# Structural and functional studies of the TRPM2 channel

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $415,625

## Abstract

Body temperature is strictly maintained in a narrow range to protect the delicate nerves in the brain and other
body tissues, because improper body temperature gives rise to fever, brain injury, and stroke. TRPM2 is the
major warmth-sensing receptor in the brain regulating core body temperature and preventing overheating as
fever occurs. TRPM2 is a Ca2+-permeable, nonselective ion channel that is highly expressed in brain but is
also found in the heart, vascular and smooth muscle, and immune cells. It is uniquely activated by Ca2+ and
ADP ribose (ADPR), a product of the metabolism of NAD+ and a secondary messenger released upon
oxidative stress. The activation of TRPM2 results in both Ca2+ entry across the plasma membrane and Ca2+
release from lysosomes. Therefore, TRPM2 plays fundamental role in Ca2+-dependent array of physiological
processes and cellular functions from insulin secretion to immune response to cell death. It has been
implicated in Alzheimer disease, stroke, and other neurodegenerative diseases.
TRPM2 belongs to the TRPM (melastatin-like transient receptor potential) subfamily of the TRP superfamily.
Despite sharing the characteristic TRPM N-terminal homology regions (MHRs) and C-terminal coiled-coil
domains, TRPM2 is uniquely assembled with a C-terminal NHDT9-H domain, a homolog to the human
mitochondrial ADP-ribose pyrophosphatase NUDT9. Functional studies, including binding assays,
electrophysiology, and molecular simulations, provided a consensus view that ADPR binds to the NUDT9-H
domain, but proof of the ADPR binding site is lacking, and the molecular basis for the action of the agonist
ADPR on TRPM2 in the presence of calcium remains unknown. The gating of TRPM2 is further modulated
by many molecules and ions that range from protons to nucleotides (cyclic ADPR, AMP, 8-Br-cADPR) to
curcumin (which is isolated from rhizomes of Curcuma longa), acting by way of multiple mechanisms. At
present, we don't know where these molecules and ions bind to TRPM2 or how they activate the channel or
modulate its function. We have obtained two cryo-EM structures of zebrafish TRPM2 in the apo/closed and ADPR/Ca2+-bound open state, with the latter representing the first active state of TRPM family members. We identified a novel ADPR binding site that is located outside the NUDT9-H domain and was completely unknown before. Building on this preliminary data, we propose to continue the structural studies of TRPM2 combined with complementary electrophysiology experiments, binding assays, and X-ray crystallography, which will define the molecular basis for a comprehensive gating mechanism and pharmacology. These advances will provide a solid
foundation for developing new drugs against neurodegenerative diseases and for a deeper understanding
the function of the entire TRPM family.

## Key facts

- **NIH application ID:** 9896879
- **Project number:** 5R01NS111031-02
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Juan Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,625
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896879

## Citation

> US National Institutes of Health, RePORTER application 9896879, Structural and functional studies of the TRPM2 channel (5R01NS111031-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896879. Licensed CC0.

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