A “cold spot” — that’s what Hyuk-Joon Lee and his colleagues at Duke University found inside the protein that makes mint feel cold.
The spot is a specific region within TRPM8, a microscopic channel embedded in sensory neurons across the skin, mouth, and eyes. It plays a key role in keeping the channel responsive during extended exposure to cold. Nobody had seen it before, because nobody had seen the channel’s full structure before. Now they have.
The findings were presented at the 70th Biophysical Society Annual Meeting in San Francisco. Using cryo-electron microscopy — a technique that fires an electron beam at rapidly frozen proteins — the team captured structural snapshots of TRPM8 shifting from a closed state to an open one. The images are the first of their kind.
How the Cold Sensor Actually Works
TRPM8 sits inside neuron membranes and opens when temperatures fall into a range of roughly 46°F to 82°F. Once open, it lets ions flow into the cell. That ion movement fires a nerve signal. The brain reads it as cold.
Menthol exploits the same system. “It attaches to a specific part of the channel and triggers it to open, just like cold temperature would,” Lee said. “So even though menthol isn’t actually freezing anything, your body gets the same signal as if it were touching ice.”
The images revealed that cold and menthol use related but distinct routes through the protein. Cold acts mainly on the pore region — the part that physically opens to admit ions. Menthol binds elsewhere on the protein and causes shape changes that ripple toward the pore, eventually forcing it open. When the two are combined, according to the announcement, “the response is enhanced synergistically” — which is how the team captured the channel in its fully open state, something cold alone hadn’t been enough to achieve.
Why Medical Researchers Are Paying Attention
Dysfunction in TRPM8 has been linked to chronic pain, migraines, dry eye disease, and certain cancers. One drug already working through this pathway is acoltremon, an FDA-approved eye drop that treats dry eye. It is a menthol analogue — it activates the cooling pathway, which stimulates tear production.
That existing drug makes the structural findings immediately relevant. Knowing precisely where menthol binds, and how cold triggers separate changes in the pore region, gives researchers a detailed map to design compounds that activate or block the channel with more precision.
“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 also resolves something that had lingered without a molecular answer: why a compound that changes nothing about actual temperature can produce a sensation indistinguishable from touching ice. The channel cannot tell the difference. Menthol simply knows which door to knock on.
Photo by iuliu illes on Unsplash
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