The phosphoprotein DARPP-32 mediates cAMP-dependent potentiation of striatal N-methyl-D-aspartate responses.
The signal transduction pathway underlying the cAMP-dependent modulation of rat striatal N-methyl-D-aspartate (NMDA) responses was investigated by using the two-electrode voltage-clamp technique. In oocytes injected with rat striatal poly(A)+ mRNA, activation of cAMP-dependent protein kinase (PKA) by forskolin potentiated NMDA responses. Inhibition of protein phosphatase 1 (PP1) and/or protein phosphatase 2A (PP2A) by the specific inhibitor calyculin A occluded the PKA-mediated potentiation of striatal NMDA responses, suggesting that the PKA effect was mediated by inhibition of a protein phosphatase. Coinjection of oocytes with striatal mRNA and antisense oligodeoxynucleotides directed against the protein phosphatase inhibitor DARPP-32 dramatically reduced the PKA enhancement of NMDA responses. NMDA responses recorded from oocytes injected with rat hippocampal poly(A)+ mRNA were not affected by stimulation of PKA. When oocytes were coinjected with rat hippocampal poly(A)+ mRNA plus complementary RNA coding for DARPP-32, NMDA responses were potentiated after stimulation of PKA. The results provide evidence that DARPP-32, which is enriched in the striatum, may participate in the signaling between the two major afferent striatal pathways, the glutamatergic and the dopaminergic projections, by the cAMP-dependent regulation of striatal NMDA currents.
Blank
T
T
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, D-37075 Goettingen, Germany. blank@mail.mpiem.gwdg.de
Nijholt
I
I
Teichert
U
U
Kügler
H
H
Behrsing
H
H
Fienberg
A
A
Greengard
P
P
Spiess
J
J
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D010750:Phosphoproteins / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016202:N-Methylaspartate; D000242:Cyclic AMP