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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

From the Monash Institute of Pharmaceutical Sciences, Parkville 3052, Australia.
Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Medivir AB, 141 Huddinge, Sweden.
Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario N7L 3N6, Canada.
Division of Neurology, Department of Medicine, Duke University, Durham, North Carolina 27710.
School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora 3083, Australia.
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

Erratum in

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


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.


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

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