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Direct Gαq gating is the sole mechanism for TRPM8 inhibition caused by Bradykinin receptor activation
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Zhang, Xuming (2019) Direct Gαq gating is the sole mechanism for TRPM8 inhibition caused by Bradykinin receptor activation. Cell Reports, 27 (12). 3672-3683.e4. doi:10.1016/j.celrep.2019.05.080 ISSN 2211-1247.
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Official URL: http://dx.doi.org/10.1016/j.celrep.2019.05.080
Abstract
Activation of Gαq-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Gαq and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP2) inhibit TRPM8. Here, I demonstrate that direct Gαq gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Gαq 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 Gαq 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-Gαq binding impaired Gαq coupling and signaling to PLCβ-PIP2. The crosstalk in the TRPM8-Gαq-B2R complex thus determines Gαq gating rather than PIP2 as a sole means of TRPM8 inhibition by bradykinin.
Item Type: | Journal Article | ||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||
Journal or Publication Title: | Cell Reports | ||||||
Publisher: | Elsevier Inc. | ||||||
ISSN: | 2211-1247 | ||||||
Official Date: | 18 June 2019 | ||||||
Dates: |
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Volume: | 27 | ||||||
Number: | 12 | ||||||
Page Range: | 3672-3683.e4 | ||||||
DOI: | 10.1016/j.celrep.2019.05.080 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 17 May 2022 | ||||||
Date of first compliant Open Access: | 17 May 2022 |
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