Proteinase-activated

Overview: Proteinase-activated receptors (PARs, nomenclature as agreed by NC-IUPHAR Subcommittee on Protease-activated Receptors, see Hollenberg and Compton, 2002) are activated by proteolytic cleavage of their amino terminal exodomains. Alternative endogenous proteinases or ligands to thrombin for PAR1, PAR3 or PAR4 have not been demonstrated. Activation of PAR2 by trypsin or tryptase release in vivo is yet to be demonstrated. Several proteases, including cathepsin G and chymotrypsin, have an inhibitory effect at the PAR1 receptor such that they cleave the exodomain of the receptor without inducing activation, thereby preventing activation by thrombin but not by agonist peptides. The role of such an action in vivo is unclear. Agonist protease-induced hydrolysis is thought to unmask 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, SLIGKV, TFRGAP and GYPGQV respectively. With the exception of PAR3, these synthetic peptide sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors.

Nomenclature	PAR1	PAR2	PAR3	PAR4
Other names	Thrombin receptor, PAR-1, PAR1	PAR-2, PAR2	Thrombin receptor, PAR-3, PAR3	Thrombin receptor, PAR-4, PAR4
Ensembl ID	ENSG00000181104	ENSG00000164251	ENSG00000164220	ENSG00000127533
Principal transduction	Gq/11/Gi/o/G12/13	Gq/11/Gi/o	Gq/11/Gi/o	Gq/11/Gi/o
Agonist proteases	Thrombin, trypsin	Trypsin, tryptase	Thrombin, trypsin, factor Xa	Thrombin, trypsin
Selective agonists	TFLLR-NH2	2-Furoyl-LIGRLO-amide (Gardell et al., 2008; Hollenberg et al., 2008), SLIGRL, SLIGKV	–	GYPGQV, GYPGKF
Selective antagonists	RWJ56110 (Andrade-Gordon et al., 1999)	–	–	–
Probes	[3H]-haTRAP (Ahn et al., 1997)	Trans-cinnamoyl-LIGRLO [N-[3H]-propionyl]-NH2 (Al Ani et al., 1999)	–	–

TFLLR-NH₂ is selective relative to the PAR₂ receptor (Blackhart et al., 1996; Kawabata et al., 1999). Thrombin is inactive at the PAR₂ receptor.

Glossary

Abbreviations:

[³H]-haTRAP

Ala-p-fluoroPhe-Ala-Arg-cyclohexylAla-homoArg-[³H]-Tyr-amide

RWJ56110

(αS)-N-([1S]-3-amino-1-[{(phenylmethyl)amino}propyl]-α-[{(1-[{2,6-dichlorophenyl}methyl]-3-[1-pyrrolidinylmethyl]-1H-indol-6-yl)amino}carbonyl]amino)-3,4-difluoro-benzenepropanamide

Further Reading

Arora P, Ricks TK, Trejo J (2007). Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci120: 921–928.

Bushell T (2007). The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders. J Physiol581: 7–16.

Hansen KK, Oikonomopoulou K, Li Y, Hollenberg MD (2008). Proteinases, proteinase-activated receptors (PARs) and the pathophysiology of cancer and diseases of the cardiovascular, musculoskeletal, nervous and gastrointestinal systems. Naunyn Schmiedebergs Arch Pharmacol377: 377–392.

Hirano K (2007). The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol27: 27–36.

Hollenberg MD, Compton SJ (2002). International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev54: 203–217.

Hollenberg MD, Oikonomopoulou K, Hansen KK, Saifeddine M, Ramachandran R, Diamandis EP (2008). Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer. Biol Chem389: 643–651.

Kawabata A, Matsunami M, Sekiguchi F (2008). Gastrointestinal roles for proteinase-activated receptors in health and disease. Br J Pharmacol153 (Suppl. 1): S230–S240.

Luo W, Wang Y, Reiser G (2007). Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection. Brain Res Rev56: 331–345.

McIntosh KA, Plevin R, Ferrell WR, Lockhart JC (2007). The therapeutic potential of proteinase-activated receptors in arthritis. Curr Opin Pharmacol7: 334–338.

Moffatt JD (2007). Proteinase-activated receptors in the lower urinary tract. Naunyn Schmiedebergs Arch Pharmacol375: 1–9.

Russo A, Soh UJ, Trejo J (2009). Proteases display biased agonism at protease-activated receptors: location matters! Mol Interv9: 87–96.

Shah R (2009). Protease-activated receptors in cardiovascular health and diseases. Am Heart J157: 253–262.

Shpacovitch V, Feld M, Bunnett NW, Steinhoff M (2007). Protease-activated receptors: novel PARtners in innate immunity. Trends Immunol28: 541–550.

Shpacovitch V, Feld M, Hollenberg MD, Luger TA, Steinhoff M (2008). Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J Leukoc Biol83: 1309–1322.

Sokolova E, Reiser G (2007). A novel therapeutic target in various lung diseases: airway proteases and protease-activated receptors. Pharmacol Ther115: 70–83.