# Conformational Energetics and Heterogeneity to Reveal Gating Mechanisms of TRPV and TRPM Ion Channels

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2024 · $47,288

## Abstract

ABSTRACT
Ion channels are integral membrane proteins with gated transmembrane pores that conduct
ions down their electrochemical gradients to transduce chemical, mechanical, and optical
signals into electrical signals. In this proposal, we leverage a host of innovative tools to decipher
allosteric gating mechanisms in two subfamilies of TRP ion channels, TRPV1-2 and TRPM2.
TRP channels are famous for their multimodal gating whereby stimulus modalities as diverse as
heat, cold, ions, lipids, nutrients, other proteins, and a variety of natural products (e.g.,
capsaicin, menthol) are allosterically integrated to determine the activity of a central ion-
conducting pore. Each stimulus modality regulates the conformational energetics of a sensing
module. The sensing modules in turn regulate the conformational energetics and conductance
of the pore. The sensing modules may be coupled to the pore, to each other, or both. TRP
channels provide an ideal system in which to decipher how allosteric conformational energetics
produce protein function because they are regulated by many stimulus modalities, and we have
significant understanding of the correspondence between their structural domains and sensing
modules. The goal of this proposal is to measure, for the first time, the conformational
energetics of TRP channel sensing domains and their coupling to the pore and to each other to
solve pressing questions in TRP channel biology. Our long-term vision is to understand the
general themes that underlie allosteric conformational transitions in ion channels. Our recent
technical advances combining fluorescence lifetime imaging microscopy (FLIM) and patch-
clamp electrophysiology to measure conformational energetics in the pore and a sensing
module simultaneously promise rapid progress toward this goal.

## Key facts

- **NIH application ID:** 11053019
- **Project number:** 3R35GM145225-03S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Sharona E Gordon
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $47,288
- **Award type:** 3
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11053019

## Citation

> US National Institutes of Health, RePORTER application 11053019, Conformational Energetics and Heterogeneity to Reveal Gating Mechanisms of TRPV and TRPM Ion Channels (3R35GM145225-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11053019. Licensed CC0.

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