Amplification of dopaminergic signaling by a positive feedback loop
- 24 October 2000
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 97 (23) , 12840-12845
- https://doi.org/10.1073/pnas.220410397
Abstract
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.Keywords
This publication has 34 references indexed in Scilit:
- Beyond the Dopamine ReceptorPublished by Elsevier ,1999
- DARPP-32: Regulator of the Efficacy of Dopaminergic NeurotransmissionScience, 1998
- Activation of protein phosphatase 2A by cAMP‐dependent protein kinase‐catalyzed phosphorylation of the 74‐kDa B″ (δ) regulatory subunit in vitro and identification of the phosphorylation sitesFEBS Letters, 1998
- cAMP Counter-regulates Insulin-mediated Protein Phosphatase-2A Inactivation in Rat Skeletal Muscle CellsPublished by Elsevier ,1996
- The B56 Family of Protein Phosphatase 2A (PP2A) Regulatory Subunits Encodes Differentiation-induced Phosphoproteins That Target PP2A to Both Nucleus and CytoplasmJournal of Biological Chemistry, 1996
- Identification of a New Family of Protein Phosphatase 2A Regulatory SubunitsJournal of Biological Chemistry, 1995
- Neuronal Cyclin‐Dependent Kinase‐5 Phosphorylation Sites in Neurofilament Protein (NF‐H) Are Dephosphorylated by Protein Phosphatase 2AJournal of Neurochemistry, 1995
- Calyculin A and okadaic acid: Inhibitors of protein phosphatase activityBiochemical and Biophysical Research Communications, 1989
- DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1Nature, 1984
- Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatumNature, 1981