# Activation and Inhibition Mechanisms of Calcium-Activated Nonselective Cation Channels

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $662,811

## Abstract

Project Summary
Ca2+-activated nonselective cation (CAN) channels are among a few ion channels that convert
intracellular Ca2+ signaling into changes in membrane potential, in contrast to most ion
channels that directly or indirectly use membrane potential to regulate intracellular Ca2+
signaling. This unique property allows CAN channels to play critical roles in many tissues and
organs. While the existence of CAN channels has been known for decades, recent evidence
has established that monovalent cation-permeable TRPM4 and TRPM5 are the long sought
for CAN channels. Indeed, numerous TRPM4 mutations are linked to severe human diseases,
e.g., cardiac conduction block, Bragada syndrome, PSEK (a skin disease). Despite their
functional significance, little is known about the molecular mechanisms governing TRPM4&5
channels activity. Ca2+ is the only known physiological activator for them, though membrane
potential also regulates channel activity but only in the presence of Ca2+. However, while the
Ca2+-binding sites have been identified by cryo-EM studies, how Ca2+ and voltage activate
TRPM4&5 channels remains unknown. Furthermore, while most known disease-causing
TRPM4 mutations lead to a gain-of-function phenotype, no effective inhibitor for TRPM4&5 is
currently available. Based on our preliminary functional data on TRPM4 Ca2+ and voltage
activation, our discovery of novel TRPM4 mutations causing human skin disease, a new
disease-causing mutant channel CRISPR mouse model exhibiting skin phenotypes, and our
recent discovery of a novel TRPM4 inhibition process, we plan to use a multidisciplinary
approach aiming at revealing the fundamental mechanisms of TRPM4&5 activation and
inhibition.

## Key facts

- **NIH application ID:** 10503201
- **Project number:** 1R01NS128180-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Juan Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $662,811
- **Award type:** 1
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10503201

## Citation

> US National Institutes of Health, RePORTER application 10503201, Activation and Inhibition Mechanisms of Calcium-Activated Nonselective Cation Channels (1R01NS128180-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10503201. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*