Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4
Zhao P, Lieu T, Barlow N, Metcalf M, Veldhuis NA, Jensen DD, Kocan M, Sostegni S, Härteis S, Baraznenok V, Henderson I, Lindstrom E, Guerrero-Alba R, Valdez-Morales EE, Liedtke W, Mcintyre P, Vanner SJ, Korbmacher C, Bunnett NW (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Publisher: American Society for Biochemistry and Molecular Biology
Book Volume: 289
Pages Range: 27215-34
Journal Issue: 39
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 G?s and formation of cAMP. In contrast to trypsin, Cat-S did not mobilize intracellular Ca(2+), activate ERK1/2, recruit ?-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.
Authors with CRIS profile
Silvia Sostegni
Lehrstuhl für Physiologie (Vegetative Physiologie)
Silke Härteis
Lehrstuhl für Physiologie (Vegetative Physiologie)
Christoph Korbmacher
Lehrstuhl für Physiologie (Vegetative Physiologie)
Involved external institutions
Monash University
Australia (AU)
Medivir AB
Sweden (SE)
Duke University
United States (USA) (US)
Royal Melbourne Institute of Technology (RMIT)
Australia (AU)
Australia (AU)
Medivir AB
Sweden (SE)
Duke University
United States (USA) (US)
Royal Melbourne Institute of Technology (RMIT)
Australia (AU)
How to cite
APA:
Zhao, P., Lieu, T., Barlow, N., Metcalf, M., Veldhuis, N.A., Jensen, D.D.,... Bunnett, N.W. (2014). Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4. Journal of Biological Chemistry, 289(39), 27215-34. https://doi.org/10.1074/jbc.M114.599712
MLA:
Zhao, Peishen, et al. "Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4." Journal of Biological Chemistry 289.39 (2014): 27215-34.
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