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Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain.

Publication ,  Journal Article
Zhao, P; Lieu, T; Barlow, N; Sostegni, S; Haerteis, S; Korbmacher, C; Liedtke, W; Jimenez-Vargas, NN; Vanner, SJ; Bunnett, NW
Published in: J Biol Chem
May 29, 2015

Proteases that cleave protease-activated receptor-2 (PAR(2)) at Arg(36)↓Ser(37) reveal a tethered ligand that binds to the cleaved receptor. PAR(2) activates transient receptor potential (TRP) channels of nociceptive neurons to induce neurogenic inflammation and pain. Although proteases that cleave PAR(2) at non-canonical sites can trigger distinct signaling cascades, the functional importance of the PAR(2)-biased agonism is uncertain. We investigated whether neutrophil elastase, a biased agonist of PAR(2), causes inflammation and pain by activating PAR2 and TRP vanilloid 4 (TRPV4). Elastase cleaved human PAR(2) at Ala(66)↓Ser(67) and Ser(67)↓Val(68). Elastase stimulated PAR(2)-dependent cAMP accumulation and ERK1/2 activation, but not Ca(2+) mobilization, in KNRK cells. Elastase induced PAR(2) coupling to Gαs but not Gαq in HEK293 cells. Although elastase did not promote recruitment of G protein-coupled receptor kinase-2 (GRK(2)) or β-arrestin to PAR(2), consistent with its inability to promote receptor endocytosis, elastase did stimulate GRK6 recruitment. Elastase caused PAR(2)-dependent sensitization of TRPV4 currents in Xenopus laevis oocytes by adenylyl cyclase- and protein kinase A (PKA)-dependent mechanisms. Elastase stimulated PAR(2)-dependent cAMP formation and ERK1/2 phosphorylation, and a PAR(2)- and TRPV4-mediated influx of extracellular Ca(2+) in mouse nociceptors. Adenylyl cyclase and PKA-mediated elastase-induced activation of TRPV4 and hyperexcitability of nociceptors. Intraplantar injection of elastase to mice caused edema and mechanical hyperalgesia by PAR(2)- and TRPV4-mediated mechanisms. Thus, the elastase-biased agonism of PAR(2) causes Gαs-dependent activation of adenylyl cyclase and PKA, which activates TRPV4 and sensitizes nociceptors to cause inflammation and pain. Our results identify a novel mechanism of elastase-induced activation of TRPV4 and expand the role of PAR(2) as a mediator of protease-driven inflammation and pain.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 29, 2015

Volume

290

Issue

22

Start / End Page

13875 / 13887

Location

United States

Related Subject Headings

  • Xenopus laevis
  • TRPV Cation Channels
  • Signal Transduction
  • Receptor, PAR-2
  • Protein Structure, Tertiary
  • Peptide Hydrolases
  • Patch-Clamp Techniques
  • Pain
  • Oocytes
  • Nociception
 

Citation

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Zhao, P., Lieu, T., Barlow, N., Sostegni, S., Haerteis, S., Korbmacher, C., … Bunnett, N. W. (2015). Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. J Biol Chem, 290(22), 13875–13887. https://doi.org/10.1074/jbc.M115.642736
Zhao, Peishen, TinaMarie Lieu, Nicholas Barlow, Silvia Sostegni, Silke Haerteis, Christoph Korbmacher, Wolfgang Liedtke, Nestor N. Jimenez-Vargas, Stephen J. Vanner, and Nigel W. Bunnett. “Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain.J Biol Chem 290, no. 22 (May 29, 2015): 13875–87. https://doi.org/10.1074/jbc.M115.642736.
Zhao P, Lieu T, Barlow N, Sostegni S, Haerteis S, Korbmacher C, et al. Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. J Biol Chem. 2015 May 29;290(22):13875–87.
Zhao, Peishen, et al. “Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain.J Biol Chem, vol. 290, no. 22, May 2015, pp. 13875–87. Pubmed, doi:10.1074/jbc.M115.642736.
Zhao P, Lieu T, Barlow N, Sostegni S, Haerteis S, Korbmacher C, Liedtke W, Jimenez-Vargas NN, Vanner SJ, Bunnett NW. Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. J Biol Chem. 2015 May 29;290(22):13875–13887.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 29, 2015

Volume

290

Issue

22

Start / End Page

13875 / 13887

Location

United States

Related Subject Headings

  • Xenopus laevis
  • TRPV Cation Channels
  • Signal Transduction
  • Receptor, PAR-2
  • Protein Structure, Tertiary
  • Peptide Hydrolases
  • Patch-Clamp Techniques
  • Pain
  • Oocytes
  • Nociception