Top ▲
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Show »« Hide
More detailed introduction
Proteinase-activated receptors (PARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Proteinase-activated Receptors [12]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are SFLLRN-NH2, SLIGKV-NH2, TFRGAP-NH2 and GYPGQV-NH2, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [24]. PAR2 ectivation by NE regulates inflammation and pain responses [21,30] and triggers mucin secretion from airway epithelial cells [31].
PAR1
C
Show summary »« Hide summary
More detailed page
|
||||||||||||||||||||||||||||||||||||||||
PAR2
C
Show summary »« Hide summary
More detailed page
|
||||||||||||||||||||||||||||||||||||||||
PAR3
C
Show summary »« Hide summary
More detailed page
|
||||||||||||||||||||||||||||||||||||||||
PAR4
C
Show summary »« Hide summary
More detailed page
|
* Key recommended reading is highlighted with an asterisk
* Adams MN, Ramachandran R, Yau MK, Suen JY, Fairlie DP, Hollenberg MD, Hooper JD. (2011) Structure, function and pathophysiology of protease activated receptors. Pharmacol. Ther., 130 (3): 248-82. [PMID:21277892]
* Canto I, Soh UJ, Trejo J. (2012) Allosteric modulation of protease-activated receptor signaling. Mini Rev Med Chem, 12 (9): 804-11. [PMID:22681248]
French SL, Hamilton JR. (2016) Protease-activated receptor 4: from structure to function and back again. Br. J. Pharmacol., 173 (20): 2952-65. [PMID:26844674]
* García PS, Gulati A, Levy JH. (2010) The role of thrombin and protease-activated receptors in pain mechanisms. Thromb. Haemost., 103 (6): 1145-51. [PMID:20431855]
* Hollenberg MD, Compton SJ. (2002) International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol. Rev., 54 (2): 203-17. [PMID:12037136]
Ramachandran R, Altier C, Oikonomopoulou K, Hollenberg MD. (2016) Proteinases, Their Extracellular Targets, and Inflammatory Signaling. Pharmacol. Rev., 68 (4): 1110-1142. [PMID:27677721]
* Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD. (2012) Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov, 11 (1): 69-86. [PMID:22212680]
Shpacovitch V, Feld M, Bunnett NW, Steinhoff M. (2007) Protease-activated receptors: novel PARtners in innate immunity. Trends Immunol., 28 (12): 541-50. [PMID:17977790]
* Soh UJ, Dores MR, Chen B, Trejo J. (2010) Signal transduction by protease-activated receptors. Br. J. Pharmacol., 160 (2): 191-203. [PMID:20423334]
Sriram K, Insel PA. (2020) Proteinase-activated receptor 1: A target for repurposing in the treatment of COVID-19?. Br J Pharmacol, 177 (21): 4971-4974. [PMID:32639031]
Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N, Luger TA, Hollenberg MD. (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr. Rev., 26 (1): 1-43. [PMID:15689571]
Vergnolle N. (2009) Protease-activated receptors as drug targets in inflammation and pain. Pharmacol. Ther., 123 (3): 292-309. [PMID:19481569]
1. Ahn HS, Foster C, Boykow G, Arik L, Smith-Torhan A, Hesk D, Chatterjee M. (1997) Binding of a thrombin receptor tethered ligand analogue to human platelet thrombin receptor. Mol. Pharmacol., 51 (2): 350-6. [PMID:9203642]
2. Ahn HS, Foster C, Boykow G, Stamford A, Manna M, Graziano M. (2000) Inhibition of cellular action of thrombin by N3-cyclopropyl-7-[[4-(1-methylethyl)phenyl]methyl]-7H-pyrrolo[3, 2-f]quinazoline-1,3-diamine (SCH 79797), a nonpeptide thrombin receptor antagonist. Biochem. Pharmacol., 60 (10): 1425-34. [PMID:11020444]
3. Al-Ani B, Saifeddine M, Kawabata A, Renaux B, Mokashi S, Hollenberg MD. (1999) Proteinase-activated receptor 2 (PAR(2)): development of a ligand-binding assay correlating with activation of PAR(2) by PAR(1)- and PAR(2)-derived peptide ligands. J. Pharmacol. Exp. Ther., 290 (2): 753-60. [PMID:10411588]
4. Andrade-Gordon P, Maryanoff BE, Derian CK, Zhang HC, Addo MF, Darrow AL, Eckardt AJ, Hoekstra WJ, McComsey DF, Oksenberg D et al.. (1999) Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proc. Natl. Acad. Sci. U.S.A., 96 (22): 12257-62. [PMID:10535908]
5. Austin KM, Covic L, Kuliopulos A. (2013) Matrix metalloproteases and PAR1 activation. Blood, 121 (3): 431-9. [PMID:23086754]
6. Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP. (2010) Novel agonists and antagonists for human protease activated receptor 2. J. Med. Chem., 53 (20): 7428-40. [PMID:20873792]
7. Blackhart BD, Emilsson K, Nguyen D, Teng W, Martelli AJ, Nystedt S, Sundelin J, Scarborough RM. (1996) Ligand cross-reactivity within the protease-activated receptor family. J. Biol. Chem., 271 (28): 16466-71. [PMID:8663335]
8. Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y, Ahn HS, Boykow G, Hsieh Y, Palamanda J, Agans-Fantuzzi J et al.. (2008) Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J. Med. Chem., 51 (11): 3061-4. [PMID:18447380]
9. Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS et al.. (2017) Structural insight into allosteric modulation of protease-activated receptor 2. Nature, 545 (7652): 112-115. [PMID:28445455]
10. Chung AW, Jurasz P, Hollenberg MD, Radomski MW. (2002) Mechanisms of action of proteinase-activated receptor agonists on human platelets. Br. J. Pharmacol., 135 (5): 1123-32. [PMID:11877318]
11. Covic L, Misra M, Badar J, Singh C, Kuliopulos A. (2002) Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat. Med., 8 (10): 1161-5. [PMID:12357249]
12. Hollenberg MD, Compton SJ. (2002) International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol. Rev., 54 (2): 203-17. [PMID:12037136]
13. Hollenberg MD, Renaux B, Hyun E, Houle S, Vergnolle N, Saifeddine M, Ramachandran R. (2008) Derivatized 2-furoyl-LIGRLO-amide, a versatile and selective probe for proteinase-activated receptor 2: binding and visualization. J. Pharmacol. Exp. Ther., 326 (2): 453-62. [PMID:18477767]
14. Jiang Y, Yau MK, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP. (2018) A Potent Antagonist of Protease-Activated Receptor 2 That Inhibits Multiple Signaling Functions in Human Cancer Cells. J. Pharmacol. Exp. Ther., 364 (2): 246-257. [PMID:29263243]
15. Jimenez-Vargas NN, Pattison LA, Zhao P, Lieu T, Latorre R, Jensen DD, Castro J, Aurelio L, Le GT, Flynn B et al.. (2018) Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome. Proc. Natl. Acad. Sci. U.S.A., 115 (31): E7438-E7447. [PMID:30012612]
16. Kanke T, Ishiwata H, Kabeya M, Saka M, Doi T, Hattori Y, Kawabata A, Plevin R. (2005) Binding of a highly potent protease-activated receptor-2 (PAR2) activating peptide, [3H]2-furoyl-LIGRL-NH2, to human PAR2. Br. J. Pharmacol., 145 (2): 255-63. [PMID:15765104]
17. Kawabata A, Saifeddine M, Al-Ani B, Leblond L, Hollenberg MD. (1999) Evaluation of proteinase-activated receptor-1 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: activation of PAR2 by PAR1-targeted ligands. J. Pharmacol. Exp. Ther., 288 (1): 358-70. [PMID:9862790]
18. Kogushi M, Matsuoka T, Kawata T, Kuramochi H, Kawaguchi S, Murakami K, Hiyoshi H, Suzuki S, Kawahara T, Kajiwara A et al.. (2011) The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs. Eur. J. Pharmacol., 657 (1-3): 131-7. [PMID:21300059]
19. Lee MC, Huang SC. (2008) Proteinase-activated receptor-1 (PAR(1)) and PAR(2) but not PAR(4) mediate contraction in human and guinea-pig gallbladders. Neurogastroenterol. Motil., 20 (4): 385-91. [PMID:18179608]
20. McGuire JJ, Saifeddine M, Triggle CR, Sun K, Hollenberg MD. (2004) 2-furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist. J. Pharmacol. Exp. Ther., 309 (3): 1124-31. [PMID:14976230]
21. Muley MM, Reid AR, Botz B, Bölcskei K, Helyes Z, McDougall JJ. (2016) Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase-activated receptor-2. Br. J. Pharmacol., 173 (4): 766-77. [PMID:26140667]
22. Ramachandran R, Mihara K, Chung H, Renaux B, Lau CS, Muruve DA, DeFea KA, Bouvier M, Hollenberg MD. (2011) Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2). J. Biol. Chem., 286 (28): 24638-48. [PMID:21576245]
23. Ramachandran R, Mihara K, Thibeault P, Vanderboor CM, Petri B, Saifeddine M, Bouvier M, Hollenberg MD. (2017) Targeting a Proteinase-Activated Receptor 4 (PAR4) Carboxyl Terminal Motif to Regulate Platelet Function. Mol. Pharmacol., 91 (4): 287-295. [PMID:28126849]
24. Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD. (2012) Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov, 11 (1): 69-86. [PMID:22212680]
25. Sevigny LM, Zhang P, Bohm A, Lazarides K, Perides G, Covic L, Kuliopulos A. (2011) Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc. Natl. Acad. Sci. U.S.A., 108 (20): 8491-6. [PMID:21536878]
26. Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ, Le GT, Fairlie DP. (2012) Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br. J. Pharmacol., 165 (5): 1413-23. [PMID:21806599]
27. Wen W, Young SE, Duvernay MT, Schulte ML, Nance KD, Melancon BJ, Engers J, Locuson 2nd CW, Wood MR, Daniels JS et al.. (2014) Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354. Bioorg. Med. Chem. Lett., 24 (19): 4708-13. [PMID:25176330]
28. Wong PC, Seiffert D, Bird JE, Watson CA, Bostwick JS, Giancarli M, Allegretto N, Hua J, Harden D, Guay J et al.. (2017) Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding. Sci Transl Med, 9 (371). [PMID:28053157]
29. Yau MK, Suen JY, Xu W, Lim J, Liu L, Adams MN, He Y, Hooper JD, Reid RC, Fairlie DP. (2016) Potent Small Agonists of Protease Activated Receptor 2. ACS Med Chem Lett, 7 (1): 105-10. [PMID:26819675]
30. Zhao P, Lieu T, Barlow N, Sostegni S, Haerteis S, Korbmacher C, Liedtke W, Jimenez-Vargas NN, Vanner SJ, Bunnett NW. (2015) Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. J. Biol. Chem., 290 (22): 13875-87. [PMID:25878251]
31. Zhou J, Perelman JM, Kolosov VP, Zhou X. (2013) Neutrophil elastase induces MUC5AC secretion via protease-activated receptor 2. Mol. Cell. Biochem., 377 (1-2): 75-85. [PMID:23392769]
Subcommittee members:
Nigel Bunnett (Chairperson)
Kathryn DeFea
Justin Hamilton
Morley D. Hollenberg |
Other contributors:
Rithwik Ramachandran
JoAnn Trejo |
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. Br J Pharmacol. 176 Issue S1: S21-S141.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License
Endogenous serine proteases (EC 3.4.21.) active at the proteinase-activated receptors include: thrombin (F2, P00734), generated by the action of Factor X (F10, P00742) on liver-derived prothrombin (F2, P00734); trypsin, generated by the action of enterokinase (TMPRSS15, P98073) on pancreatic-derived trypsinogen (PRSS1, P07477); tryptase, a family of enzymes (α/β1 TPSAB1, Q15661 ; γ1 TPSG1, Q9NRR2; δ1 TPSD1, Q9BZJ3) secreted from mast cells; cathepsin G (CTSG, P08311) generated from leukocytes; liver-derived protein C (PROC, P04070) generated in plasma by thrombin (F2, P00734) and matrix metalloproteinase 1 (MMP1, P45452).