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Papers of the Week

Papers: 15 Jun 2019 - 21 Jun 2019

Animal Studies

2019 Jun 18

Cell Rep



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


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