Direct inhibition of the cold-Activated TRPM8 ion channel by Gα q
| Autor: | Bristol Denlinger, Xuming Zhang, Lin Li, Andres Parra, Carlos Belmonte, Peter A. McNaughton, Stephanie W.Y. Mak |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular TRPM8 sensory transduction G protein inflammatory mediators TRPV1 TRPM Cation Channels Crystallography X-Ray Article Mice 03 medical and health sciences GPCR 0302 clinical medicine Animals Humans pain Receptor Cells Cultured Ion channel 030304 developmental biology Neurons 0303 health sciences biology Phospholipase C Cell Biology Cell biology Cold Temperature Mice Inbred C57BL Gq alpha subunit biology.protein GTP-Binding Protein alpha Subunits Gq-G11 Signal transduction 030217 neurology & neurosurgery Protein Binding Signal Transduction G proteins |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Nature cell biology |
| ISSN: | 1476-4679 |
| Popis: | 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 GÎ 2Î 3, 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. © 2012 Macmillan Publishers Limited. All rights reserved. This work was supported by an MRC new investigator research grant (G0801387 to X.Z.), a BBSRC research grant (BB/F003072/1 to P.A.M.) and a grant from the Fundacion BBVA (to P.A.M., to support a BBVA visiting professorship at the Instituto de Neurociencias, Alicante, Spain). |
| Databáze: | OpenAIRE |
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