Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the F2RL1gene. PAR2 modulates inflammatory responses, obesity, metabolism, and acts as a sensor for proteolytic enzymes generated during infection.
PAR2 is a member of the large family of 7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins. PAR2 is also a member of the protease-activated receptor family. It is activated by trypsin, but not by thrombin. It is activated by proteolytic cleavage of its extracellular amino terminus. The new amino terminus functions as a tethered ligand and activates the receptor. Additionally, these receptors can be activated by exogenous proteases, such as house dust mite protein Der P9. These receptors can also be activated non-protealytically, by exogenous peptide sequences that mimic the final amino acids of the tethered ligand.
Functional selectivity occurs with PAR2, several proteases cleave PAR2 at distinct sites leading to biased signalling. Synthetic small ligands also modulate biased signalling leading to different functional responses.
So far, PAR2 has been co-crystallized with two different antagonist ligands, while an agonist-bound state model of PAR2 (with the endogenous ligand SLIGKV) has been determined through mutagenesis and structure-based drug design.
^Sun G, Stacey MA, Schmidt M, Mori L, Mattoli S (July 2001). "Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells". Journal of Immunology. 167 (2): 1014–21. doi:10.4049/jimmunol.167.2.1014. PMID11441110.
^Gardell LR, Ma JN, Seitzberg JG, Knapp AE, Schiffer HH, Tabatabaei A, Davis CN, Owens M, Clemons B, Wong KK, Lund B, Nash NR, Gao Y, Lameh J, Schmelzer K, Olsson R, Burstein ES (December 2008). "Identification and characterization of novel small-molecule protease-activated receptor 2 agonists". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 799–808. doi:10.1124/jpet.108.142570. PMID18768780.
^Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP (October 2010). "Novel agonists and antagonists for human protease activated receptor 2". Journal of Medicinal Chemistry. 53 (20): 7428–40. doi:10.1021/jm100984y. PMID20873792.
Kawabata A (July 2002). "PAR-2: structure, function and relevance to human diseases of the gastric mucosa". Expert Reviews in Molecular Medicine. 4 (16): 1–17. doi:10.1017/S1462399402004799. PMID14585156.
Nystedt S, Emilsson K, Larsson AK, Strömbeck B, Sundelin J (August 1995). "Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2". European Journal of Biochemistry. 232 (1): 84–9. doi:10.1111/j.1432-1033.1995.tb20784.x. PMID7556175.
Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie JA, Schechter N, Woolkalis M, Brass LF (February 1997). "Interactions of mast cell tryptase with thrombin receptors and PAR-2". The Journal of Biological Chemistry. 272 (7): 4043–9. doi:10.1074/jbc.272.7.4043. PMID9020112.
Howells GL, Macey MG, Chinni C, Hou L, Fox MT, Harriott P, Stone SR (April 1997). "Proteinase-activated receptor-2: expression by human neutrophils". Journal of Cell Science. 110 ( Pt 7) (7): 881–7. PMID9133675.
D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, Darrow AL, Santulli RJ, Brass LF, Andrade-Gordon P (February 1998). "Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues". The Journal of Histochemistry and Cytochemistry. 46 (2): 157–64. doi:10.1177/002215549804600204. PMID9446822.
Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, Ansel JC, Bunnett NW (August 1999). "Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase". Experimental Dermatology. 8 (4): 282–94. doi:10.1111/j.1600-0625.1999.tb00383.x. PMID10439226.
Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS (August 2000). "Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates". The Journal of Biological Chemistry. 275 (34): 26333–42. doi:10.1074/jbc.M002941200. PMID10831593.
Loew D, Perrault C, Morales M, Moog S, Ravanat C, Schuhler S, Arcone R, Pietropaolo C, Cazenave JP, van Dorsselaer A, Lanza F (September 2000). "Proteolysis of the exodomain of recombinant protease-activated receptors: prediction of receptor activation or inactivation by MALDI mass spectrometry". Biochemistry. 39 (35): 10812–22. doi:10.1021/bi0003341. PMID10978167.
Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ (November 2001). "Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma". The Journal of Allergy and Clinical Immunology. 108 (5): 797–803. doi:10.1067/mai.2001.119025. PMID11692107.
Miike S, McWilliam AS, Kita H (December 2001). "Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2". Journal of Immunology. 167 (11): 6615–22. doi:10.4049/jimmunol.167.11.6615. PMID11714832.
Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, Thompson PJ, Stewart GA (April 2002). "Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells". Journal of Immunology. 168 (7): 3577–85. doi:10.4049/jimmunol.168.7.3577. PMID11907122.