The saying “cold hands, warm heart” is usually meant metaphorically — but new research from UC Davis School of Medicine and collaborating institutions suggests it has a striking biological parallel.
In a study of TRPM4 ion channel mutations, researchers found that body temperature plays a key role in which tissues are affected. One mutation becomes active only in cooler skin, and another exerts its effects only at the heart’s warmer, core body temperature. Cell type and local chemical signals also play a role.
The findings, published in the Proceedings of the National Academy of Sciences (PNAS), offer a clear explanation for why disease‑causing TRPM4 mutations lead to mutually exclusive conditions.
“This has been a mystery in the field for years,” said Yuhua Tian, first author of the study, and a visiting assistant professor in the Department of Physiology and Membrane Biology. “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.”
What Is TRPM4?
The TRPM4 gene, found on Chromosome 19, provides instructions for making a protein that acts like a gate in the cell membrane.
When calcium levels inside the cell rise, the gate opens, allowing cations (small ions with a positive charge, such as sodium) to flow into the cell. This alters the cell’s electrical state and sends multiple signals to the cell.
This process is important in many organs, including the heart, where electrical signaling plays a major role in maintaining a normal heart rhythm.
In the skin and immune system, this gated activity helps regulate inflammation and cell migration.
A medical mystery
Doctors and researchers have known for years that some TRPM4 mutations cause inherited heart disorders. These include progressive familial heart block, which alters the normal beating of the heart, and Brugada syndrome, a condition that disrupts the heart’s normal rhythm.
Other TRPM4 mutations cause rare, but severe, skin diseases, including progressive symmetric erythrokeratodermia (PSEK).
Strikingly, however, patients never develop both, even though the mutations increase TRPM4 activity.
“This didn’t make sense under traditional genetic models,” said Jie Zheng, senior author and professor of physiology and membrane biology at UC Davis. “If the same channel is overactive, why doesn’t it affect every tissue the same way?”
What the researchers discovered
The researchers combined electrophysiology, molecular modeling and mouse genetics to examine how disease‑linked TRPM4 mutations respond to calcium, membrane lipids and temperature. By measuring ion channel activity and cell behavior under skin‑like and heart‑like temperature conditions, they uncovered how heat and cold determine where these mutations cause disease.
The research shows that TRPM4 is controlled by a three‑part system:
- Calcium levels inside the cell
- A membrane lipid called PIP2 (phosphatidylinositol 4,5-bisphosphate), which acts as an on-off switch for activity in a cell
- Temperature, which differs between the skin and the internal organs
Together, these factors determine when and where TRPM4 is active.