Temperature dictates TRPM4 mutation risk for skin disease, arrhythmia

First author Yuhua Tian, front, and senior author Jie Zheng in the Zheng lab on the UC Davis campus. Photo courtesy Regents of the University of California

Body temperature may determine whether a single overactive ion channel causes a localized skin disorder or even a potentially lethal arrhythmia, according to new research published in the Proceedings of the National Academy of Sciences (PNAS).

In a mechanistic study of TRPM4 gain‑of‑function mutations, investigators at the University of California, Davis, and collaborating centres report that tissue‑specific temperature, phosphatidylinositol 4,5-bisphosphate (PIP2) signalling, and intracellular calcium form an integrated control system that confines pathology either to the skin or to the heart—but never both.

“This has been a mystery in the field for years,” said first author Yuhua Tian, PhD, a visiting assistant professor in the Department of Physiology and Membrane Biology, in a press release. “We now understand that it's not just the mutation itself that matters, but where in the body the protein is active and under what conditions.”

TRPM4, a calcium‑activated, temperature‑sensitive cation channel encoded on chromosome 19, links intracellular calcium signals to membrane depolarization in multiple tissues, including cardiomyocytes, keratinocytes, and immune cells. Using electrophysiology, molecular modelling, and mouse genetics, the authors demonstrated that PIP2 is a required cofactor that “locks or unlocks” TRPM4 by modulating its calcium sensitivity, with a high‑affinity binding site proposed adjacent to the S4–S5 linker.

Skin‑disease–associated mutations disrupt PIP2‑mediated control, producing sustained TRPM4 activity at skin‑surface temperatures of 25 to 30°C, while channel hyperactivity is lost at core body temperature. In contrast, cardiac mutations primarily increase channel number and augment electrical signalling only at 37°C, with little effect in cooler peripheral tissues. “This explains why skin mutations cause damage only in the skin, and heart mutations affect only the heart,” said senior author Jie Zheng, PhD. “The channel is responding to its environment.”

For dermatologists, the work offers a framework for re‑thinking genotype–phenotype correlations in rare inherited keratinization disorders such as progressive symmetric erythrokeratodermia. “This work shows that a mutation's effects depend on tissue context, not just DNA sequence,” said co‑author Samuel Hwang, MD, PhD, chair of dermatology at UC Davis Health. “That insight helps explain why some patients develop skin disease without heart involvement, and it suggests new strategies for treating these conditions more precisely.”