# Mechanistic studies of the menthol receptor TRPM8: a novel target for analgesic drugs

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $121,230

## Abstract

Project Summary
Chronic pain sufferers, an estimated one third of the American population, struggle to identify ways to reduce
pain and improve their daily lives. Transient receptor potential (TRP) channels detect a wide range of physical
and chemical stimuli, and through their integration of and response to these stimuli have an essential role in
the pathophysiology of many chronic pain disorders. Notably, many natural products from plants and
venomous animals target TRP channels, and can therefore be used to identify and characterize these
important contributors to pain sensation. For instance, TRP melastatin 8 (TRPM8), the somatosensory receptor
gated by cold temperatures, is also activated by natural cooling agents, such as menthol and eucalyptol,
commonly used topical analgesic agents. Furthermore, TRPM8 is essential for the development of cold
allodynia, a debilitating hypersensitivity to cold resulting from chemotherapy or other neuropathic insults.
Despite the importance of TRPM8 and other TRP channels to the transition from acute to chronic pain states,
the molecular basis for ligand binding, channel gating, and ion permeation remain incompletely understood.
The objective of this proposal is to determine the mechanisms whereby TRPM8 conducts ions across cellular
membranes in response to diverse signals, including those from plant-derived compounds that produce a cold
sensation. The specific aims are to: 1) determine atomic structures of TRPM8 in different conformational states
(K99 phase), 2) study the electrophysiological properties of TRPM8 (K99 phase), and 3) probe mechanisms of
TRPM8 modulation by phosphatidylinositol lipids (R00 phase). Single-particle electron cryo-microscopy (cryo-
EM) structures will be determined of TRPM8 alone and in complex with agonists, antagonists, or natural toxins.
In particular, toxins from animal venoms are powerful tools for elucidating the structural mechanisms
underlying channel gating and modulation. Structure-function analyses aimed at determining gating
mechanisms and validating ligand binding sites will be conducted, as will biophysical studies of purified,
reconstituted protein to functionally characterize intrinsic gating of TRPM8. Modulation by bioactive lipids is a
unifying functional trait of TRP channels, including TRPM8, and thus effects of phosphatidylinositol lipids on
TRPM8 will be explored and non-covalently bound lipids will be identified using native mass spectrometry.
These goals are significant because they will enhance the biophysical and molecular understanding of pain
sensation and, specifically, how TRPM8 modulation contributes to chronic pain. Ultimately, the aim is to assist
in the rational design of novel TRPM8-based analgesic drugs. My mentor, Dr. Julius, as well as my expert
advisors in cryo-EM (Dr. Cheng), electrophysiology (Dr. Kirichok), protein-lipid interactions (Dr. Marty), and
pain signaling (Dr. von Zastrow), will provide training, in preparation for my career as a...

## Key facts

- **NIH application ID:** 9994838
- **Project number:** 5K99AT010478-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Melinda Diver
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $121,230
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994838

## Citation

> US National Institutes of Health, RePORTER application 9994838, Mechanistic studies of the menthol receptor TRPM8: a novel target for analgesic drugs (5K99AT010478-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9994838. Licensed CC0.

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