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

Research output: Contribution to journalArticle

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 Gα(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Gα(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a Gα(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated Gα(q) protein, but not Gβγ, potently inhibits TRPM8 in excised patches. We conclude that Gα(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)851-858
Number of pages8
JournalNature Cell Biology
Volume14
Issue number8
Early online date1 Jul 2012
DOIs
Publication statusPublished - Aug 2012

Bibliographical note

Copyright © 2012, Springer Nature. Nature Cell Biology volume 14, pages 851–858 (2012). https://doi.org/10.1038/ncb2529

Keywords

  • cultured cells
  • cold temperature
  • X-ray crystallography
  • GTP-binding protein alpha subunits
  • Gq-G11
  • molecular models
  • neurons
  • protein binding
  • signal transduction
  • TRPM cation channels

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    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), 851-858. https://doi.org/10.1038/ncb2529