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J Biol Chem. 2014 Sep 26;289(39):27215-34. doi: 10.1074/jbc.M114.599712. Epub 2014 Aug 12.

Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4.

Author information

1
From the Monash Institute of Pharmaceutical Sciences, Parkville 3052, Australia.
2
Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
3
Medivir AB, 141 Huddinge, Sweden.
4
Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario N7L 3N6, Canada.
5
Division of Neurology, Department of Medicine, Duke University, Durham, North Carolina 27710.
6
School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora 3083, Australia.
7
From the Monash Institute of Pharmaceutical Sciences, Parkville 3052, Australia, Department of Pharmacology, University of Melbourne, Melbourne 3010, Australia, and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville 3052, Australia Nigel.Bunnett@Monash.edu.

Erratum in

  • J Biol Chem. 2014 Dec 26;289(52):35858.

Abstract

Serine proteases such as trypsin and mast cell tryptase cleave protease-activated receptor-2 (PAR2) at R(36)↓S(37) and reveal a tethered ligand that excites nociceptors, causing neurogenic inflammation and pain. Whether proteases that cleave PAR2 at distinct sites are biased agonists that also induce inflammation and pain is unexplored. Cathepsin S (Cat-S) is a lysosomal cysteine protease of antigen-presenting cells that is secreted during inflammation and which retains activity at extracellular pH. We observed that Cat-S cleaved PAR2 at E(56)↓T(57), which removed the canonical tethered ligand and prevented trypsin activation. In HEK and KNRK cell lines and in nociceptive neurons of mouse dorsal root ganglia, Cat-S and a decapeptide mimicking the Cat-S-revealed tethered ligand-stimulated PAR2 coupling to Gαs and formation of cAMP. In contrast to trypsin, Cat-S did not mobilize intracellular Ca(2+), activate ERK1/2, recruit β-arrestins, or induce PAR2 endocytosis. Cat-S caused PAR2-dependent activation of transient receptor potential vanilloid 4 (TRPV4) in Xenopus laevis oocytes, HEK cells and nociceptive neurons, and stimulated neuronal hyperexcitability by adenylyl cyclase and protein kinase A-dependent mechanisms. Intraplantar injection of Cat-S caused inflammation and hyperalgesia in mice that was attenuated by PAR2 or TRPV4 deletion and adenylyl cyclase inhibition. Cat-S and PAR2 antagonists suppressed formalin-induced inflammation and pain, which implicates endogenous Cat-S and PAR2 in inflammatory pain. Our results identify Cat-S as a biased agonist of PAR2 that causes PAR2- and TRPV4-dependent inflammation and pain. They expand the role of PAR2 as a mediator of protease-driven inflammatory pain.

KEYWORDS:

G Protein-coupled Receptor (GPCR); Inflammation; Pain; Protease; Protease-activated Receptors; Transient Receptor Potential Channels (TRP Channels)

PMID:
25118282
PMCID:
PMC4175355
DOI:
10.1074/jbc.M114.599712
[Indexed for MEDLINE]
Free PMC Article

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