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 affects transmembrane signaling.

Products
Background
Literature
Gene Data

Agonists

Cat No Product Name / Activity
3370 AC 264613
PAR2 receptor agonist
3369 AC 55541
Potent and selective PAR2 agonist
1487 AY-NH2
Selective PAR4 agonist
3015 2-Furoyl-LIGRLO-amide
Potent and selective PAR2 agonist
3394 LRGILS-NH2
Control peptide for SLIGRL-NH2 (Cat. No. 1468)
3393 RLLFT-NH2
Control peptide for TFLLR-NH2 (Cat. No. 1464)
3010 SLIGKV-NH2
PAR2 receptor agonist
1468 SLIGRL-NH2
PAR2-activating peptide
1464 TFLLR-NH2
PAR1-activating peptide
1185 Thrombin Receptor Agonist Peptide
Causes platelet aggregation and secretion
3497 TRAP-6
PAR1 peptide fragment (residues 42-47); acts as a PAR1 agonist
3392 VKGILS-NH2
Control peptide for SLIGKV-NH2 (Cat. No. 3010)

Antagonists

Cat No Product Name / Activity
3643 FR 171113
PAR1 antagonist
4751 FSLLRY-NH2
PAR2 peptide antagonist
5387 ML 354
Selective PAR4 antagonist
2614 RWJ 56110
Selective PAR1 antagonist
1592 SCH 79797 dihydrochloride
Potent, selective non-peptide PAR1 antagonist
1488 tcY-NH2
Selective PAR4 antagonist

Modulators

Cat No Product Name / Activity
4755 Q94 hydrochloride
Negative allosteric modulator at PAR1 receptor

Inhibitors

Cat No Product Name / Activity
2511 APC 366
Tryptase inhibitor
1798 Gabexate mesylate
Serine protease inhibitor; inhibits thrombin, trypsin, kallikrein and plasmin

Other

Cat No Product Name / Activity
4570 ML 161
Inhibits PAR1-mediated platelet activation
3553 Parstatin (human)
Peptide cleaved from PAR1 upon receptor activation
3554 Parstatin (mouse)
Peptide cleaved from PAR1 upon receptor activation

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 (PAR1-4).

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/ETA 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 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 :

Literature for Protease-Activated Receptors

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A collection of over 250 products for cardiovascular research, the guide includes research tools for the study of:

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Proteinase-Activated Receptor (PAR) Gene Data

Gene Species Gene Symbol Gene Accession No. Protein Accession No.
PAR1 Human F2R NM_001992 P25116
Mouse F2r NM_010169 P30558
Rat F2r NM_012950 P26824
PAR2 Human F2RL1 NM_005242 P55085
Mouse F2rl1 NM_007974 P55086
Rat F2rl1 NM_053897 Q63645
PAR3 Human F2rl2 NM_004101 O00254
Mouse F2rl2 NM_010170 O08675
Rat F2rl2 NM_053313 Q920E1
PAR4 Human F2rl3 NM_003950 Q96RI0
Mouse F2rl3 NM_007975 O88634
Rat F2rl3 NM_053808 Q920E0

Proteinase-Activated Receptor Pharmacological Data

Receptor Subtype PAR1 PAR2 PAR3 PAR4
Transduction Mechanism Gq/11 (↑IP3/DAG)
Gi
G12/13
Gq/11 (↑IP3/DAG)
Gi
Not Known Gq/11 (↑IP3/DAG)
Agonist Protease Thrombin Trypsin Thrombin Thrombin/Trypsin
Primary Distribution Platelets, endothelium, vascular smooth muscle, Gl tract epithelium, leukocytes, fibroblasts, neurons, mast cells Endothelium, leukocytes, Gl tract epithelium, airway and vascular smooth muscle, neurons, mast cells, renal tubular cells Airway smooth muscle, platelets Platelets, megakaryocytes
Likely Physiological Roles Platelet activation, pro-inflammatory, embryonic development, regulation of vascular tone Pro-inflammatory, mediates nociceptin, airway protection, regulation of vascular tone Cofactor for PAR4 Platelet activation
Selective Agonists TFLLR-NH2 (1464)
(EC50 = 1.9 μM)
SLIGRL-NH2 (1468)
(EC50 ~ 5 μM)
SLIGKV-NH2 (3010)
(IC50 = 10.4 μM)
- AY-NH2 (AYPGKF-NH2) (1487)
(EC50 = 15 μM)
Selective Antagonists SCH 79797 (1592)
(EC50 = 70 nM)
- - tcY-NH2 (trans-cinnamoyl-YPGKF-NH2) (1488)

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.