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

ARPP-21 is a cyclic AMP-regulated phosphoprotein of M-r 21 kDa that is enri ched in the cell bodies and terminals of medium-sized spiny neurons in the basal ganglia. Using a new phosphorylation state-specific antibody selectiv e for the detection of ARPP-21 phosphorylated on Ser(55), we have demonstra ted that activation of dopamine D1 receptors increased the level of ARPP-21 phosphorylation in mouse striatal slices. Conversely, activation of D2 rec eptors caused a large decrease in ARPP-21 phosphorylation. Treatment of mic e with either methamphetamine or cocaine resulted in increased ARPP-21 phos phorylation in vivo. Studies using specific inhibitors of protein phosphata ses and experiments in mice bearing a targeted deletion of the gene for DAR PP-32, a dopamine-activated inhibitor of protein phosphatase-1, indicated t hat protein phosphatase-2A is primarily responsible for dephosphorylation o f 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 do pamine and certain drugs of abuse in the basal ganglia. (C) 2000 Elsevier S cience Ltd. All rights reserved.