Protease-Activated Receptors

Supporting information

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 PGF1α 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.

To view external sources of pharmacological information for Protease-Activated Receptors, please click here: IUPHAR Receptor Code and BJP Guide

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
PAR1 Human F2R NM_001992 P25116
Mouse F2r NM_010169 P20558
Rat F2r NM_012950 P26824
PAR2 Human F2RL1 NM_005242 P55085
Mouse F2rl1 NM_007974 P55086
Rat F2rl1 NM_053897 Q63645
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Literature for Protease-Activated Receptors

Cardiovascular Research Product Guide

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

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  • Thrombosis and Hemostasis
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Cardiovascular disease remains one of the major causes of morbidity and mortality in the Western world and therefore this therapeutic area continues to be of great interest to researchers. This poster highlights the key GPCRs regulating vascular reactivity.

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Cardiovascular Life Science Poster

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GPCR Product Listing

GPCR Product Listing

Highlights over 450 products for GPCRs. Request copy or view PDF today.

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Cardiovascular Research Product Guide

Cardiovascular Research Product Guide

Our Cardiovascular Guide highlights over 250 products for cardiovascular research. Request copy or view PDF today.

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Cardiovascular Life Science Poster

Written by J.J. Maguire and A.P. Davenport

Cardiovascular Life Science Poster

Our Cardiovascular poster highlights the key G protein-coupled receptors involved in the regulation of vascular reactivity. Request copy or view PDF today.

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