Drugs of abuse modulate the phosphorylation of ARPP-21, a cyclic AMP-regulated phosphoprotein enriched in the basal ganglia

Neuropharmacology. 2000 Jul 10;39(9):1637-44. doi: 10.1016/s0028-3908(99)00230-0.


ARPP-21 is a cyclic AMP-regulated phosphoprotein of M(r) 21 kDa that is enriched in the cell bodies and terminals of medium-sized spiny neurons in the basal ganglia. Using a new phosphorylation state-specific antibody selective for the detection of ARPP-21 phosphorylated on Ser(55), we have demonstrated that activation of dopamine D1 receptors increased the level of ARPP-21 phosphorylation in mouse striatal slices. Conversely, activation of D2 receptors caused a large decrease in ARPP-21 phosphorylation. Treatment of mice with either methamphetamine or cocaine resulted in increased ARPP-21 phosphorylation in vivo. Studies using specific inhibitors of protein phosphatases and experiments in mice bearing a targeted deletion of the gene for DARPP-32, a dopamine-activated inhibitor of protein phosphatase-1, indicated that protein phosphatase-2A is primarily responsible for dephosphorylation of ARPP-21 in mouse striatum. These results demonstrate that phosphorylation and dephosphorylation of ARPP-21 are tightly regulated in the striatum. We speculate that ARPP-21 might mediate some of the physiologic effects of dopamine and certain drugs of abuse in the basal ganglia.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Basal Ganglia / drug effects*
  • Basal Ganglia / metabolism
  • Cattle
  • Cocaine / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Cyclosporine / pharmacology
  • Dopamine Uptake Inhibitors / pharmacology
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Enzyme Inhibitors / pharmacology
  • Illicit Drugs / pharmacology*
  • Marine Toxins
  • Methamphetamine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins*
  • Okadaic Acid / pharmacology
  • Oxazoles / pharmacology
  • Phosphoproteins / drug effects*
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • Phosphoproteins / pharmacology
  • Phosphorylation / drug effects
  • Rats


  • Antibodies, Monoclonal
  • Dopamine Uptake Inhibitors
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Enzyme Inhibitors
  • Illicit Drugs
  • Marine Toxins
  • Nerve Tissue Proteins
  • Oxazoles
  • Phosphoproteins
  • cyclic AMP-regulated phosphoprotein ARPP-21
  • Okadaic Acid
  • Methamphetamine
  • calyculin A
  • Cyclosporine
  • Cocaine