Protease-activated receptor 1 (PAR1) is a G-protein coupled receptor that is activated when serine proteases such as thrombin cleave the extracellular N-terminus of the receptor. The newly formed Nterminus interacts with the second extracellular loop to activate the receptor. Although first described for its role in platelet activation, PAR1 has been found throughout the human central nervous system. While its physiologic role remains unclear, many studies have shown that PAR1 plays a critical role in the pathophysiology of neurodegeneration. For example, PAR1 -/- animals have been shown to be protected in a number of different models of neuronal death including transient focal ischemia. Likewise, administration of a PAR1 antagonist to wild-type (WT) animals leads to levels of protection similar to the PAR1 knockout. The Substantia Nigra pars Compacta (SNc), an area of high levels of PAR1 expression, is the site of several neurodegenerative pathologies, including ischemic damage, and Parkinson's disease. We hypothesize that PAR1 is activated by serine proteases entering the brain following compromise of the blood-brain-barrier. Further, we hypothesize that activation of PAR1 in the SNc will alter glial and neuronal function and this change will render neurons more susceptible to damage. Completion of the proposed experiments will help define the role of PAR1 in SNc physiology along with the potential role of PAR1 in pathophysiological states.
| Hamill, Cecily E; Mannaioni, Guido; Lyuboslavsky, Polina et al. (2009) Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function. Exp Neurol 217:136-46 |
