Abstract
Abnormal function of NMDA receptor has been suggested to be correlated with the pathogenesis of Parkinson's disease (PD) as well as with the development of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Here we show that NMDA receptor NR2 subunits display specific alterations of their subcellular distribution in striata from unilateral 6-hydroxydopamine-lesioned, L-DOPA-treated dyskinetic, and L-DOPA-treated nondyskinetic rats. Dyskinetic animals have significantly higher levels of NR2A subunit in the postsynaptic compartment than all other experimental groups, whereas NR2B subunit shows a significant reduction in both dopamine-denervated and dyskinetic rats. These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102. Treatment of nondyskinetic animals with a synthetic peptide (TAT2B) able to affect NR2B binding to MAGUK proteins as well as synaptic localization of this subunit in nondyskinetic rats was sufficient to induce a shift of treated rats toward a dyskinetic motor behavior. These data indicate abnormal NR2B redistribution between synaptic and extrasynaptic membranes as an important molecular disturbance of the glutamatergic synapse involved in L-DOPA-induced dyskinesia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antiparkinson Agents / therapeutic use*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Corpus Striatum / chemistry
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Corpus Striatum / ultrastructure
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Disks Large Homolog 4 Protein
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / metabolism*
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Levodopa / therapeutic use*
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Male
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism*
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Motor Activity / drug effects
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Neuropeptides / chemistry
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Neuropeptides / metabolism*
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Oxidopamine / toxicity
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / drug therapy
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Parkinsonian Disorders / metabolism*
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Parkinsonian Disorders / pathology
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Phosphorylation
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Protein Binding
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Protein Interaction Mapping
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Protein Processing, Post-Translational
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Protein Structure, Tertiary
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Protein Transport
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Protein-Tyrosine Kinases / metabolism
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Psychomotor Performance / drug effects
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Rats
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Rats, Wistar
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Receptors, N-Methyl-D-Aspartate / analysis*
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Receptors, N-Methyl-D-Aspartate / chemistry
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Recombinant Fusion Proteins / pharmacology*
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Recombinant Fusion Proteins / therapeutic use*
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Subcellular Fractions / chemistry
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Synapses / chemistry
Substances
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Adaptor Proteins, Signal Transducing
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Antiparkinson Agents
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Disks Large Homolog 4 Protein
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Dlg1 protein, rat
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Dlg3 protein, rat
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Dlg4 protein, rat
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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NR2A NMDA receptor
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NR2B NMDA receptor
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Neuropeptides
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Receptors, N-Methyl-D-Aspartate
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Recombinant Fusion Proteins
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TAT2B protein
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Levodopa
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Oxidopamine
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Protein-Tyrosine Kinases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases