Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV4

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

Authors: Peishen Zhao, Tinamarie Lieu, Nicholas Barlow, Matthew Metcalf, Nicholas A Veldhuis, Dane D Jensen, Martina Kocan, Silvia Sostegni, Silke Haerteis, Vera Baraznenok, Ian Henderson, Erik Lindström, Raquel Guerrero-Alba, Eduardo E Valdez-Morales, Wolfgang Liedtke, Peter McIntyre, Stephen J Vanner, Christoph Korbmacher, Nigel W Bunnett

Journal, date & volume: J. Biol. Chem., 2014 Sep 26 , 289, 27215-34

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25118282

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.