Direct Gαq Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation

Cell Rep. 2019 Jun 18;27(12):3672-3683.e4. doi: 10.1016/j.celrep.2019.05.080.


Activation of Gαq-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Gαq and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2) inhibit TRPM8. Here, I demonstrate that direct Gαq gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Gαq depends on binding to three arginine residues in the N terminus of TRPM8. Neutralization of these residues markedly increased sensitivity of the channel to agonist and membrane voltage and completely abolished TRPM8 inhibition by both Gαq and bradykinin while sparing the channel sensitivity to PIP2. Interestingly, the bradykinin receptor B2R also binds to TRPM8, rendering TRPM8 insensitive to PIP2 depletion. Furthermore, TRPM8-Gαq binding impaired Gαq coupling and signaling to PLCβ-PIP2. The crosstalk in the TRPM8-Gαq-B2R complex thus determines Gαq gating rather than PIP2 as a sole means of TRPM8 inhibition by bradykinin.

Keywords: G protein; GPCR signaling; PIP(2); TRPM8; bradykinin; cold; inflammatory mediator; pain; protein-protein interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bradykinin / pharmacology*
  • Cells, Cultured
  • Cold Temperature
  • Female
  • GTP-Binding Protein alpha Subunits, Gq-G11 / physiology*
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Receptors, Bradykinin / genetics
  • Receptors, Bradykinin / metabolism*
  • Sensory Receptor Cells / cytology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Signal Transduction
  • TRPM Cation Channels / antagonists & inhibitors*
  • Vasodilator Agents / pharmacology*


  • Inflammation Mediators
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Bradykinin
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Vasodilator Agents
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Bradykinin