Abstract
Glutamatergic inputs from corticostriatal and thalamostriatal pathways have been shown to modulate dopaminergic signaling in neostriatal neurons. DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M (r) 32 kDa) is a signal transduction molecule that regulates the efficacy of dopamine signaling in neostriatal neurons. Dopamine signaling is mediated in part through phosphorylation of DARPP-32 at Thr34 by cAMP-dependent protein kinase, and antagonized by phosphorylation of DARPP-32 at Thr75 by cyclin-dependent protein kinase 5. We have now investigated the effects of the ionotropic glutamate NMDA and AMPA receptors on DARPP-32 phosphorylation in neostriatal slices. Activation of NMDA and AMPA receptors decreased the state of phosphorylation of DARPP-32 at Thr34 and Thr75. The decrease in Thr34 phosphorylation was mediated through Ca(2+) -dependent activation of the Ca(2+) -/calmodulin-dependent phosphatase, calcineurin. In contrast, the decrease in Thr75 phosphorylation was mediated through Ca(2+) -dependent activation of dephosphorylation by protein phosphatase-2A. The results provide support for a complex effect of glutamate on dopaminergic signaling through the regulation of dephosphorylation of different sites of DARPP-32 by different protein phosphatases.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites / physiology
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Calcineurin / metabolism
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Calcium / metabolism
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Cobalt / pharmacology
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Cyclin-Dependent Kinase 5
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Cyclin-Dependent Kinases / metabolism*
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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In Vitro Techniques
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Male
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Mice
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Mice, Inbred C57BL
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins*
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Okadaic Acid / pharmacology
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / metabolism
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Phosphoproteins / drug effects
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Phosphoproteins / metabolism*
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Phosphorylation / drug effects
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Potassium Chloride / pharmacology
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Protein Phosphatase 2
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Receptors, AMPA / agonists
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Receptors, AMPA / metabolism*
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Receptors, N-Methyl-D-Aspartate / agonists
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Receptors, N-Methyl-D-Aspartate / metabolism*
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Nerve Tissue Proteins
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Phosphoproteins
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Receptors, AMPA
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Receptors, N-Methyl-D-Aspartate
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Okadaic Acid
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Cobalt
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N-Methylaspartate
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Potassium Chloride
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Cyclin-Dependent Kinase 5
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Cyclic AMP-Dependent Protein Kinases
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Cdk5 protein, mouse
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Cyclin-Dependent Kinases
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Calcineurin
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Calcium