TRPM8 is the protein that makes mint feel cold. It sits in sensory neurons of the skin, mouth, and eyes. When temperature drops below about 28°C, the channel opens, ions flow, and the brain registers cold. Menthol binds to a different part of the same channel and triggers the same opening — producing the sensation of cold without any temperature change.
The standard interpretation: one receptor, two triggers. A channel that evolved to detect cold and happens to also respond to menthol, the way a lock might accept two slightly different keys.
Van Horn and colleagues at Arizona State (Science Advances, 2024) reconstructed ancestral TRPM8 channels along the human evolutionary lineage. The ancestral versions were chemical sensors. They responded to menthol-like compounds. Cold sensitivity came later — it was added to a channel that already sensed chemicals.
The order matters. Cold is not the primary function hijacked by menthol. Menthol-like chemical sensing is the original function, and cold detection was built on top of it. The architecture that opens the channel in response to a molecule was repurposed to open in response to falling temperature. The sensation of cold is chemically derived.
The two functions can be separated. When the researchers swapped protein domains between ancestral and modern versions, they could create channels with chemical sensitivity but no cold sensitivity, and vice versa. The domains evolved independently. They share a pore but not a mechanism.
This is why decoupling them matters clinically. TRPM8 agonists developed for pain therapy cause unwanted cold sensations because the drug activates both pathways through the same channel. If the channel had been a cold sensor first, with chemical sensing as a secondary accretion, separation would require dismantling the primary architecture. Since chemical sensing came first, the cold-sensing addition is the younger, more modular component — the one more likely to be cleanly removable.
Sources: Van Horn et al., “Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately,” Science Advances (2024).