How Your Body Senses Cold: Scientists Unlock the Molecular Mechanism
When you reach into a bucket of ice, step outside on a snowy day, or feel the tingle of menthol toothpaste, a protein in your nerve cells called TRPM8 springs into action, opening like a tiny gate to send a “cold” signal to your brain. Now, researchers at the University of California, San Francisco (UCSF) have discovered exactly how TRPM8 changes its shape when exposed to cool temperatures, providing a detailed understanding of the molecular process behind cold sensation.
The study, published in Nature on March 25, 2026, could pave the way for fresh pain therapies, particularly for conditions involving cold sensitivity. It also sheds light on why birds are less sensitive to cold than mammals.
Unraveling a Long-Standing Mystery
“Everyone always wants to know how temperature sensing works, but it turns out to be a very technically challenging question to answer,” said David Julius, PhD, co-senior author of the study, chair of Physiology, and the Morris Herzstein Chair in Molecular Biology and Medicine at UCSF. “So, to finally have insight into this is really very exciting.”
Julius was awarded the 2021 Nobel Prize in Physiology or Medicine for his discovery of TRPV1, a protein that enables nerves to sense capsaicin, the spicy heat of chili peppers.
Seeing Proteins in Motion
A key breakthrough in the current research was the ability to visualize proteins as they change shape. “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,” explained Yifan Cheng, PhD, UCSF professor of biochemistry and biophysics and an investigator at the Howard Hughes Medical Institute (HHMI), who co-led the work.
Overcoming Challenges in Studying TRPM8
TRPM8, responsible for both cold sensation and the cooling effect of menthol, has been a challenging protein to study. It tends to break apart when isolated from cells, and traditional imaging methods require proteins to be in a stable configuration.
The UCSF team overcame these challenges by imaging TRPM8 while it remained embedded in cell membranes. “We realized that the protein is particularly sensitive to how you handle it. Keeping it in the native membrane was what finally let us spot what was actually happening,” said Kevin Choi, a graduate student at UCSF and co-first author of the study.
Mapping the Molecular Changes
Researchers used two techniques: cryo-electron microscopy (cryo-EM) and hydrogen-deuterium exchange mass spectrometry (HDX-MS). Cryo-EM provided static images of the protein, while HDX-MS tracked its movements in real-time as the temperature changed.
The analysis revealed that cold temperatures stabilize a specific region of the TRPM8 channel, triggering a helix to move. This movement allows a lipid molecule to slide into place, locking the channel open and sustaining the cold signal. Comparing human TRPM8 to the avian version, which is less sensitive to cold, helped pinpoint the features responsible for cold detection.
Implications for Structural Biology and Pain Treatment
This research provides valuable lessons for studying other dynamic proteins. “The lessons we learned in studying this channel are actually very broadly useful,” Cheng said. “Dynamic behavior is critical for the function of many proteins, and you can’t understand dynamic behavior from one snapshot of a protein’s structure.”
Julius and Cheng are now applying this approach to study TRPV1, the heat-sensing channel. They also plan to investigate how compounds that block TRPM8 – some of which are in clinical trials for pain – affect the protein’s structure, potentially leading to more targeted treatments for conditions like cold allodynia, where even mild cold triggers severe pain.