Editors' ChoiceCell Biology

A G Protein Blocks the Chilling Effect

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Science Signaling  04 Sep 2012:
Vol. 5, Issue 240, pp. ec229
DOI: 10.1126/scisignal.2003561

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is stimulated by cold temperatures and, when activated by the ligand menthol, has an analgesic effect. TRPM8 activity in membrane patches is increased in the presence of the membrane lipid PIP2 and is decreased when PIP2 is removed. Given that G protein–coupled receptors (GPCRs) that couple to Gαq, such as the bradykinin (BK) receptor, stimulate phospholipase C (PLC) activity, which hydrolyzes PIP2, it is thought that these receptors inhibit TRPM8 activity. Zhang et al. found that decreasing temperature stimulated TRPM8-dependent nerve impulses in cold-sensitive fibers in mouse corneas but that these responses were inhibited in the presence of a cocktail of inflammatory mediators, including BK and histamine. BK also inhibited menthol-dependent, TRPM8-mediated calcium responses in cultured dorsal root ganglion (DRG) neurons. The inhibitory effects of BK on TRPM8 activity were not blocked by inhibitors of downstream effectors of the BK receptor, including protein kinase C and PLC. In transfected human embryonic kidney–293 cells, overexpression of a constitutively active form of Gαq substantially inhibited TRPM8 currents in response to menthol, and this effect was not blocked by a PLC inhibitor. Coimmunoprecipitation studies showed that Gαq physically interacted with TRPM8 in transfected cells and in DRG neurons in the absence of GPCR ligand. Application of purified Gαq protein to excised membrane patches containing TRPM8 inhibited activity of the channel. Addition of a G protein activator to inside-out membrane patches reduced TRPM8 activity; however, this effect was not observed in experiments with membrane patches from cells deficient in endogenous Gαq. Together, these data provide evidence for a previously uncharacterized mechanism of ion channel modulation, whereby Gαq physically associates with TRPM8 and responds to inflammatory GPCR ligands by inhibiting channel activity.

X. Zhang, S. Mak, L. Li, A. Parra, B. Denlinger, C. Belmonte, P. A. McNaughton, Direct inhibition of the cold-activated TRPM8 ion channel by Gαq. Nat. Cell Biol. 14, 850–858 (2012). [PubMed]

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