| First Author | Zhang X | Year | 2019 |
| Journal | Cell Rep | Volume | 27 |
| Issue | 12 | Pages | 3672-3683.e4 |
| PubMed ID | 31216483 | Mgi Jnum | J:288529 |
| Mgi Id | MGI:6432146 | Doi | 10.1016/j.celrep.2019.05.080 |
| Citation | Zhang X (2019) Direct Galphaq Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation. Cell Rep 27(12):3672-3683.e4 |
| abstractText | Activation of Galphaq-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Galphaq and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2) inhibit TRPM8. Here, I demonstrate that direct Galphaq gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Galphaq 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 Galphaq 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-Galphaq binding impaired Galphaq coupling and signaling to PLCbeta-PIP2. The crosstalk in the TRPM8-Galphaq-B2R complex thus determines Galphaq gating rather than PIP2 as a sole means of TRPM8 inhibition by bradykinin. |
