A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia.
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.
Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy.
Fabrizio
F
Gardoni
Barbara
B
Picconi
Veronica
V
Ghiglieri
Federica
F
Polli
Vincenza
V
Bagetta
Giorgio
G
Bernardi
Flaminio
F
Cattabeni
Monica
M
Di Luca
Paolo
P
Calabresi
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D013347:Subcellular Fractions / Q000737:chemistry; D013569:Synapses / Q000737:chemistry
D048868:Adaptor Proteins, Signal Transducing; D000978:Antiparkinson Agents; D000076122:Disks Large Homolog 4 Protein; C501119:Dlg1 protein, rat; C101195:Dlg3 protein, rat; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009479:Neuropeptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C509620:TAT2B protein; D007980:Levodopa; D016627:Oxidopamine; D011505:Protein-Tyrosine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases