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PAR

Protease-activated receptors (PARs) are unique members of the large superfamily of GPCRs, transduce cellular responses to extracellular proteases, and are important drug targets. It’s the main effector protease in primary haemostasis in that it activates platelets with subsequent release of platelet activators ADP, serotonin and thromboxane A2. Activation of PARs, mainly PAR1 and -4 by thrombin on platelets is considered as a haemostatic effect. PARs belong to a family of the G protein-coupled receptors, which are characterized by a single polypeptide chain with seven transmembrane α-helices that are connected by three intra- and extracellular loops.  Activation of PARs occurs through a unique mechanism: proteases cleave the N-terminal extracellular domain thereby generating a new N-terminus which acts as a new N-terminal tethered ligand that activates the cleaved G-protein coupled receptor. 
The intracellular domains of PARs tightly bind Gα and Gβγ subunits; activation of the receptor stimulates the exchange of GTP for GDP, resulting in phosphorylation of the intracellular Gα subunit, which induces the release of the Gα subunit from its tight binding to the Gβγ subunit.  PAR1, the family prototype, transmits cellular responses to thrombin, the key effector protease of the coagulation cascade. PAR3 and PAR4 are also activated by thrombin, whereas PAR2 is activated by trypsin-like serine proteases. PAR1 was the first PAR discovered in a search for a receptor that conferred thrombin responses on human platelets. PAR2 was discovered next in a genomic library screen and found to mediate trypsin responses. PAR3 and PAR4 were identified subsequently and shown to mediate thrombin signaling in mouse platelets, indicating that PARs are expressed differentially in distinct cell types in a species-specific manner. PAR1, PAR3, and PAR4 are expressed primarily in various cell types in the vasculature, including platelets, fibroblasts, and endothelial and smooth muscle cells, and are major effectors of thrombin signaling in vivo.

References

1.Hamilton JR, Trejo J. Annu Rev Pharmacol Toxicol. 2017;57:349–373.