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

Anthone W. Dunah, Yuehua Wang, Robert P. Yasuda, Kimihiko Kameyama, Richard L Huganir, Barry B. Wolfe, David G. Standaert

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)342-352
Number of pages11
JournalMolecular Pharmacology
Volume57
Issue number2
StatePublished - 2000

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Corpus Striatum
Oxidopamine
Glutamate Receptors
N-Methyl-D-Aspartate Receptors
Parkinson Disease
Phosphorylation
Serine
Membranes
Levodopa
Tyrosine
Parkinsonian Disorders
N-methylglutamate
Membrane Proteins
Cell Membrane
Proteins

ASJC Scopus subject areas

  • Pharmacology

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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. / Dunah, Anthone W.; Wang, Yuehua; Yasuda, Robert P.; Kameyama, Kimihiko; Huganir, Richard L; Wolfe, Barry B.; Standaert, David G.

In: Molecular Pharmacology, Vol. 57, No. 2, 2000, p. 342-352.

Research output: Contribution to journalArticle

Dunah, Anthone W. ; Wang, Yuehua ; Yasuda, Robert P. ; Kameyama, Kimihiko ; Huganir, Richard L ; Wolfe, Barry B. ; Standaert, David G. / 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. In: Molecular Pharmacology. 2000 ; Vol. 57, No. 2. pp. 342-352.
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