Scientists finally reveal why mint feels cold

The research centered on a protein channel known as TRPM8. "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."

TRPM8 is embedded 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. This movement triggers a nerve signal that travels to the brain and produces the sensation of cold. The same mechanism explains why menthol, eucalyptus, and related compounds create a cooling feeling even when the temperature has not actually dropped.

"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."

Cryo-Electron Microscopy Reveals How TRPM8 Opens

To examine the process in detail, the team used cryo-electron microscopy (a method that images rapidly frozen proteins with an electron beam). This allowed them to capture several structural snapshots of TRPM8 as it shifts from a closed state to an open one.

The images showed that cold temperatures and menthol activate the channel through related but distinct pathways within the protein. Cold mainly causes structural changes in the pore region (the part that opens to allow ions through). Menthol binds to a separate area of the protein and triggers shape changes that spread toward the pore, eventually opening it.

"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."

Potential Medical Benefits of Understanding the Cold Sensor

Understanding TRPM8 could also help scientists develop new medical treatments. Problems with this channel have been linked to conditions such as chronic pain, migraines, dry eye and certain cancers. One drug that targets this pathway is acoltremon, an FDA-approved eye drop used to treat dry eye disease. As a menthol analogue, it activates the cooling pathway, which helps stimulate tear production and relieve irritation.

The researchers also discovered what they describe as a "cold spot," a specific part of the protein that plays a key role in detecting temperature and helps keep 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."

Solving a Longstanding Mystery of Cool Sensations

The study provides the first molecular explanation of how temperature and chemical signals combine to produce the sensation of coolness. By showing how TRPM8 integrates both cold and menthol signals, the work answers a longstanding question in sensory biology that scientists have been trying to solve for decades.