important insight into the regulation of Piezo2 by membrane lipids, and the knowledge gained from this study
has the potential to be utilized in the future development of Piezo2 inhibitors for treating various pain
conditions.

## Key facts

- **NIH application ID:** 10905241
- **Project number:** 1R01GM154420-01
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Tibor Rohacs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $329,551
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905241

## Citation

> US National Institutes of Health, RePORTER application 10905241, Regulation of mechanically activated Piezo2 ion channels by membrane lipids (1R01GM154420-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10905241. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*