Protease-activated receptor

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coagulation factor II (thrombin) receptor
Alt. symbolsPAR1
Other data
LocusChr. 5 q13
coagulation factor II (thrombin) receptor-like 1
Alt. symbolsPAR2, GPR11
Other data
LocusChr. 5 q13
coagulation factor II (thrombin) receptor-like 2
Alt. symbolsPAR3
Other data
LocusChr. 5 q13
coagulation factor II (thrombin) receptor-like 3
Alt. symbolsPAR4
Other data
LocusChr. 19 p12

Protease-activated receptors are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.[1]


There are 4 known protease-activated receptors, PAR1, PAR2, PAR3, and PAR4. They are members of the seven-transmembrane G-protein-coupled receptor superfamily, and are expressed throughout the body.


Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by specific cleavage of the amino terminal sequence that exposes a new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor.[2] Four types of PAR receptors have been identified by molecular cloning, and classified according to the main enzyme that is able to activate it. It has been determined that a large group of proteases cleave and activate PARs receptors, including proteases from: a) the coagulation cascade, b) inflammatory cells, and c) the digestive tract. The wide distribution of PARs in a variety of cells supports the idea that they are involved in many process related with the gastrointestinal physiology.[2] Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide (SLIGKV) that mimics the new N-terminal sequence produced after the cleavage, activates PAR-2 receptors without its proteolytic processing. In this sense, here we report that TFF3 isolated from human breast milk activates PAR-2 receptors of intestinal epithelial cells HT-29. These findings suggest that TFF3 activates intestinal epithelial cells through G-protein-coupled PAR-2, and could actively participate in the immune system of breastfed babies inducing the production of peptides related to innate defense, such as defensins and cytokines.[2]

PARs are activated by the action of serine proteases such as thrombin (acts on PARs 1, 3 and 4) and trypsin (PAR 2).[3] These enzymes cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response.

Most of the PAR family act through the actions of G-proteins i (cAMP inhibitory), 12/13 (Rho and Ras activation) and q (calcium signalling) to cause cellular actions.


The cellular effects of thrombin are mediated by protease-activated receptors (PARs). Thrombin signalling in platelets contributes to hemostasis and thrombosis. Endothelial PARs participate in the regulation of vascular tone and permeability while in vascular smooth muscle they mediate contraction, proliferation, and hypertrophy. PARs contribute to the pro-inflammatory response observed in atherosclerosis and restenosis. Recent research has also implicated these novel receptors in muscle growth and bone cell differentiation and proliferation.[4]

In T cells, activation of PAR1, PAR2 and PAR3 induce tyrosine phosphorylation of VAV1. Activation of PARs also led to an increase in tyrosine phosphorylation of ZAP-70 and SLP-76, two key proteins in T cell receptor (TCR) signalling.[5]


  1. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (June 2001). "Proteinase-activated receptors" (abstract). Pharmacological Reviews. 53 (2): 245–82. PMID 11356985.
  2. 2.0 2.1 2.2 Barrera GJ, Tortolero GS (2016). "Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins". Bratislavske Lekarske Listy. 117 (6): 332–9. PMID 27546365.
  3. Coughlin SR, Camerer E (January 2003). "PARticipation in inflammation". The Journal of Clinical Investigation. 111 (1): 25–7. doi:10.1172/JCI17564. PMC 151847. PMID 12511583.
  4. Martorell L, Martínez-González J, Rodríguez C, Gentile M, Calvayrac O, Badimon L (February 2008). "Thrombin and protease-activated receptors (PARs) in atherothrombosis". Thrombosis and Haemostasis. 99 (2): 305–15. doi:10.1160/TH07-08-0481. PMID 18278179.
  5. Bar-Shavit R, Maoz M, Yongjun Y, Groysman M, Dekel I, Katzav S (January 2002). "Signalling pathways induced by protease-activated receptors and integrins in T cells". Immunology. 105 (1): 35–46. doi:10.1046/j.0019-2805.2001.01351.x. PMC 1782632. PMID 11849313.

Further reading

  • Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (June 2001). "Proteinase-activated receptors". Pharmacological Reviews. 53 (2): 245–82. PMID 11356985.
  • Hollenberg MD, Compton SJ (June 2002). "International Union of Pharmacology. XXVIII. Proteinase-activated receptors". Pharmacological Reviews. 54 (2): 203–17. PMID 12037136.
  • Coughlin SR (August 2005). "Protease-activated receptors in hemostasis, thrombosis and vascular biology". Journal of Thrombosis and Haemostasis. 3 (8): 1800–14. doi:10.1111/j.1538-7836.2005.01377.x. PMID 16102047.
  • Adams MN, Ramachandran R, Yau MK, Suen JY, Fairlie DP, Hollenberg MD, Hooper JD (June 2011). "Structure, function and pathophysiology of protease activated receptors". Pharmacology & Therapeutics. 130 (3): 248–82. doi:10.1016/j.pharmthera.2011.01.003. PMID 21277892.

External links