The sensation of coolness, whether from a winter breeze or a minty balm, isn’t simply a matter of temperature. Scientists have, for the first time, captured detailed images of the molecular sensor responsible for detecting cold and triggering that familiar cooling sensation, revealing how it responds to both actual cold and compounds like menthol. This breakthrough in understanding sensory biology, presented at the 70th Biophysical Society Annual Meeting in San Francisco February 21-25, 2026, could pave the way for new treatments for chronic pain, migraines, and other conditions.
The key to this sensation lies in a protein channel called TRPM8, often described as a microscopic thermometer within the body. Researchers at Duke University, led by Seok-Yong Lee and postdoctoral fellow Hyuk-Joon Lee, used cryo-electron microscopy – a technique that images flash-frozen proteins with an electron beam – to visualize TRPM8 in action. This allowed them to observe how the channel opens and closes in response to different stimuli. Understanding how TRPM8 functions is crucial, as it’s the primary sensor that alerts the brain to temperature drops, and is too responsible for the cooling effects of menthol, eucalyptus, and similar compounds.
TRPM8 is strategically located in the membranes of sensory neurons throughout the skin, mouth, and eyes. It activates when temperatures fall between approximately 46°F and 82°F, allowing ions to flow into the cell and sending a signal to the brain. But the channel isn’t solely activated by cold. As Hyuk-Joon Lee explained, “Menthol is like a trick,” attaching to a specific part of the channel and mimicking the effect of cold temperatures. “So even though menthol isn’t actually freezing anything, your body gets the same signal as if it were touching ice.”
How Menthol ‘Tricks’ Your Brain
The research revealed that cold and menthol activate TRPM8 through slightly different mechanisms. Cold primarily causes changes in the pore region of the channel – the part that actually opens to allow ions through. Menthol, however, binds to a different area of the protein, inducing shape changes that ultimately propagate to the pore. Interestingly, the combination of cold and menthol creates a synergistic effect, enhancing the response and allowing researchers to capture the channel in its open state more easily than with cold alone. This combined activation was key to obtaining the detailed images of TRPM8’s function.
The implications of this research extend beyond simply understanding how we perceive temperature. Dysfunction of TRPM8 has been linked to a range of medical conditions, including chronic pain, migraines, dry eye, and even certain cancers. Acoltremon, an FDA-approved eye drop for dry eye disease, leverages this understanding. As a menthol analogue, it activates the TRPM8 channel to stimulate tear production and provide relief from irritation, as News-Medical.net reports.
Identifying a ‘Cold Spot’ for Future Treatments
The team also identified a specific region of the TRPM8 protein, dubbed a “cold spot,” that is critical for sensing temperature and preventing the channel from becoming desensitized during prolonged cold exposure. This discovery provides a potential target for developing new therapies. “Previously, it was unclear how cold activates this channel at the structural level,” Lee said. “Now You can see that cold triggers specific structural changes in the pore region. This gives us a foundation for developing new treatments that target this pathway.”
This work represents the first molecular-level definition of how the body integrates cold and chemical stimuli to create the sensation of coolness, resolving a long-standing question in sensory biology. The detailed images of TRPM8’s function, captured through cryo-electron microscopy, offer a new understanding of this fundamental process.
Looking ahead, researchers will continue to explore the intricacies of TRPM8 and its role in various physiological processes. Further investigation into the “cold spot” and the distinct activation mechanisms of cold and menthol could lead to the development of more targeted and effective treatments for conditions linked to TRPM8 dysfunction.
What are your thoughts on this new understanding of how we perceive temperature? Share your comments below, and let’s continue the conversation.
