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Direct inhibition of the cold-activated TRPM8 ion channel by Gαq
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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. doi:10.1038/ncb2529 ISSN 1465-7392.
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Official URL: http://dx.doi.org/10.1038/ncb2529
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 Gαq instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Gαq largely abolished inhibition of TRPM8, and inhibition was rescued by a Gαq chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated Gαq protein, but not Gβγ, potently inhibits TRPM8 in excised patches. We conclude that Gαq 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.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Nature Cell Biology | ||||
Publisher: | Nature Publishing Group | ||||
ISSN: | 1465-7392 | ||||
Official Date: | August 2012 | ||||
Dates: |
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Volume: | 14 | ||||
Number: | 8 | ||||
Page Range: | pp. 851-858 | ||||
DOI: | 10.1038/ncb2529 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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