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Direct G?q Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation.

ABSTRACT: Activation of G?q-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both G?q and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2) inhibit TRPM8. Here, I demonstrate that direct G?q gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of G?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 G?q and bradykinin while sparing the channel sensitivity to PIP2. Interestingly, the bradykinin receptor B2R also binds to TRPM8, rendering TRPM8 insensitive to PIP2 depletion. Furthermore, TRPM8-G?q binding impaired G?q coupling and signaling to PLC?-PIP2. The crosstalk in the TRPM8-G?q-B2R complex thus determines G?q gating rather than PIP2 as a sole means of TRPM8 inhibition by bradykinin.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC6595177 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Direct Gα<sub>q</sub> Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation.

Zhang Xuming X  

Cell reports 20190601 12

Activation of Gα<sub>q</sub>-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Gα<sub>q</sub> and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP<sub>2</sub>) inhibit TRPM8. Here, I demonstrate that direct Gα<sub>q</sub> gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Gα<sub>q</sub> depends on binding to th  ...[more]

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