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Zhao P
,
Lieu T
,
Barlow N
,
Sostegni S
,
Haerteis S
,
Korbmacher C
,
Liedtke W
,
Jimenez-Vargas NN
,
Vanner SJ
,
Bunnett NW
.
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Proteases that cleave protease-activated receptor-2 (PAR(2)) at Arg(36)↓Ser(37) reveal a tethered ligand that binds to the cleaved receptor. PAR(2) activates transient receptor potential (TRP) channels of nociceptive neurons to induce neurogenic inflammation and pain. Although proteases that cleave PAR(2) at non-canonical sites can trigger distinct signaling cascades, the functional importance of the PAR(2)-biased agonism is uncertain. We investigated whether neutrophil elastase, a biased agonist of PAR(2), causes inflammation and pain by activating PAR2 and TRP vanilloid 4 (TRPV4). Elastase cleaved human PAR(2) at Ala(66)↓Ser(67) and Ser(67)↓Val(68). Elastase stimulated PAR(2)-dependent cAMP accumulation and ERK1/2 activation, but not Ca(2+) mobilization, in KNRK cells. Elastase induced PAR(2) coupling to Gαs but not Gαq in HEK293 cells. Although elastase did not promote recruitment of G protein-coupled receptor kinase-2 (GRK(2)) or β-arrestin to PAR(2), consistent with its inability to promote receptor endocytosis, elastase did stimulate GRK6 recruitment. Elastase caused PAR(2)-dependent sensitization of TRPV4 currents in Xenopus laevis oocytes by adenylyl cyclase- and protein kinase A (PKA)-dependent mechanisms. Elastase stimulated PAR(2)-dependent cAMP formation and ERK1/2 phosphorylation, and a PAR(2)- and TRPV4-mediated influx of extracellular Ca(2+) in mouse nociceptors. Adenylyl cyclase and PKA-mediated elastase-induced activation of TRPV4 and hyperexcitability of nociceptors. Intraplantar injection of elastase to mice caused edema and mechanical hyperalgesia by PAR(2)- and TRPV4-mediated mechanisms. Thus, the elastase-biased agonism of PAR(2) causes Gαs-dependent activation of adenylyl cyclase and PKA, which activates TRPV4 and sensitizes nociceptors to cause inflammation and pain. Our results identify a novel mechanism of elastase-induced activation of TRPV4 and expand the role of PAR(2) as a mediator of protease-driven inflammation and pain.
Amadesi,
Protease-activated receptors: protease signaling in the gastrointestinal tract.
2004, Pubmed
Amadesi,
Protease-activated receptors: protease signaling in the gastrointestinal tract.
2004,
Pubmed
Amadesi,
Protein kinase D isoforms are expressed in rat and mouse primary sensory neurons and are activated by agonists of protease-activated receptor 2.
2009,
Pubmed
Amadesi,
Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia.
2004,
Pubmed
Ayoub,
Interaction of Protease-Activated Receptor 2 with G Proteins and β-Arrestin 1 Studied by Bioluminescence Resonance Energy Transfer.
2013,
Pubmed
Bledsoe,
Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury.
2008,
Pubmed
Böhm,
Mechanisms of desensitization and resensitization of proteinase-activated receptor-2.
1996,
Pubmed
Caldwell,
Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport.
2005,
Pubmed
Camerer,
Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa.
2000,
Pubmed
,
Xenbase
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
Diakov,
Cleavage in the {gamma}-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels.
2008,
Pubmed
,
Xenbase
Dulon,
Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells.
2005,
Pubmed
Dulon,
Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases.
2003,
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
Eijkelkamp,
G protein-coupled receptor kinase 6 controls post-inflammatory visceral hyperalgesia.
2009,
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
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
Gurevich,
G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.
2012,
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
Henriksen,
The potential of neutrophil elastase inhibitors as anti-inflammatory therapies.
2014,
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
Kayssi,
Mechanisms of protease-activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon.
2007,
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
Li,
TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles.
2011,
Pubmed
Liedtke,
Abnormal osmotic regulation in trpv4-/- mice.
2003,
Pubmed
Lindner,
Delayed onset of inflammation in protease-activated receptor-2-deficient mice.
2000,
Pubmed
Loew,
Proteolysis of the exodomain of recombinant protease-activated receptors: prediction of receptor activation or inactivation by MALDI mass spectrometry.
2000,
Pubmed
Macfarlane,
Proteinase-activated receptors.
2001,
Pubmed
Mihara,
Neutrophil elastase and proteinase-3 trigger G protein-biased signaling through proteinase-activated receptor-1 (PAR1).
2013,
Pubmed
Molino,
Interactions of mast cell tryptase with thrombin receptors and PAR-2.
1997,
Pubmed
Moore,
Regulation of receptor trafficking by GRKs and arrestins.
2007,
Pubmed
Nystedt,
Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2.
1995,
Pubmed
Oikonomopoulou,
Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs).
2006,
Pubmed
Ossovskaya,
Protease-activated receptors: contribution to physiology and disease.
2004,
Pubmed
Pitcher,
G protein-coupled receptor kinases.
1998,
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
Prior,
Direct visualization of Ras proteins in spatially distinct cell surface microdomains.
2003,
Pubmed
Ramachandran,
Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2).
2011,
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
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
Rauh,
A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition.
2010,
Pubmed
,
Xenbase
Reed,
Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons.
2003,
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
Sostegni,
Sensitisation of TRPV4 by PAR2 is independent of intracellular calcium signalling and can be mediated by the biased agonist neutrophil elastase.
2015,
Pubmed
,
Xenbase
Steinhoff,
Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.
2000,
Pubmed
Stoffel,
Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family.
1994,
Pubmed
Sun,
Expression of G-protein-coupled receptor kinase 6 (GRK6) after acute spinal cord injury in adult rat.
2013,
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
Vergnolle,
A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation.
2010,
Pubmed
Vergnolle,
Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway.
2001,
Pubmed
Vergnolle,
Protease-activated receptors as drug targets in inflammation and pain.
2009,
Pubmed
Watanabe,
Modulation of TRPV4 gating by intra- and extracellular Ca2+.
2003,
Pubmed
Willoughby,
Organization of cAMP signalling microdomains for optimal regulation by Ca2+ entry.
2012,
Pubmed
Wilson,
The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells.
2005,
Pubmed
Zhao,
Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4.
2014,
Pubmed
,
Xenbase
Zhou,
Decreased expression and role of GRK6 in spinal cord of rats after chronic constriction injury.
2013,
Pubmed
de Garavilla,
Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism.
2001,
Pubmed
