TY - JOUR T1 - Exacerbation of Dopaminergic Terminal Damage in a Mouse Model of Parkinson's Disease by the G-Protein-Coupled Receptor Protease-Activated Receptor 1 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 653 LP - 664 DO - 10.1124/mol.107.038158 VL - 72 IS - 3 AU - Cecily E. Hamill AU - W. Michael Caudle AU - Jason R. Richardson AU - Hongjie Yuan AU - Kurt D. Pennell AU - James G. Greene AU - Gary W. Miller AU - Stephen F. Traynelis Y1 - 2007/09/01 UR - http://molpharm.aspetjournals.org/content/72/3/653.abstract N2 - Protease-activated receptor 1 (PAR1) is a G-protein-coupled receptor activated by serine proteases and expressed in astrocytes, microglia, and specific neuronal populations. We examined the effects of genetic deletion and pharmacologic blockade of PAR1 in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease, a neurodegenerative disease characterized by nigrostriatal dopamine damage and gliosis. After MPTP injection, PAR1–/– mice showed significantly higher residual levels of dopamine, dopamine transporter, and tyrosine hydroxylase and diminished microgliosis compared with wild-type mice. Comparable levels of dopaminergic neuroprotection from MPTP-induced toxicity were obtained by infusion of the PAR1 antagonist, BMS-200261 into the right lateral cerebral ventricle. MPTP administration caused changes in the brain protease system, including increased levels of mRNA for two PAR1 activators, matrix metalloprotease-1 and Factor Xa, suggesting a mechanism by which MPTP administration could lead to overactivation of PAR1. We also report that PAR1 is expressed in human substantia nigra pars compacta glia as well as tyrosine hydroxylase-positive neurons. Together, these data suggest that PAR1 might be a target for therapeutic intervention in Parkinson's disease. The American Society for Pharmacology and Experimental Therapeutics ER -