Stepping into chilly air or tasting a mint sets off a specialized sensor in your body that signals the brain that something feels cold. Researchers have now obtained the first high-resolution images showing how this sensor works, revealing how it responds both to low temperatures and to menthol, the cooling compound found in mint plants. The findings were recently presented at the 70th Biophysical Society Annual Meeting in San Francisco.
The research centers on TRPM8, a protein channel that detects cool conditions. “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 is located in the membranes of sensory nerve cells that serve the skin, mouth, and eyes. When temperatures drop to roughly between 46°F and 82°F, the channel opens and allows charged particles known as ions to enter the cell. This movement of ions generates an electrical signal that travels to the brain, where it is interpreted as a cooling sensation. The same pathway explains why menthol, eucalyptus, and similar substances create a cool feeling even when the temperature does not change.
“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.”
Visualizing the Channel in Action
To understand how TRPM8 changes shape during activation, the team used cryo-electron microscopy, a method that images rapidly frozen proteins with an electron beam. This approach allowed them to capture a series of structural states as the channel shifted from closed to open.
Their analysis showed that cold and menthol activate TRPM8 through overlapping but distinct internal pathways. Cold exposure mainly alters the pore region, which is the part of the channel that opens to let ions pass. Menthol binds at a separate site on the protein and triggers structural changes that spread through the molecule until the pore opens.
