title: Direct inhibition of the cold-activated TRPM8 ion channel by Gαq.
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.
authors: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. xz213@cam.ac.uk
authors: Xuming
authors: X
authors: Zhang
authors: Stephanie
authors: S
authors: Mak
authors: Lin
authors: L
authors: Li
authors: Andres
authors: A
authors: Parra
authors: Bristol
authors: B
authors: Denlinger
authors: Carlos
authors: C
authors: Belmonte
authors: Peter A
authors: PA
authors: McNaughton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003080:Cold Temperature; D018360:Crystallography, X-Ray; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D043802:GTP-Binding Protein alpha Subunits, Gq-G11