BETHESDA, MD – When you step outside on a winter morning or pop a mint into your mouth, a tiny molecular sensor in your body springs into action, alerting your brain to the sensation of cold. Scientists have now captured the first detailed images of this sensor at work, revealing exactly how it detects both actual cold and the perceived cool of menthol, a compound derived from mint plants. The research will be presented at the 70th Biophysical Society Annual Meeting in San Francisco from February 21–25, 2026.
The study focused on a protein channel called TRPM8. “Imagine TRPM8 as a microscopic thermometer inside your body,” said Hyuk-Joon Lee, a postdoctoral fellow from Seok-Yong Lee’s laboratory at Duke University. “It’s the primary sensor that tells your brain when it’s cold. We've known for a long time that this happens, but we didn't know how. Now we can see it.”
TRPM8 sits in the membranes of sensory neurons innervating the skin, oral cavity, and eyes. It responds to cold temperatures—roughly between 46°F and 82°F—by opening up and allowing ions to flow into the cell, which triggers a nerve signal to the brain. It's also the reason menthol, eucalyptus, and certain other compounds produce that characteristic cooling sensation.
“Menthol is like a trick,” Lee explained. “It attaches to a specific part of the channel and triggers it to open, just like cold temperature would. So even though menthol isn’t actually freezing anything, your body gets the same signal as if it were touching ice.”
Using cryo-electron microscopy—a technique that images flash-frozen proteins with an electron beam—Lee and colleagues captured multiple conformational snapshots of TRPM8 as it transitions from closed to open. They discovered that cold and menthol activate the channel through shared yet distinct allosteric networks: cold primarily triggers changes in the pore region (the part that actually opens to let ions through), while menthol binds a different part of the protein and induces shape changes that propagate to the pore.
“When cold is combined with menthol, the response is enhanced synergistically,” Lee said. “We used this combination to capture the channel in its open state—something that hadn't been achieved with cold by itself.”
The findings have medical implications. When TRPM8 doesn't function properly, it has been linked to conditions including chronic pain, migraines, dry eye and certain cancers. Acoltremon, a drug that activates TRPM8, is an FDA-approved eye drop for dry eye disease. As a menthol analogue, it works by activating the cooling pathway to stimulate tear production and soothe irritated eyes.
The researchers also identified what they call a “cold spot”—a specific region of the protein that is uniquely important for sensing temperature and helps prevent the channel from becoming desensitized during prolonged cold exposure.
“Previously, it was unclear how cold activates this channel at the structural level,” Lee said. “Now we 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.”
The work offers the first molecular definition of how cold and chemical stimuli are integrated to create the sensation of coolness—answering a fundamental question in sensory biology that has puzzled scientists for decades.
Image Caption
Using cryo-electron microscopy—a technique that images flash-frozen proteins with an electron beam—researchers captured multiple conformational snapshots of the cold sensing channel, TRPM8, as it transitions from closed to open.
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