Activation of glycogen synthase kinase-3 beta is required for hyperdopamine and D2 receptor-mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex.
The interactions between dopamine and glutamate systems play an essential role in normal brain functions and neuropsychiatric disorders. The mechanism of NMDA receptor regulation through high concentrations of dopamine, however, remains unclear. Here, we show the signaling pathways involved in hyperdopaminergic regulation of NMDA receptor functions in the prefrontal cortex by incubating cortical slices with high concentration of dopamine or administering dopamine reuptake inhibitor 1-(2-[bis-(4-fluorophenyl)methoxy]ethyl)- 4-(3-phenylpropyl)piperazine (GBR12909) in vivo. We found that, under both conditions, the synaptic NMDA receptor-mediated currents were significantly attenuated by excessive dopamine stimulation through activation of D(2) receptors. Furthermore, high dose of dopamine failed to affect NMDA receptor-mediated currents after blockade of NR2B subunits but triggered a dynamin-dependent endocytosis of NMDA receptors. The high-dose dopamine/D(2) receptor-mediated suppression of NMDA receptors was involved in the increase of glycogen synthase kinase-3beta (GSK-3beta) activity, which in turn phosphorylates beta-catenin and disrupts beta-catenin-NR2B interaction, but was dependent on neither Gq11 nor PLC (phospholipase C). Moreover, the hyperdopamine induced by GBR12909 significantly decreased the expression of both surface and intracellular NR2B proteins, as well as NR2B mRNA levels, suggesting an inhibition of protein synthesis. These effects were, however, completely reversed by administration of either GSK-3beta inhibitor or D(2) receptor antagonist. These results therefore suggest that GSK-3beta is required for the hyperdopamine/D(2) receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D(2) receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.
Li
Yan-Chun
YC
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.
Xi
Dong
D
Roman
Joy
J
Huang
Yue-Qiao
YQ
Gao
Wen-Jun
WJ
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D066298:In Vitro Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
C495268:Ctnnb1 protein, rat; D065127:Dopamine D2 Receptor Antagonists; C121001:NR2B NMDA receptor; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D034281:Dynamins; D004298:Dopamine