Proteinase-activated receptors (PARs, nomenclature as agreed by NC-IUPHAR Subcommittee on Protease-activated Receptors, [7]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. Tethered ligand sequences at human PAR1–4 are SFLLRN-NH2, SLIGKV-NH₂, TFRGAP-NH2 and GYPGQV-NH₂, respectively. With the exception of PAR3, these synthetic peptide 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 the PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation, thereby preventing activation by activating proteinases but not by agonist peptides. The role of such an action in vivo is unclear.

TFLLR-NH₂ is selective relative to the PAR₂ receptor [4,9]. thrombin is inactive at the PAR₂ receptor.

Endogenous serine proteases (EC 3.4.21.) active at the proteinase-activated receptors include: thrombin, generated by the action of Factor X (ENSG00000126218) on liver-derived prothrombin (ENSG00000180210); trypsin, generated by the action of enterokinase (ENSG00000154646) on pancreatic-derived trypsinogen (ENSG00000204983); tryptase, a family of enzymes (α/β1 ENSG00000172236; γ1 ENSG00000116176; δ1 ENSG00000095917) secreted from mast cells; cathepsin G (ENSG00000100448) generated from leukocytes; liver-derived protein C (ENSG00000115718) generated in plasma by thrombin and matrix metalloproteinase 1.

2-Furoyl-LIGRLO-NH₂ activity was measured via calcium mobilisation in HEK 293 cells which constitutively coexpress human PAR₁ and PAR₂.

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]

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]

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]

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. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. Hollenberg, MD; Compton, SJ. (2002) International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol. Rev., 54 (2): 203-17. [PMID:12037136]

8. 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]

9. 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]

10. 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]

11. 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]

12. Serebruany, VL; Kogushi, M; Dastros-Pitei, D; Flather, M; Bhatt, DL. (2009) The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb. Haemost., 102 (1): 111-9. [PMID:19572075]