Stepping outside or putting mint in your mouth on a cold winter morning will instantly give you a cooling sensation. The sensation begins with tiny sensors in your body that signal your brain when something is cold. Scientists have created the first detailed images of how this sensor works, revealing how it responds to both actual temperature drops and menthol, a cooling compound found in mint plants. The findings were presented at the 70th Annual Meeting of the Biophysical Society in San Francisco.
The study focused on a protein channel known as TRPM8. “Imagine TRPM8 as a microscopic thermometer inside your body,” said Hyukjun Lee, a postdoctoral fellow in Seokyoung Lee’s lab at Duke University. “This is the main sensor that tells the brain that it’s cold. We’ve known for a long time that this happens, but we didn’t know how. Now we can confirm it.”
TRPM8 is embedded in the membranes of sensory neurons that function in the skin, oral cavity, and eyes. When the temperature drops to a range of about 46°F to 82°F, the channels open, allowing ions to move into the cell. This movement triggers nerve signals that are sent to the brain, causing a sensation of coldness. The same mechanism explains why menthol, eucalyptus, and related compounds produce a cooling sensation even when the temperature has not actually decreased.
“Menthol is like a trick,” Lee explained. “The menthol attaches to certain parts of the channels, and the cold triggers them to open. So, even though the menthol isn’t actually freezing anything, your body receives the same signals as if you were touching ice.”
Cryogenic electron microscopy reveals the mechanism by which TRPM8 opens
To examine this process in detail, the research team used cryo-electron microscopy, a method that images proteins rapidly frozen with an electron beam. This allowed us to obtain several structural snapshots of TRPM8 as it transitions from the closed to open state.
The images showed that low temperature and menthol activate the channel through different but related pathways within the protein. Cold mainly causes structural changes in the pore region (the part that opens to allow ions to pass through). Menthol binds to another region of the protein, causing a shape change that spreads toward the pore and ultimately opens it.
“When you combine cold air and menthol, the reaction is synergistically enhanced,” Lee said. “We used this combination to capture channels in the open state, something we could not have achieved with cold alone.”
Potential medical benefits of understanding cold sensors
Understanding TRPM8 could also help scientists develop new treatments. Problems with this pathway have been linked to conditions such as chronic pain, migraines, dry eyes, and certain cancers. One drug that targets this pathway is acoltremon, an FDA-approved eye drop used to treat dry eye disease. As an analog of menthol, it activates cooling pathways, stimulates tear production, and relieves irritation.
The researchers also discovered what they called “cold spots.” This is a specific part of the protein that plays a key role in temperature sensing and helps maintain channel responsiveness during prolonged exposure to cold.
“Until now, it was unclear how cold air activates this channel at the structural level,” Lee said. “We now know that cold weather induces specific structural changes in the pore region. This provides the basis for developing new treatments targeting this pathway.”
Solving a long-standing mystery about cold sensations
The study provides the first molecular explanation of how temperature and chemical signals combine to produce the sensation of cold. By showing how TRPM8 integrates both cold and menthol signals, this study answers a long-standing question in sensory biology that scientists have been trying to answer for decades.
