Direct Gα q Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation

Abstract

Activation of Gα q-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Gα q and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP 2) inhibit TRPM8. Here, I demonstrate that direct Gα q gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Gα q depends on binding to three arginine residues in the N terminus of TRPM8. Neutralization of these residues markedly increased sensitivity of the channel to agonist and membrane voltage and completely abolished TRPM8 inhibition by both Gα q and bradykinin while sparing the channel sensitivity to PIP 2. Interestingly, the bradykinin receptor B2R also binds to TRPM8, rendering TRPM8 insensitive to PIP 2 depletion. Furthermore, TRPM8-Gα q binding impaired Gα q coupling and signaling to PLCβ-PIP 2. The crosstalk in the TRPM8-Gα q-B2R complex thus determines Gα q gating rather than PIP 2 as a sole means of TRPM8 inhibition by bradykinin. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2.

Publication DOI: https://doi.org/10.1016/j.celrep.2019.05.080
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
Funding Information: I would like to thank Dr. Dan Rathbone for assistance with protein structure modeling and Dr. Gerry Hammond for help with live imaging and analysis. This work was supported by an MRC grant ( G0801387 ) and intramural funding from Aston University . Origin
Additional Information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Funding: MRC grant G0801387.
Uncontrolled Keywords: bradykinin,cold,G protein,GPCR signaling,inflammatory mediator,pain,PIP,protein-protein interaction,TRPM8,Biochemistry, Genetics and Molecular Biology(all)
Publication ISSN: 2211-1247
Last Modified: 22 Feb 2024 08:11
Date Deposited: 20 Jun 2019 10:50
Full Text Link:
Related URLs: https://www.sci ... 7193?via%3Dihub (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2019-06-18
Accepted Date: 2019-05-21
Authors: Zhang, Xuming (ORCID Profile 0000-0002-5331-8675)

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