How Body Senses Cold Revealed in New Study

UCSF researchers uncover the molecular mechanism behind how the TRPM8 protein in nerve cells opens to detect cold temperatures.

Mar. 26, 2026 at 3:07am by Ben Kaplan

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Researchers at the University of California, San Francisco have discovered the exact molecular changes that occur in the TRPM8 protein when exposed to cold temperatures. Using cryo-electron microscopy and mass spectrometry, the team was able to visualize how TRPM8 shifts its shape to open a 'gate' and send a 'cold' signal to the brain. This breakthrough provides new insights into how temperature sensing works and could lead to better pain treatments.

Why it matters

Understanding the molecular mechanisms behind temperature sensing has been a longstanding challenge in pain research. This discovery of how the TRPM8 protein responds to cold temperatures not only answers a key scientific question, but also opens new avenues for developing targeted therapies for conditions like cold allodynia, where even mild cold triggers severe pain.

The details

The researchers used two complementary techniques - cryo-electron microscopy and hydrogen-deuterium exchange mass spectrometry - to capture TRPM8 in action as temperatures dropped below 79°F. They found that cold temperatures stabilize a specific region of the TRPM8 channel, triggering a key helix to move and allowing a lipid molecule to slide in and lock the channel open, sustaining the cold signal. Comparing the human TRPM8 protein to the less cold-sensitive bird version also revealed the specific features responsible for detecting cold.

  • The study was published in the journal Nature on March 25, 2026.

The players

David Julius

Co-senior author of the study, chair of Physiology and the Morris Herzstein Chair in Molecular Biology and Medicine at UCSF. He received the 2021 Nobel Prize in Physiology or Medicine for discovering TRPV1, the heat-sensing protein.

Yifan Cheng

Co-senior author of the study, UCSF professor of biochemistry and biophysics and an investigator at the Howard Hughes Medical Institute (HHMI).

Kevin Choi

Graduate student at UCSF and co-first author of the study.

Xiaoxuan Lin

HHMI staff scientist working in Cheng's lab at UCSF and co-first author of the study.

TRPM8

A protein in nerve cells that opens like a 'gate' to send a 'cold' signal to the brain when exposed to cold temperatures.

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What they’re saying

“Everyone always wants to know how temperature sensing works, but it turns out to be a very technically challenging question to answer. So, to finally have insight into this is really very exciting.”

— David Julius, Co-senior author

“For decades, structural biology has focused on capturing proteins in stable, frozen states. This work shows that to truly understand how a protein functions, you also have to understand how it moves.”

— Yifan Cheng, Co-senior author

“We realized that the protein is particularly sensitive to how you handle it. Keeping it in the native membrane was what finally let us see what was actually happening.”

— Kevin Choi, Co-first author

What’s next

Julius and Cheng are now applying the same strategy to study the structure and dynamics of TRPV1, the heat-sensing channel that Julius discovered in 1997. They also plan to examine how compounds that block TRPM8 - several of which are in clinical trials for pain - affect the structure of the protein, which could lead to more targeted treatments for conditions like cold allodynia.

The takeaway

This groundbreaking study not only solves a longstanding mystery in pain research, but also demonstrates the power of combining advanced imaging techniques to visualize the dynamic behavior of proteins. The insights gained could pave the way for developing more effective treatments for a range of temperature-related pain conditions.