THE PHOSPHOPROTEIN DARPP-32 MEDIATES CAMP-DEPENDENT POTENTIATION OF STRIATAL N-METHYL-D-ASPARTATE RESPONSES

The signal transduction pathway underlying the cAMP-dependent modulati on of rat striatal N-methyl-D-aspartate (NMDA) responses was investiga ted by using the two-electrode voltage-clamp technique, In oocytes inj ected with rat striatal poly(A)(+) mRNA, activation of cAMP-dependent protein kinase (PKA) by forskolin potentiated NMDA responses, Inhibiti on of protein phosphatase 1 (PP1) and/or protein phosphatase 2A (PP2A) by the specific inhibitor calyculin A occluded the PKA-mediated poten tiation of striatal NMDA responses, suggesting that the PKA effect was mediated by inhibition of a protein phosphatase. Coinjection of oocyt es with striatal mRNA and antisense oligodeoxynucleotides directed aga inst the protein phosphatase inhibitor DARPP-32 dramatically reduced t he PKA enhancement of NMDA responses, NMDA responses recorded from ooc ytes injected with rat hippocampal poly(A)(+) mRNA were not affected b y stimulation of PKA, When oocytes were coinjected with rat hippocampa l poly(A)(+) mRNA plus complementary RNA coding for DARPP-32, NMDA res ponses were potentiated after stimulation of PKA, The results provide evidence that DARPP-32, which is enriched in the striatum, may partici pate in the signaling between the two major afferent striatal pathways , the glutamatergic and the dopaminergic projections, by the cAMP-depe ndent regulation of striatal NMDA currents.