Differential expression and ser897 phosphorylation of striatal N-methyl-d-aspartate receptor subunit NR1 in animal models of Parkinson's disease.
Parkinson's disease (PD) is associated with complex compensatory changes in the functional and neurochemical anatomy of the basal ganglia resulting from striatal dopamine deficiency. Available evidence suggests that glutamatergic corticostriatal pathway becomes overactive following nigrostriatal dopaminergic denervation. Since N-methyl-d-aspartate (NMDA) receptors are abundant and functionally important in the striatum, we examined the effects of striatal dopamine deficiency on the distribution and density of NMDA receptor subunit 1 (NR1) and serine phosphorylation (ser897) of NR1 in the striatum. Phosphorylation at this residue is believed to be dependent on protein kinase A. In both 6-hydroxydopamine-lesioned rats and MPTP-treated monkeys, striatal dopamine denervation resulted in down-regulation of NR1 expression and an increase in the expression of ser897-phosphorylated NR1 by striatal neurons. The decreased NR1 expression may be a compensatory response to overactive glutamatergic inputs, which appear to occur in response to striatal dopamine denervation in animal models of PD. Furthermore, the alterations observed in protein kinase A-dependent phosphorylation of NR1 are suggestive of receptor internalization and subcellular trafficking of NR1 in response to increased striatal glutamatergic activity.
Betarbet
Ranjita
R
Department of Neurology and the Center for Neurodegenerative Disease, Emory University, Atlanta GA 30322, USA. rbetarb@emory.edu
Poisik
Olga
O
Sherer
Todd B
TB
Greenamyre
J Timothy
JT
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008297:Male; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D017868:Cyclic AMP-Dependent Protein Kinases