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

Xuming Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2.

Original languageEnglish
Pages (from-to)3672-3683.e4
JournalCell Reports
Volume27
Issue number12
DOIs
Publication statusPublished - 18 Jun 2019

Fingerprint

Bradykinin Receptors
Bradykinin
Chemical activation
Programmable logic controllers
Crosstalk
Phosphatidylinositols
Inflammation
Pain
Neurons
Arginine
Hydrolysis
Sensory Receptor Cells
Membranes
Electric potential
Inhibition (Psychology)

Bibliographical note

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Funding: MRC grant G0801387.

Keywords

  • bradykinin
  • cold
  • G protein
  • GPCR signaling
  • inflammatory mediator
  • pain
  • PIP
  • protein-protein interaction
  • TRPM8

Cite this

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title = "Direct Gα q Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation",
abstract = "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. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2.",
keywords = "bradykinin, cold, G protein, GPCR signaling, inflammatory mediator, pain, PIP, protein-protein interaction, TRPM8",
author = "Xuming Zhang",
note = "This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Funding: MRC grant G0801387.",
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Direct Gα q Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation. / Zhang, Xuming.

In: Cell Reports, Vol. 27, No. 12, 18.06.2019, p. 3672-3683.e4.

Research output: Contribution to journalArticle

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T1 - Direct Gα q Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation

AU - Zhang, Xuming

N1 - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Funding: MRC grant G0801387.

PY - 2019/6/18

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N2 - 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. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2.

AB - 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. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2.

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