Protein-activated receptors in neuronal development, neurodegeneration, and neuroprotection: Thrombin as signaling molecule in the brain

Protease-activated receptors (PARs) belong to the superfamily of seven transmembrane domain G protein-coupled receptors. Four PAR subtypes are known, PAR-1 to -4. PARs are highly homologous between the species and are expressed in a wide variety of tissues and cell types. Of particular interest is the role which these receptors play in the brain, with regard to neuroprotection or degeneration under pathological conditions. The main agonist of PARs is thrombin, a multifunctional serine protease, known to be present not only in blood plasma but also in the brain. PARs possess an irreversible activation mechanism. Binding of agonist and subsequent cleavage of the extracellular N-terminus of the receptor results in exposure of a so-called tethered ligand domain, which then binds to extracellular loop 2 of the receptor leading to receptor activation. PARs exhibit an extensive expression pattern in both the central and the peripheral nervous system. PARs participate in several mechanisms important for normal cellular functioning and during critical situations involving cellular survival and death. In the last few years, research on Alzheimer's disease and stroke has linked PARs to the pathophysiology of these neurodegenerative disorders. Actions of thrombin are concentration-dependent, and therefore, depending on cellular function and environment, serve as a double-edged sword. Thrombin can be neuroprotective during stress conditions, whereas under normal conditions high concentrations of thrombin are toxic to cells.