Protease-activated GPCR Family Subtypes and Products

What Are Protease-activated Receptors?

Protease-activated receptors are a family of G protein-coupled receptors (GPCRs) comprised of four receptor subtypes: PAR1, PAR2, PAR3, and PAR4. These receptors are expressed in cells all throughout the body, primarily in platelets and endothelial cells. PARs are involved in growth, contraction, and hypertrophy in smooth muscles, and play a role in hemostasis and thrombosis. These receptors have also been linked to the inflammation present in atherosclerosis and restenosis.

Protease-activated Receptor Information

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PAR1 is one of the four members of G protein-coupled protease- activated receptor family (PAR1, PAR2, PAR3, and PAR4). PAR1 is activated by coagulant protease thrombin via an irreversible proteolytic mechanism: thrombin specifically cleaves the extracellular N-termini of the receptor to unmask a new amino acid terminus, which in turn acts as a peptide ligand by binding intramolecularly to the body of the receptor. An increased thrombin generation and PAR1 expression are observed on cells within atherosclerotic plaque and thrombus and following vascular injury. PAR1 may play important role in thrombosis and restenosis and thus a PAR1 antagonist possesses the therapeutic potential in treating these diseases.

PAR-2 (protease-activated receptor 2) is a G-protein-coupled receptor activated by certain serine proteases such as trypsin and tryptase. It is widely distributed in the body in various tissues, and is involved in the alimentary, circulatory, respiratory and neuronal systems. In the gastric mucosa, PAR-2 modulates multiple functions and exerts mucosal cytoprotection mainly by activating sensory neurons. Thus, PAR-2 may be an important therapeutic target for treatment of gastric mucosal injury. Other research have shown PAR-2 to play an important role in vascular diseases. PAR2-derived peptide agonists have been shown to reduce vascular tone, and therefore increase blood flow. A mechanism for PAR2-mediated endothelial- dependent relaxation and hyperpolarization of vascular smooth muscle in select arterial vascular beds suggests a strategy for correction of endothelium-based vascular dysfunction. In diseases and conditions such as atherosclerosis or to injury, vascular tissue show variable changes of PAR-2 expression. PAR-2 agonists and antagonists may become leads for a new class of therapeutic agents for treatment of vascular diseases.

Protease-activated receptor 4 (PAR-4) is also known as coagulation factor II (thrombin) receptor-like 3, and is activated by proteolytic cleavage of its extracellular amino terminus by a protease, specifically thrombin or trypsin. In humans, PAR-4 has been shown to be highly expressed in many tissues, and in high levels in the lung, pancreas, thyroid, testis, and small intestine. Thrombin signaling through PARs have been shown to affect many physiological activities such as platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function. In the blood coagulation process, it has been determined that clot elasticity is decreased significantly when PAR-4 receptor is inhibited. Furthermore, PAR-4 is likely activated by low concentrations of thrombin during the initial phase of thrombin generation and is important for the clotting time, and the PAR-4 receptor may play a role in stabilizing the coagulum.

Protease-activated Cell Lines

Receptor FamilyReceptorSpeciesParentalStable Cell Lines Division-Arrested Cells Membranes