Nat Cell Biol. 2012 Aug;14(8):851-8. doi: 10.1038/ncb2529. Epub 2012 Jul 1.

Direct inhibition of the cold-activated TRPM8 ion channel by Galphaq.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Zhang, X., Mak, S., Li, L., Parra, A., Denlinger, B., Belmonte, C., McNaughton, P. A.,
["Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. xz213@cam.ac.uk"]
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 Galpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Galpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a Galpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated Galpha(q) protein, but not Gbetagamma, potently inhibits TRPM8 in excised patches. We conclude that Galpha(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.
PMID: 22750945External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Validation: In vitro validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with recombinant proteins Reference
TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Expression system Species Region Expression system
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Fusion protein-pull down assay Human Full-length HEK293 lysates Human Full-length HEK293 lysates 22750945
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Fusion protein-pull down assay Human Full-length E. coli Human Full-length HEK293 lysates 22750945
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Co-immunoprecipitation Mouse dorsal root ganglion cell 22750945
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Characterization Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Binding region mapping Stoichiometry Affinity (Kd) Reference
TRP channel Interactor
TRP channel Interactor Method Species Region Species Region
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Fusion protein-pull down assay Human 1-691 Human Not determined 22750945
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Fusion protein-pull down assay Human 980-1104 Human Not determined 22750945
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Fusion protein-pull down assay Human Not determined Human 222-245 22750945
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Functional consequence Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
TRP channel Interactor Method Post-translational modification Subcellular trafficking Activity Reference
TRPM8 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Gơq Patch clamp Inhibition 22750945
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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