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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.JB

Abstract

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.

Authors+Show Affiliations

From the Monash Institute of Pharmaceutical Sciences and.From the Monash Institute of Pharmaceutical Sciences and.From the Monash Institute of Pharmaceutical Sciences and.the Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.the Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.the Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany.the Department of Neurology, School of Medicine, Duke University, Durham, North Carolina 27710.the Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario N7L 3N6, Canada, and.the Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario N7L 3N6, Canada, and.From the Monash Institute of Pharmaceutical Sciences and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville 3052, Australia, the Department of Pharmacology, University of Melbourne, Melbourne 3010, Australia Nigel.Bunnett@Monash.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25878251

Citation

Zhao, Peishen, et al. "Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain." The Journal of Biological Chemistry, vol. 290, no. 22, 2015, pp. 13875-87.
Zhao P, Lieu T, Barlow N, 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;290(22):13875-87.
Zhao, P., Lieu, T., Barlow, N., Sostegni, S., Haerteis, S., Korbmacher, C., Liedtke, W., Jimenez-Vargas, N. N., Vanner, S. J., & Bunnett, N. W. (2015). Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. The Journal of Biological Chemistry, 290(22), 13875-87. https://doi.org/10.1074/jbc.M115.642736
Zhao P, 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. PubMed PMID: 25878251.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. AU - Zhao,Peishen, AU - Lieu,TinaMarie, AU - Barlow,Nicholas, AU - Sostegni,Silvia, AU - Haerteis,Silke, AU - Korbmacher,Christoph, AU - Liedtke,Wolfgang, AU - Jimenez-Vargas,Nestor N, AU - Vanner,Stephen J, AU - Bunnett,Nigel W, Y1 - 2015/04/15/ PY - 2015/02/02/received PY - 2015/4/17/entrez PY - 2015/4/17/pubmed PY - 2015/8/19/medline KW - G protein-coupled receptor (GPCR) KW - biased agonism KW - cell signaling KW - inflammation KW - nociception KW - protease KW - protease-activated receptor KW - transient receptor potential channels (TRP channels) SP - 13875 EP - 87 JF - The Journal of biological chemistry JO - J Biol Chem VL - 290 IS - 22 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/25878251/Neutrophil_Elastase_Activates_Protease_activated_Receptor_2__PAR2__and_Transient_Receptor_Potential_Vanilloid_4__TRPV4__to_Cause_Inflammation_and_Pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(18)80897-3 DB - PRIME DP - Unbound Medicine ER -