TY - JOUR T1 - Design Maps of TRPM8 as a Thermometer for Cold Detection JF - bioRxiv DO - 10.1101/2022.01.02.474742 SP - 2022.01.02.474742 AU - Guangyu Wang Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/12/2022.01.02.474742.abstract N2 - The menthol sensor TRPM8 can be activated by cold and thus serves as a thermometer in a primary afferent sensory neuron for noxious cold detection. However, the underlying design principle is unknown. Here, a hairpin topological structural model and graph theory were prepared to test a role of the cold-dependent hairpin formation in the cold-evoked gating pathway of TRPM8. The results showed that the formation of a large lipid-dependent hairpin initiates a low temperature threshold in favor of TRPM8 activation. Furthermore, two smaller hairpins, which enhance the coupled interactions of the voltage-sensor-like domain with both the pore domain and the TRP domain, can stabilize the cold efficacy and work as a fuse to prevent cold denaturation. The cold-induced hairpin rearrangements along the gating pathway may be necessary for the high cold sensitivity. This hairpin model may provide a structural basis for activation of the thermo-gated TRP channels at low temperature.Competing Interest StatementThe authors have declared no competing interest.CHScholesterol hemisuccinateCFTRcystic fibrosis transmembrane conductance regulatorcryo-EMcryo-electron microscopyDMEMDulbecco’s modified Eagle’s mediumHTHhelix-turn-helixPIP2phosphatidylinositol-4,5-bisphosphateTRPtransient receptor potentialTRPM8TRP melastatin-8cfTRPM8collared flycatcher TRPM8hTRPMihuman TRPMi (i=1, 2, 3, 4, 5, 6, 7, 8)mTRPM8mouse TRPM8pmTRPM8Parus major TRPM8rTRPM8rat TRPM8TRPV1TRP vanilloid-1VBEVanillyl butyl etherVSLDvoltage-sensor-like domain ER -