Abstract
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 Statement
The authors have declared no competing interest.
Conventions and Abbreviations
- CHS
- cholesterol hemisuccinate
- CFTR
- cystic fibrosis transmembrane conductance regulator
- cryo-EM
- cryo-electron microscopy
- DMEM
- Dulbecco’s modified Eagle’s medium
- HTH
- helix-turn-helix
- PIP2
- phosphatidylinositol-4,5-bisphosphate
- TRP
- transient receptor potential
- TRPM8
- TRP melastatin-8
- cfTRPM8
- collared flycatcher TRPM8
- hTRPMi
- human TRPMi (i=1, 2, 3, 4, 5, 6, 7, 8)
- mTRPM8
- mouse TRPM8
- pmTRPM8
- Parus major TRPM8
- rTRPM8
- rat TRPM8
- TRPV1
- TRP vanilloid-1
- VBE
- Vanillyl butyl ether
- VSLD
- voltage-sensor-like domain