Protease-Activated Receptors

Protease-activated receptors (PARs, also known as thrombin receptors) are G-protein-coupled receptors, activated by cleavage of their N-terminal domains by serine proteases. Hydrolysis reveals a tethered peptide ligand, which interacts with the receptor within extracellular loop-2 to affect transmembrane signaling. Four subtypes of receptors have so far been cloned (PAR_1-4).

PAR₁ is the most well characterized member of this receptor family and is activated by the endogenous serine protease thrombin. Thrombin has a primary role in vessel wound healing and revascularization and acts via PAR₁ receptors on platelets, endothelial cells, smooth muscle cells, neutrophils, leukocytes, neurons and glial cells to facilitate a coordinated response to vessel damage. Thrombin-mediated PAR₁ activation induces platelet aggregation. Thrombin stimulates 5-HT, ATP and thromboxane A₂ release, integrin αIIb/β3 activation, and P-selectin and CD40 translocation to facilitate the binding of platelets to endothelial cells. Activation of endothelial cells is a key component in clotting and wound healing, and is mediated by PAR₁ stimulation. Activation of PAR₁ by thrombin stimulates von Willebrand factor release, tissue factor expression and adhesion molecule expression, which further promotes clotting and coagulation as well as facilitating the rapid adherence of neutrophils, monocytes and lymphocytes to endothelial cells. Thrombin has direct promitogenic activity in fibroblasts, vascular smooth muscle cells, endothelial cells and some myeloid cells. Thrombin-mediated PAR₁ activation also induces expression of promitogenic factors and their receptors such as PDGF/PDGFR and ET-1/ET_A and ET-_B. PAR₁ is known to couple to several heterotrimeric G proteins and regulates multiple kinase signaling pathways including PI 3-K, Src family tyrosine kinases, JNK, Rho kinases, JAK2 and FAK.

PAR₂ is expressed in vascular tissue and highly vascular organs, which indicates a role for this receptor in the regulation of vascular tone. Trypsin is the endogenous agonist for PAR₂ and receptor activation has been coupled to the nitric oxide signaling pathway, causing vasodilation and hypotension. PAR₂ is implicated in chronic responses associated with vessel inflammation and wound healing. This receptor stimulates activation of T-cells and neutrophils, promotes leukocyte rolling, adhesion and extravasation, increases capillary permeability and enhances production of cytokines. In addition to its vascular roles, PAR₂ has multiple functions in the gastrointestinal tract. It is strongly expressed in enterocytes and stimulates prostaglandin (PG) E₂ and PGF_1α synthesis. Pancreatic PAR₂ expression and activation promotes secretory function; in particular, it increases amylin secretion.

PAR₃, along with PAR₁ and PAR₂, is localized to chromosome 5q13. In humans, PAR₃ is expressed in a variety of tissues, including the heart, small intestine, bone marrow, airway smooth muscle, vascular endothelium and astrocytes, but there is no PAR₃ expression on platelets. However, PAR₃ expression is species-specific as murine PAR₃ is strongly expressed in megakaryocytes and is important for achieving full thrombin-mediated platelet activation.

PAR₄ tissue distribution is different from other PAR family members, with highest levels detected in the lung, pancreas, thyroid and testes. This receptor is localized to human chromosome 19p12. PAR₄ is sensitive to both α- and γ-thrombin, yet has a low affinity for the peptide. PAR₄ therefore may function as a low affinity thrombin receptor that is activated at conditions where high concentrations of thrombin are achieved. This receptor helps to sustain platelet aggregation during prolonged thrombin exposure, as unlike PAR₁, it is slowly inactivated.

As thrombin-mediated PAR activation stimulates the clotting cascade, thrombin inhibitors have been suggested as potential antithrombotic agents. In addition, PAR₁ activation has been implicated in several other cardiovascular diseases.

External sources of pharmacological information for Protease-Activated Receptors :

• IUPHAR Receptor Code

• BJP Guide

Proteinase-Activated Receptor (PAR) Gene Data

Proteinase-Activated Receptor Pharmacological Data

References

Hollenberg and Compton (2002) International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol.Rev. 54 203. de Garavilla et al (2001) Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism. Br.J.Pharmacol. 133 975. Nystedt et al (1994) Molecular cloning of a potential proteinase activated receptor. Proc.Natl.Acad.Sci.USA 91 9208. Hollenberg and Saifeddine (2001) Proteinase-activated receptor 4 (PAR4): activation and inhibition of rat platelet aggregation by PAR4-derived peptides. Can.J.Physiol.Pharmacol. 79 439. Ahn et al (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 (SCH79797), a nonpeptide thrombin receptor antagonist. Biochem.Pharmacol. 60 1425.