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Thrombin is a multifunctional serine protease involved in a number of pathophysiological processes that include blood clotting, inflammation, repair processes and tumor metastasis. In brain, thrombin regulates the viability of neurons and astrocytes by in ...creasing survival under conditions of hypoglycemia and oxidative stress and inducing apoptosis under other conditions. Thrombin is also chemotactic for macrophages and mitogenic for smooth muscle cells, fibroblasts, and astrocytes and induces secretion of growth factors and cytokines from fibroblasts and smooth muscle cells. Most of the thrombin-mediated effects are preceded by morphological changes in cells that follow activation of PARs (Protease-Activated Receptors). PARs are a unique class of heterotrimeric, transmembrane GPCRs (G-Protein Coupled Receptors) activated by serine proteases that cleave specific regions of the extracellular NH2 terminus of the molecule to unmask a new NH2 terminus that serves as a \"tethered ligand\" docking intramolecularly with the body of the receptor to effect transmembrane signaling. To date, three PARs have been identified with distinct N-terminal cleavage sites and tethered ligand pharmacology, out of which, PAR1, PAR3, and PAR4 are activated by Thrombin. While PAR1 and PAR4 are direct cellular targets of Thrombin (PAR1 is the most potent and PAR4 functions as a low affinity thrombin receptor that is activated in conditions where high concentrations of Thrombin are achieved), PAR3 seems to play a role in the activation of other PARs but does not itself transduce a signal directly. A variety of G-Proteins can be coupled to the activated PARs (PAR1 and PAR4) and this determines the pluripotent nature of the cellular responses to Thrombin.
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