Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices.
In the caudate-putamen the glutamatergic cortical input and the dopaminergic nigrostriatal input have opposite effects on the firing rate of striatal neurons. Although little is known of the biochemical mechanisms underlying this antagonism, one action of dopamine is to stimulate the cyclic AMP-dependent phosphorylation of DARPP-32 (dopamine and cAMP-regulated phospho-protein, of relative molecular mass 32,000 (32K]. This phosphorylation converts DARPP-32 from an inactive molecule into a potent inhibitor of protein phosphatase-1. Here we show that activation of the NMDA (N-methyl-D-aspartate) subclass of glutamate receptors reverses the cAMP-stimulated phosphorylation of DARPP-32 in striatal slices through NMDA-induced dephosphorylation of DARPP-32. Thus, the antagonistic effects of dopamine and glutamate on the excitability of striatal neurons are reflected in antagonistic effects of these neurotransmitters on the state of phosphorylation of DARPP-32. Our results indicate that stimulation of NMDA receptors leads to the activation of a neuronal protein phosphatase, presumably the calcium-dependent phosphatase calcineurin, and show, in an intact cell preparation, that signal transduction in the nervous system can be mediated by protein dephosphorylation.
Halpain
S
S
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York 10021.
Girault
J A
JA
Greengard
P
P
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004789:Enzyme Activation / Q000187:drug effects; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010750:Phosphoproteins; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D003986:Dibenzocycloheptenes; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010710:Phosphates; D010750:Phosphoproteins; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D010769:Phosphothreonine; D005576:Colforsin; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C056639:2-amino-5-phosphopentanoic acid; D000242:Cyclic AMP; D011494:Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D014633:Valine