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].

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).

* Key recommended reading is highlighted with an asterisk

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* 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]

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Subcommittee members: Nigel Bunnett (Chairperson) NHMRC Australia Fellow Professor of Pharmacology and Medicine Monash Institute of Pharmaceutical Sciences 318 Royal Parade Parkville VIC 3052 Australia Kathryn DeFea Biomedical Sciences Division School of Medicine University of California Riverside Riverside California, USA. Justin Hamilton Australian Centre for Blood Diseases & Department of Clinical Haematology Monash University Melbourne 3004 Australia Morley D. Hollenberg Department of Physiology and Pharmacology Faculty of Medicine, University of Calgary Alberta T2N 4N1, Canada

Other contributors: Rithwik Ramachandran Physiology and Pharmacology Schulich School of Medicine and Dentistry University of Western Ontario London ON, N6A5C1 Canada JoAnn Trejo Department of Pharmacology 9500 Gilman Drive Biomedical Sciences Bldg. University of California, San Diego La Jolla, CA 92093