Regulation of DARPP-32 Dephosphorylation at PKA- And Cdk5-sites by NMDA and AMPA Receptors: Distinct Roles of Calcineurin and Protein phosphatase-2A

J Neurochem. 2002 May;81(4):832-41. doi: 10.1046/j.1471-4159.2002.00876.x.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / physiology
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Cobalt / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases / metabolism*
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • N-Methylaspartate / pharmacology
  • Nerve Tissue Proteins*
  • Okadaic Acid / pharmacology
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Potassium Chloride / pharmacology
  • Protein Phosphatase 2
  • Receptors, AMPA / agonists
  • Receptors, AMPA / metabolism*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Okadaic Acid
  • Cobalt
  • N-Methylaspartate
  • Potassium Chloride
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Cyclin-Dependent Kinase 5
  • Cyclic AMP-Dependent Protein Kinases
  • Cdk5 protein, mouse
  • Cyclin-Dependent Kinases
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Calcium