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

Xuming Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Activation of Gα q-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Gα q and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP 2) inhibit TRPM8. Here, I demonstrate that direct Gα q gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Gα q 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 Gα q and bradykinin while sparing the channel sensitivity to PIP 2. Interestingly, the bradykinin receptor B2R also binds to TRPM8, rendering TRPM8 insensitive to PIP 2 depletion. Furthermore, TRPM8-Gα q binding impaired Gα q coupling and signaling to PLCβ-PIP 2. The crosstalk in the TRPM8-Gα q-B2R complex thus determines Gα q gating rather than PIP 2 as a sole means of TRPM8 inhibition by bradykinin. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2.

Original languageEnglish
Pages (from-to)3672-3683.e4
JournalCell Reports
Volume27
Issue number12
DOIs
Publication statusPublished - 18 Jun 2019

Bibliographical note

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Funding: MRC grant G0801387.

Keywords

  • bradykinin
  • cold
  • G protein
  • GPCR signaling
  • inflammatory mediator
  • pain
  • PIP
  • protein-protein interaction
  • TRPM8

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