Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2

Science. 2022 Oct 14;378(6616):eadd1268. doi: 10.1126/science.add1268. Epub 2022 Oct 14.


The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP2-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cold Temperature*
  • Cryoelectron Microscopy
  • Ion Channel Gating* / drug effects
  • Ion Channel Gating* / physiology
  • Ligands
  • Menthol / chemistry
  • Menthol / pharmacology
  • Mice
  • Phosphatidylinositol 4,5-Diphosphate* / chemistry
  • Phosphatidylinositol 4,5-Diphosphate* / pharmacology
  • Protein Conformation
  • Pyrimidinones* / chemistry
  • Pyrimidinones* / pharmacology
  • TRPM Cation Channels* / agonists
  • TRPM Cation Channels* / chemistry
  • Thermosensing* / drug effects
  • Thermosensing* / physiology


  • Ligands
  • Menthol
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Phosphatidylinositol 4,5-Diphosphate
  • icilin
  • Pyrimidinones