A folding reaction at the C-terminal domain drives temperature sensing in TRPM8 channels

Significance Sensory and homeostatic responses in several organisms depend on the exquisite temperature dependence of ion channels of the transient receptor potential family (thermo-TRP). To date, this temperature dependence has been explained either in terms of the existence of a dedicated temperature sensor or by the increase in the molar heat capacity during channel gating. We found that the Carboxy Terminus Domain (CTD) is required for temperature-driven gating of the cold-activated TRPM8 channel and that this domain folds in response to cold. Here we propose that the CTD of the TRPM8 channel is a bona fide temperature sensor that drives channel gating due to an increase in the molar heat capacity during the folded-to-unfolded transition.