A dopamine/D1 receptor/protein kinase A/dopamine- and cAMP-regulated phosphoprotein (Mr 32 kDa)/protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor.
We have investigated the mechanism by which activation of dopamine (DA) receptors regulates the glutamate sensitivity of medium spiny neurons of the nucleus accumbens. Our results demonstrate that DA regulates the phosphorylation state of the NR1 subunit of NMDA-type glutamate receptors. The effect of DA was mimicked by SKF82526, a D1-type DA receptor agonist, and by forskolin, an activator of cAMP-dependent protein kinase (PKA), and was blocked by H-89, a PKA inhibitor. These data indicate that DA increases NR1 phosphorylation through a PKA-dependent pathway. DA-induced phosphorylation of NR1 was blocked in mice bearing a targeted deletion of the gene for dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32), a phosphoprotein that is a potent and selective inhibitor of protein phosphatase-1, indicating that the effect of PKA is mediated, in part, by regulation of the DARPP-32/protein phosphatase-1 cascade. In support of this interpretation, NR1 phosphorylation was increased by calyculin A, a protein phosphatase-1/2A inhibitor. A model is proposed in which the ability of DA to regulate NMDA receptor sensitivity is attributable to a synergistic action involving increased phosphorylation and decreased dephosphorylation of the NR1 subunit of the NMDA receptor.
Snyder
G L
GL
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA.
Fienberg
A A
AA
Huganir
R L
RL
Greengard
P
P
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004298:Dopamine / Q000502:physiology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D009419:Nerve Tissue Proteins; D010080:Oxazoles; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D011493:Protein Kinase C; D054645:Protein Phosphatase 1; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C059041:calyculin A