Direct inhibition of the cold-activated TRPM8 ion channel by Gαq

Xuming Zhang*, Stephanie Mak, Lin Li, Andres Parra, Bristol Denlinger, Carlos Belmonte, Peter A. McNaughton

*Corresponding author for this work

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G alpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G alpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G alpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G alpha(q) protein, but not G beta gamma, potently inhibits TRPM8 in excised patches. We conclude that G alpha(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

Original languageEnglish
Pages (from-to)850-858
Number of pages8
JournalNature Cell Biology
Volume14
Issue number8
Early online date1 Jul 2012
DOIs
Publication statusPublished - Aug 2012

Keywords

  • living cells
  • G-proteins
  • phosphatidylinositol 4,5-bisphosphate
  • phospholipase-C
  • alpha-subunits
  • receptor
  • mice
  • phosphorylation
  • membrane
  • TRPV1

Cite this

Zhang, X., Mak, S., Li, L., Parra, A., Denlinger, B., Belmonte, C., & McNaughton, P. A. (2012). Direct inhibition of the cold-activated TRPM8 ion channel by Gαq. Nature Cell Biology, 14(8), 850-858. https://doi.org/10.1038/ncb2529