Amplification of dopaminergic signaling by a positive feedback loop.
Dopamine and cAMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) plays an obligatory role in most of the actions of dopamine. In resting neostriatal slices, cyclin-dependent kinase 5 (Cdk5) phosphorylates DARPP-32 at Thr-75, thereby reducing the efficacy of dopaminergic signaling. We report here that dopamine, in slices, and acute cocaine, in whole animals, decreases the state of phosphorylation of striatal DARPP-32 at Thr-75 and thereby removes this inhibitory constraint. This effect of dopamine is achieved through dopamine D1 receptor-mediated activation of cAMP-dependent protein kinase (PKA). The activated PKA, by decreasing the state of phosphorylation of DARPP-32-Thr-75, de-inhibits itself. Dopamine D2 receptor stimulation has the opposite effect. The ability of activated PKA to reduce the state of phosphorylation of DARPP-32-Thr-75 is apparently attributable to increased protein phosphatase-2A activity, with Cdk5 being unaffected. Together, these results indicate that via positive feedback mechanisms, Cdk5 signaling and PKA signaling are mutually antagonistic.
Nishi
A
A
Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. nishia@med.kurume-u.ac.jp
Bibb
J A
JA
Snyder
G L
GL
Higashi
H
H
Nairn
A C
AC
Greengard
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P
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005246:Feedback; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D003042:Cocaine; D004298:Dopamine