Protease-activated receptors in the brain: Receptor expression, activation, and functions in neurodegeneration and neuroprotection

Protease-activated receptors (PARs) are G protein-coupled receptors that regulate the cellular response to extracellular serine proteases, like thrombin, trypsin, and tryptase. The PAR family consists of four members: PAR-1, -3, and -4 as thrombin receptors and PAR-2 as the trypsin/tryptase receptor, which are abundantly expressed in the brain throughout development. Recent evidence has supported the direct involvement of PARs in brain development and function. The expression of PARs in the brain is differentially upregulated or downregulated under pathological conditions in neurodegenerative disorders, like Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke, and human immunodeficiency virus-associated dementia. Activation of PARs mediates cell death or cell survival in the brain, depending on the amplitude and the duration of agonist stimulation. Interference or potentiation of PAR activation is beneficial in animal models of neurodegenerative diseases. Therefore, PARs mediate either neurodegeneration or neuroprotection in neurodegenerative diseases and represent attractive therapeutic targets for treatment of brain injuries. Here, we review the abnormal expression of PARs in the brain under pathological conditions, the functions of PARs in neurodegenerative disorders, and the molecular mechanisms involved.