Abstract
Thrombin results from the activation of the blood coagulation system. It is a multifunctional protein that has, besides its function in hemostasis and thrombosis, several cellular effects that link the coagulation system with the inflammatory response. Many years of investigations were necessary for the discovery of the first functional thrombin receptor, which was found to have a unique mechanism of activation. The receptor was named protease-activated receptor 1 (PAR-1) because proteolysis is necessary for its activation. Subsequent studies led to the identification of the other PARs, PAR-2, PAR-3, and PAR-4. PAR-2 is activated by trypsin, tryptase, factor Xa, or factor VIIa, but it cannot be activated by thrombin, PAR-3 and PAR-4 can also be activated by thrombin. Activation of PARs by protease involves proteolytic cleavage and unmasking of an amino-terminal receptor sequence, which acts as a tethered ligand by binding to the second extracellular loop of the receptor to initiate transmembrane signaling. Sequence analysis has shown that all PARs are members of the 7-transmembrane domain receptor superfamily. Expression of PARs has been detected in most tissues and in numerous cells, and thus these molecules have been implicated in several physiological processes and in the pathogenesis of several diseases.
Published Version
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