# Regulation of Piezo2 Channels by G-protein Coupled Receptors and Endocytosis

> **NIH NIH F99** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $19,344

## Abstract

ABSTRACT
Mechanical allodynia is a hallmark symptom of chronic pain characterized by painful responses to innocuous
stimuli. However, little is known about the cellular and molecular regulation of this process. Recently, the
mechanically activated Piezo2 channels were identified as key players of mechanical allodynia in mice and
humans, but the molecules and proteins responsible for the sensitization of Piezo2 channels upon injury are
still poorly understood. Recent data from our lab show that activation of Gi-protein coupled receptors induces a
long-lasting potentiation of Piezo2 currents in Dorsal Root Ganglion (DRG) neurons and HEK293 cells. The
potentiation of Piezo2 currents was abolished by inhibiting the activity of Gβγ. Surprisingly, the inhibition of
Gβγ-downstream kinases, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK),
also abolished the potentiation of Piezo2 current suggesting an indirect effect of Gβγ on Piezo2 channels.
Therefore, for aim 1 (Ph.D. progress), we described a novel mechanism of regulation of Piezo2 currents by Gi-
protein coupled receptors. On the other hand, our lab has also shown that activation of Transient Receptor
Potential Vanilloids 1 (TRPV1) channels by capsaicin leads to robust inhibition of Piezo2 currents in DRG
neurons and heterologous systems. This inhibition is abolished by removing Ca2+ from the extracellular
solution, confirming a pivotal role of Ca2+ on Piezo2 channels. Preliminary data in our lab using total internal
reflection fluorescence (TIRF) show that Piezo2 channels are internalized upon activation of TRPV1 channels
in HEK293 cells, but whether Piezo2 channels are internalized via endocytosis is not known. For aim 2 (F99
phase), we hypothesize that activation of TRPV1 induces a Ca2+-triggered endocytosis that orchestrate the
inhibition of Piezo2 currents. We aim to identify molecules and proteins that regulate the activity of the
mechanically activated Piezo2 channels. We hope these novel findings could help us understand the process
of tactile allodynia and investigate the changes that affect the periphery and influence the central nervous
systems (aim 3-K00 phase) with the ultimate goal of providing new avenues for treatments of mechanical-pain
syndromes.

## Key facts

- **NIH application ID:** 10198568
- **Project number:** 3F99NS113422-01S1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** John Smith Del Rosario
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $19,344
- **Award type:** 3
- **Project period:** 2020-07-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198568

## Citation

> US National Institutes of Health, RePORTER application 10198568, Regulation of Piezo2 Channels by G-protein Coupled Receptors and Endocytosis (3F99NS113422-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10198568. Licensed CC0.

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