Design Maps of TRPM8 as a Thermometer for Cold Detection
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.