PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain

Nat Neurosci. 2005 May;8(5):626-34. doi: 10.1038/nn1451. Epub 2005 Apr 24.


The subjective feeling of cold is mediated by the activation of TRPM8 channels in thermoreceptive neurons by cold or by cooling agents such as menthol. Here, we demonstrate a central role for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in the activation of recombinant TRPM8 channels by both cold and menthol. Moreover, we show that Ca(2+) influx through these channels activates a Ca(2+)-sensitive phospholipase C and that the subsequent depletion of PI(4,5)P(2) limits channel activity, serving as a unique mechanism for desensitization of TRPM8 channels. Finally, we find that mutation of conserved positive residues in the highly conserved proximal C-terminal TRP domain of TRPM8 and two other family members, TRPM5 and TRPV5, reduces the sensitivity of the channels for PI(4,5)P(2) and increases inhibition by PI(4,5)P(2) depletion. These data suggest that the TRP domain of these channels may serve as a PI(4,5)P(2)-interacting site and that regulation by PI(4,5)P(2) is a common feature of members of the TRP channel family.

Publication types

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

MeSH terms

  • Animals
  • COS Cells
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Chlorocebus aethiops
  • Cold Temperature*
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Menthol / pharmacology
  • Mutation / physiology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Patch-Clamp Techniques
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Protein Structure, Tertiary / drug effects
  • Protein Structure, Tertiary / physiology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • TRPV Cation Channels
  • Thermosensing / drug effects
  • Thermosensing / physiology*


  • Calcium Channels
  • Ion Channels
  • Membrane Proteins
  • Neoplasm Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • TRPV Cation Channels
  • TRPV5 protein, human
  • Menthol
  • Calcium