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Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.

Publication ,  Journal Article
Poole, DP; Amadesi, S; Veldhuis, NA; Abogadie, FC; Lieu, T; Darby, W; Liedtke, W; Lew, MJ; McIntyre, P; Bunnett, NW
Published in: J Biol Chem
February 22, 2013

G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR(2)), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain. We investigated the signaling mechanisms by which PAR(2) regulates TRPV4 and determined the importance of tyrosine phosphorylation in this process. Human TRPV4 was expressed in HEK293 cells under control of a tetracycline-inducible promoter, allowing controlled and graded channel expression. In cells lacking TRPV4, the PAR(2) agonist stimulated a transient increase in [Ca(2+)](i). TRPV4 expression led to a markedly sustained increase in [Ca(2+)](i). Removal of extracellular Ca(2+) and treatment with the TRPV4 antagonists Ruthenium Red or HC067047 prevented the sustained response. Inhibitors of phospholipase A(2) and cytochrome P450 epoxygenase attenuated the sustained response, suggesting that PAR(2) generates arachidonic acid-derived lipid mediators, such as 5',6'-EET, that activate TRPV4. Src inhibitor 1 suppressed PAR(2)-induced activation of TRPV4, indicating the importance of tyrosine phosphorylation. The TRPV4 tyrosine mutants Y110F, Y805F, and Y110F/Y805F were expressed normally at the cell surface. However, PAR(2) was unable to activate TRPV4 with the Y110F mutation. TRPV4 antagonism suppressed PAR(2) signaling to primary nociceptive neurons, and TRPV4 deletion attenuated PAR(2)-stimulated neurogenic inflammation. Thus, PAR(2) activation generates a signal that induces sustained activation of TRPV4, which requires a key tyrosine residue (TRPV4-Tyr-110). This mechanism partly mediates the proinflammatory actions of PAR(2).

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 22, 2013

Volume

288

Issue

8

Start / End Page

5790 / 5802

Location

United States

Related Subject Headings

  • Tyrosine
  • TRPV Cation Channels
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Receptor, PAR-2
  • Rats, Sprague-Dawley
  • Rats
  • Phosphorylation
  • Phospholipase A2 Inhibitors
  • Pain
 

Citation

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Poole, D. P., Amadesi, S., Veldhuis, N. A., Abogadie, F. C., Lieu, T., Darby, W., … Bunnett, N. W. (2013). Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling. J Biol Chem, 288(8), 5790–5802. https://doi.org/10.1074/jbc.M112.438184
Poole, Daniel P., Silvia Amadesi, Nicholas A. Veldhuis, Fe C. Abogadie, TinaMarie Lieu, William Darby, Wolfgang Liedtke, Michael J. Lew, Peter McIntyre, and Nigel W. Bunnett. “Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.J Biol Chem 288, no. 8 (February 22, 2013): 5790–5802. https://doi.org/10.1074/jbc.M112.438184.
Poole DP, Amadesi S, Veldhuis NA, Abogadie FC, Lieu T, Darby W, et al. Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling. J Biol Chem. 2013 Feb 22;288(8):5790–802.
Poole, Daniel P., et al. “Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.J Biol Chem, vol. 288, no. 8, Feb. 2013, pp. 5790–802. Pubmed, doi:10.1074/jbc.M112.438184.
Poole DP, Amadesi S, Veldhuis NA, Abogadie FC, Lieu T, Darby W, Liedtke W, Lew MJ, McIntyre P, Bunnett NW. Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling. J Biol Chem. 2013 Feb 22;288(8):5790–5802.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 22, 2013

Volume

288

Issue

8

Start / End Page

5790 / 5802

Location

United States

Related Subject Headings

  • Tyrosine
  • TRPV Cation Channels
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Receptor, PAR-2
  • Rats, Sprague-Dawley
  • Rats
  • Phosphorylation
  • Phospholipase A2 Inhibitors
  • Pain