Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson's disease

Recent evidence has linked striatal N-methyl-D-aspartate (NMDA) receptor fu nction to the adverse effects of long-term dopaminergic treatment in Parkin son's disease. We have studied the abundance, composition, and phosphorylat ion of NMDA receptor subunits (NRs) in the rat 6-hydroxydopamine lesion mod el of parkinsonism. In lesioned striatum, the abundance of NR1 and NR2B in striatal membranes was decreased to 68 +/- 3.2 and 62 +/- 4.4%, respectivel y, relative to the unlesioned striata, whereas the abundance of NR2A was un changed. Coimmunoprecipitation of NMDA receptors under nondenaturing condit ions revealed that these changes reflected a selective depletion of recepto rs composed of NR1/NR2B, without alteration in receptors composed of NR1/NR 2A. However, the abundance and composition of striatal NMDA receptors in ex tracts containing both cytoplasmic and membrane proteins were not altered i n lesioned rats, suggesting that the changes in the membrane fraction resul ted from intracellular redistribution of receptors. The phosphorylation of NR1 protein at serine 890 and serine 896, but not at serine 897, and the ty rosine phosphorylation of NR2B but not NR2A were decreased in the membrane fraction of the lesioned striatum. Chronic treatment of lesioned rats with L-dopa normalized the alterations in the abundance and subunit composition of the NMDA receptors in striatal membranes, and produced striking hyperpho sphorylation, both of NR1 at serine residues, and NR2A and NR2B at tyrosine residues. These findings suggest that the adverse motor effects of chronic L-dopa therapy may result from alterations in regulatory phosphorylation s ites on NMDA receptors.