Scientists have captured detailed structural images of TRPM8—often described as the body’s “cold sensor”—showing how the channel responds to cooling temperatures and to menthol, the compound behind mint’s chill. The work, presented at the 70th Biophysical Society Annual Meeting in San Francisco, helps explain the molecular basis of cool sensations and may aid drug development for conditions including dry eye and pain disorders.
The cooling sting of winter air—or the refreshment of a mint—begins with a protein channel called TRPM8, which sits in the membranes of sensory neurons that serve the skin, oral cavity and eyes. When temperatures fall into a range of about 46°F to 82°F, the channel opens and allows ions to move into the cell, triggering nerve signals that the brain interprets as cold.
“Imagine TRPM8 as a microscopic thermometer inside your body,” said Hyuk-Joon Lee, a postdoctoral fellow in 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.”
Using cryo-electron microscopy, the researchers captured structural snapshots of TRPM8 as it shifts from a closed state to an open one. The images suggest that cold and menthol activate the channel through related but distinct routes within the protein: cooling mainly drives structural changes in the pore region—the part that opens to let ions through—while menthol binds to a separate area and induces shape changes that propagate toward the pore.
“Menthol is like a trick,” Lee said. “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.”
The team reported that combining cold and menthol enhanced the channel’s response, and that this combination enabled them to capture the channel in its open state—something they said had not been achieved using cold alone.
Beyond explaining everyday sensations, the researchers pointed to possible medical implications. They said TRPM8 has been linked to conditions including chronic pain, migraines, dry eye and certain cancers. One drug that targets this pathway is acoltremon, an FDA-approved eye drop for dry eye disease; the researchers described it as a menthol analogue that activates the cooling pathway to help stimulate tear production.
The work also identified what the researchers called a “cold spot,” a region of the protein they said is important for temperature sensing and for keeping the channel responsive during extended exposure to cold.
“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 findings were presented at the 70th Biophysical Society Annual Meeting in San Francisco.
