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Proteinase-activated receptors C
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).
Overview
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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 [29]. PAR2 activation by NE regulates inflammation and pain responses [25,34] and triggers mucin secretion from airway epithelial cells [35].
Receptors
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PAR1
C
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PAR2
C
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PAR3
C
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PAR4
C
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Further reading
* 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]
* Peach CJ, Edgington-Mitchell LE, Bunnett NW, Schmidt BL. (2023) Protease-activated receptors in health and disease. Physiol Rev, 103 (1): 717-785. [PMID:35901239]
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]
References
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 USA, 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. Avet C, Sturino C, Grastilleur S, Gouill CL, Semache M, Gross F, Gendron L, Bennani Y, Mancini JA, Sayegh CE et al.. (2020) The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects. Commun Biol, 3 (1): 719. [PMID:33247181]
7. 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]
8. 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]
9. 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]
10. 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]
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. Hollenberg MD, Saifeddine M, al-Ani B, Kawabata A. (1997) Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptides. Can J Physiol Pharmacol, 75 (7): 832-41. [PMID:9315351]
15. 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]
16. 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 USA, 115 (31): E7438-E7447. [PMID:30012612]
17. 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]
18. 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]
19. Kennedy AJ, Sundström L, Geschwindner S, Poon EKY, Jiang Y, Chen R, Cooke R, Johnstone S, Madin A, Lim J et al.. (2020) Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition. Commun Biol, 3 (1): 782. [PMID:33335291]
20. 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]
21. 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]
22. LeSarge JC, Thibeault P, Milne M, Ramachandran R, Luyt LG. (2019) High Affinity Fluorescent Probe for Proteinase-Activated Receptor 2 (PAR2). ACS Med Chem Lett, 10 (7): 1045-1050. [PMID:31312406]
23. LeSarge JC, Thibeault P, Yu L, Childs MD, Mirka VM, Qi Q, Fox MS, Kovacs MS, Ramachandran R, Luyt LG. (2023) Protease-activated receptor 2 (PAR2)-targeting peptide derivatives for positron emission tomography (PET) imaging. Eur J Med Chem, 246: 114989. [PMID:36527934]
24. 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]
25. 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]
26. Priestley ES, Banville J, Deon D, Dubé L, Gagnon M, Guy J, Lapointe P, Lavallée JF, Martel A, Plamondon S et al.. (2022) Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4. J Med Chem, 65 (13): 8843-8854. [PMID:35729784]
27. 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]
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]
33. 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]
34. 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]
35. 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]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Nigel Bunnett (Chairperson)
Kathryn DeFea
Justin Hamilton
Morley D. Hollenberg |
Other contributors:
Rithwik Ramachandran
JoAnn Trejo |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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).