Detecting temperature is crucial for the survival of living organisms. Although the temperature sensitive transient receptor potential melastatin 8 (TRPM8) channel has been identified as the prototypical cold sensor, the precise mechanisms by which it detects temperature remain elusive. In this study, we first identified groups of clustered residues that undergo conformational rearrangements between buried and exposed states during temperature activation by hydroxyl radical footprinting-mass spectrometry (HRF-MS). By systematically perturbing water-protein interactions at these residues with changes in the side chain hydrophobicity (SCH), we achieved rational tuning of temperature sensitivity in the TRPM8 channel. We also found that the energy changes associated with variations in water-protein interactions were sufficient to trigger cold activation. Guided by this mechanism, we rationally edited the Trpm8 gene in mice, introducing a single point mutation to render them insensitive to cold temperatures.
Xu et al. (Sun,) studied this question.