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Vol. 57, Issue 2, 342-352, February 2000
Department of Neurology, Massachusetts General Hospital and Harvard
Medical School, Boston, Massachusetts (A.W.D., D.G.S.); Department of
Pharmacology, Georgetown University School of Medicine, Washington DC
(Y.W., B.B.W.); Department of Neuroscience, Johns Hopkins University
School of Medicine, Baltimore, Maryland (R.P.Y., K.K., R.L.H.).
Recent evidence has linked striatal
N-methyl-D-aspartate (NMDA) receptor
function to the adverse effects of long-term dopaminergic treatment in
Parkinson's disease. We have studied the abundance, composition, and
phosphorylation of NMDA receptor subunits (NRs) in the rat
6-hydroxydopamine lesion model of parkinsonism. In lesioned striatum,
the abundance of NR1 and NR2B in striatal membranes was decreased to
68 ± 3.2 and 62 ± 4.4%, respectively, relative to the
unlesioned striata, whereas the abundance of NR2A was unchanged. Coimmunoprecipitation of NMDA receptors under nondenaturing conditions revealed that these changes reflected a selective depletion of receptors composed of NR1/NR2B, without alteration in receptors composed of NR1/NR2A. However, the abundance and composition of striatal NMDA receptors in extracts containing both cytoplasmic and
membrane proteins were not altered in lesioned rats, suggesting that
the changes in the membrane fraction resulted from intracellular redistribution of receptors. The phosphorylation of NR1 protein at
serine 890 and serine 896, but not at serine 897, and the tyrosine 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 hyperphosphorylation, 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 sites on NMDA receptors.
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