Amplification of dopaminergic signaling by a positive feedback loop

Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12840-5. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Cocaine / metabolism
  • Cocaine / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases / metabolism*
  • Dopamine / metabolism*
  • Dopamine / pharmacology
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Feedback
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Neostriatum / drug effects
  • Neostriatum / metabolism*
  • Neostriatum / pathology
  • Nerve Tissue Proteins*
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Phosphatase 2
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Signal Transduction / physiology*

Substances

  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Cyclin-Dependent Kinase 5
  • Cyclic AMP-Dependent Protein Kinases
  • Cdk5 protein, mouse
  • Cyclin-Dependent Kinases
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Cocaine
  • Dopamine