# Structural and functional studies of the human TRPM4 and TRPM5 channels

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $579,796

## Abstract

PROJECT SUMMARY
Blood flow from the heart to the brain is strictly regulated to protect the delicate brain tissue, because improper
blood flow can give rise to numerous cardiovascular diseases and brain injuries. TRPM4 is one of the major
actors regulating blood flow in the vascular smooth muscle cells in the cerebral arteries when intracellular
pressure changes. Mutation or dysfunction of TRPM4 is linked to numerous cardiovascular diseases,
including stroke and Brugada syndrome. TRPM4 and its closest homolog, TRPM5, are Ca2+-activated,
nonselective, voltage-gated ion channels. TRPM5 is highly expressed in pancreatic beta cells, and
dysfunction or mutation in TRPM5 is associated in type II diabetes and obesity. In addition, TRPM4 and
TRPM5 in the taste bud cells play an important role in taste signaling, and loss of both channels abolishes
the ability to detect bitter, sweet, or umami stimuli. Taken together, TRPM4 and TRPM5 have a wide range
of roles in physiology and pathophysiology.
Both TRPM4 and TRPM5 belong to the TRPM (melastatin-like transient receptor potential) subfamily of the
TRP superfamily, and they are the only two members impermeable to Ca2+. The lack of a canonical positively
charged voltage-sensing domain makes a mystery of how TRPM4 and TRPM5 sense voltage. Despite
sharing 45% amino acid identity, TRPM4 and M5 have distinct functional and pharmacological properties in
terms of kinetics and sensitivities to drugs. A collaboration has been built between Takeda California, Inc.
and our lab to study the important role of TRPM5 in treatment of diabetes. The high-affinity drugs specifically
targeting TRPM5 provided by Takeda and the potential future drug development strengthen our proposal on
studying the pharmacology of these two channels. At present, we do not understand, in molecular detail, how
the channels are activated in a voltage-dependent manner, how they are modulated by small molecules
binding to them at specific sites, how they are distinguished by various drugs, or how their channel functions
are modulated by other proteins such as calmodulin.
Building on the success of solving the first human TRPM4 structure in closed state, we propose to continue
the cryo-EM studies of TRPM4 and TRPM5 and their pharmacology, combined with complementary
electrophysiology experiments and collaboration with Takeda. The outcome of this proposal will define the
molecular basis for the voltage-dependent gating activity of these ion channels, for ligand recognition, and
for the action of modulators. These advances, in turn, will provide a foundation for developing new therapeutic
agents against cardiovascular diseases and diabetes and for a deeper understanding of the function of the
voltage-gated TRPM family members.

## Key facts

- **NIH application ID:** 10033970
- **Project number:** 1R01HL153219-01
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Wei Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $579,796
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033970

## Citation

> US National Institutes of Health, RePORTER application 10033970, Structural and functional studies of the human TRPM4 and TRPM5 channels (1R01HL153219-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10033970. Licensed CC0.

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