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

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 essentia...

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Detalles Bibliográficos
Autor principal: Zhang, Xuming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595177/
https://www.ncbi.nlm.nih.gov/pubmed/31216483
http://dx.doi.org/10.1016/j.celrep.2019.05.080
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author Zhang, Xuming
author_facet Zhang, Xuming
author_sort Zhang, Xuming
collection PubMed
description 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.
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spelling pubmed-65951772019-07-11 Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation Zhang, Xuming Cell Rep Article 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. Cell Press 2019-06-18 /pmc/articles/PMC6595177/ /pubmed/31216483 http://dx.doi.org/10.1016/j.celrep.2019.05.080 Text en Crown Copyright © 2019 Published by Elsevier Inc. All rights reserved. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Xuming
Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
title Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
title_full Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
title_fullStr Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
title_full_unstemmed Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
title_short Direct Gα(q) Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
title_sort direct gα(q) gating is the sole mechanism for trpm8 inhibition caused by bradykinin receptor activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595177/
https://www.ncbi.nlm.nih.gov/pubmed/31216483
http://dx.doi.org/10.1016/j.celrep.2019.05.080
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