Cathepsin S Causes Inflammatory Pain via Biased Agonism of PAR2 and TRPV4

摘要: Serine proteases such as trypsin and mast cell tryptase cleave protease-activated receptor-2 (PAR2) at R36↓S37 reveal a tethered ligand that excites nociceptors, causing neurogenic inflammation pain. Whether PAR2 distinct sites are biased agonists also induce pain is unexplored. Cathepsin S (Cat-S) lysosomal cysteine protease of antigen-presenting cells secreted during which retains activity extracellular pH. We observed Cat-S cleaved E56↓T57, removed the canonical prevented activation. In HEK KNRK lines in nociceptive neurons mouse dorsal root ganglia, decapeptide mimicking Cat-S-revealed ligand-stimulated coupling to Gαs formation cAMP. contrast trypsin, did not mobilize intracellular Ca2+, activate ERK1/2, recruit β-arrestins, or endocytosis. caused PAR2-dependent activation transient receptor potential vanilloid 4 (TRPV4) Xenopus laevis oocytes, neurons, stimulated neuronal hyperexcitability by adenylyl cyclase protein kinase A-dependent mechanisms. Intraplantar injection hyperalgesia mice was attenuated TRPV4 deletion inhibition. antagonists suppressed formalin-induced pain, implicates endogenous inflammatory Our results identify agonist causes PAR2- TRPV4-dependent They expand role mediator protease-driven