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

Zhang, Xuming, Mak, Stephanie, Li, Lin, Parra, Andres, Denlinger, Bristol, Belmonte, Carlos and McNaughton, Peter A. (2012). Direct inhibition of the cold-activated TRPM8 ion channel by Gαq. Nature Cell Biology, 14 (8), pp. 851-858.

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.

Publication DOI: https://doi.org/10.1038/ncb2529
Divisions: Life & Health Sciences
Additional Information: Copyright © 2012, Springer Nature. Nature Cell Biology volume 14, pages 851–858 (2012). https://doi.org/10.1038/ncb2529
Uncontrolled 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
Published Date: 2012-08
Authors: Zhang, Xuming ( 0000-0002-5331-8675)
Mak, Stephanie
Li, Lin
Parra, Andres
Denlinger, Bristol
Belmonte, Carlos
McNaughton, Peter A.

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