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Updated: Aug 6, 2026
08:35
A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice
Published on: March 17, 2015
Symmetry-driven gating of TRPM8 by PIP2 and menthol
Sun-Hong Kim1, Chansik Hong2, Hyunwoo Park1
1Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Nature Communications
|July 21, 2026
Summary
Phosphoinositide 2 (PIP2) binding to the TRPM8 channel initiates activation, with cooling agents like menthol stabilizing this state. This reveals a stepwise mechanism for how PIP2 and cooling compounds gate the cold-activated ion channel.
Area of Science:
- Molecular Biology
- Structural Biology
- Biophysics
Background:
- TRPM8 is a cold-activated ion channel crucial for sensing cooling agents like menthol.
- Phosphatidylinositol 4,5-bisphosphate (PIP2) is vital for TRPM8 activation, but its precise role and menthol's binding mode are unclear.
Purpose of the Study:
- To elucidate the cooperative mechanism and binding mode of menthol in TRPM8 activation.
- To determine the structural basis for PIP2 and cooling agonist gating of TRPM8.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine structures of mouse TRPM8.
- Structures captured diverse conformations, including PIP2-induced and icilin-bound states.
Main Results:
- PIP2 binding triggers a symmetry-breaking event, creating intermediate states for activation.
- Cooling agonists induce a transition back to four-fold symmetry.
- Menthol stabilizes the PIP2-bound state, preventing desensitization; icilin and calcium stabilize the open state.
Conclusions:
- A stepwise activation pathway for TRPM8 involving distinct symmetry transitions was revealed.
- The cooperative allosteric mechanism of PIP2 and cooling agonists gating TRPM8 was defined.
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