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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
,
Haerteis S
,
Baraznenok V
,
Henderson I
,
Lindström E
,
Guerrero-Alba R
,
Valdez-Morales EE
,
Liedtke W
,
McIntyre P
,
Vanner SJ
,
Korbmacher C
,
Bunnett NW
.
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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.
Amadesi,
Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia.
2004, Pubmed
Amadesi,
Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia.
2004,
Pubmed
Austin,
Matrix metalloproteases and PAR1 activation.
2013,
Pubmed
Ayoub,
Interaction of Protease-Activated Receptor 2 with G Proteins and β-Arrestin 1 Studied by Bioluminescence Resonance Energy Transfer.
2013,
Pubmed
Barclay,
Role of the cysteine protease cathepsin S in neuropathic hyperalgesia.
2007,
Pubmed
Biniossek,
Proteomic identification of protease cleavage sites characterizes prime and non-prime specificity of cysteine cathepsins B, L, and S.
2011,
Pubmed
Bohm,
Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2.
1996,
Pubmed
Böhm,
Mechanisms of desensitization and resensitization of proteinase-activated receptor-2.
1996,
Pubmed
Boire,
PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.
2005,
Pubmed
Camerer,
Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa.
2000,
Pubmed
,
Xenbase
Cattaruzza,
Cathepsin S is activated during colitis and causes visceral hyperalgesia by a PAR2-dependent mechanism in mice.
2011,
Pubmed
Cenac,
Role for protease activity in visceral pain in irritable bowel syndrome.
2007,
Pubmed
Chaplan,
Quantitative assessment of tactile allodynia in the rat paw.
1994,
Pubmed
Choe,
Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities.
2006,
Pubmed
Clark,
The liberation of fractalkine in the dorsal horn requires microglial cathepsin S.
2009,
Pubmed
Clark,
Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor.
2010,
Pubmed
Clark,
Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain.
2007,
Pubmed
Clark,
Microglial signalling mechanisms: Cathepsin S and Fractalkine.
2012,
Pubmed
Corvera,
Mast cell tryptase regulates rat colonic myocytes through proteinase-activated receptor 2.
1997,
Pubmed
Cottrell,
Trypsin IV, a novel agonist of protease-activated receptors 2 and 4.
2004,
Pubmed
Dai,
Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain.
2007,
Pubmed
DeFea,
beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2.
2000,
Pubmed
Denadai-Souza,
Role of transient receptor potential vanilloid 4 in rat joint inflammation.
2012,
Pubmed
Déry,
Trafficking of proteinase-activated receptor-2 and beta-arrestin-1 tagged with green fluorescent protein. beta-Arrestin-dependent endocytosis of a proteinase receptor.
1999,
Pubmed
Dulon,
Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases.
2003,
Pubmed
Dulon,
Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells.
2005,
Pubmed
Elmariah,
Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist.
2014,
Pubmed
Fan,
Activation of the TRPV4 ion channel is enhanced by phosphorylation.
2009,
Pubmed
Fichna,
Transient receptor potential vanilloid 4 blockade protects against experimental colitis in mice: a new strategy for inflammatory bowel diseases treatment?
2012,
Pubmed
Galés,
Real-time monitoring of receptor and G-protein interactions in living cells.
2005,
Pubmed
Grant,
Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice.
2007,
Pubmed
Haerteis,
Proteolytic activation of the epithelial sodium channel (ENaC) by the cysteine protease cathepsin-S.
2012,
Pubmed
,
Xenbase
Hansen,
A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis.
2005,
Pubmed
Jensen,
The bile acid receptor TGR5 does not interact with β-arrestins or traffic to endosomes but transmits sustained signals from plasma membrane rafts.
2013,
Pubmed
Kenakin,
Signalling bias in new drug discovery: detection, quantification and therapeutic impact.
2013,
Pubmed
Knecht,
Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia.
2007,
Pubmed
Kocan,
Enhanced BRET Technology for the Monitoring of Agonist-Induced and Agonist-Independent Interactions between GPCRs and β-Arrestins.
2010,
Pubmed
Lerner,
Agonist recognition by proteinase-activated receptor 2 and thrombin receptor. Importance of extracellular loop interactions for receptor function.
1996,
Pubmed
Liedtke,
Abnormal osmotic regulation in trpv4-/- mice.
2003,
Pubmed
Lindner,
Delayed onset of inflammation in protease-activated receptor-2-deficient mice.
2000,
Pubmed
Liuzzo,
Inflammatory mediators regulate cathepsin S in macrophages and microglia: A role in attenuating heparan sulfate interactions.
1999,
Pubmed
Lohman,
An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats.
2012,
Pubmed
McGuire,
2-furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist.
2004,
Pubmed
Mihara,
Neutrophil elastase and proteinase-3 trigger G protein-biased signaling through proteinase-activated receptor-1 (PAR1).
2013,
Pubmed
Mize,
Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2.
2008,
Pubmed
Molino,
Interactions of mast cell tryptase with thrombin receptors and PAR-2.
1997,
Pubmed
Mosnier,
Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46.
2012,
Pubmed
Nystedt,
Molecular cloning of a potential proteinase activated receptor.
1994,
Pubmed
,
Xenbase
Oikonomopoulou,
Proteinase-activated receptors, targets for kallikrein signaling.
2006,
Pubmed
Ossovskaya,
Protease-activated receptors: contribution to physiology and disease.
2004,
Pubmed
Poole,
Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.
2013,
Pubmed
Pozgan,
Expression and activity profiling of selected cysteine cathepsins and matrix metalloproteinases in synovial fluids from patients with rheumatoid arthritis and osteoarthritis.
2010,
Pubmed
Ramachandran,
Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2).
2011,
Pubmed
Ramsay,
Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs).
2008,
Pubmed
Ramsay,
Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression.
2008,
Pubmed
Schuepbach,
Protease-activated receptor-1 cleaved at R46 mediates cytoprotective effects.
2012,
Pubmed
Sipe,
Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia.
2008,
Pubmed
Smith,
Evidence for the activation of PAR-2 by the sperm protease, acrosin: expression of the receptor on oocytes.
2000,
Pubmed
Steinhoff,
Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase.
1999,
Pubmed
Steinhoff,
Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.
2000,
Pubmed
Suen,
Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110).
2012,
Pubmed
Takeuchi,
Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates.
2000,
Pubmed
,
Xenbase
Trivedi,
Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site.
2009,
Pubmed
Vergnolle,
Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway.
2001,
Pubmed
Vergnolle,
A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation.
2010,
Pubmed
Wilson,
The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells.
2005,
Pubmed
