The Akt-GSK-3 signaling cascade in the actions of dopamine

Trends Pharmacol Sci. 2007 Apr;28(4):166-72. doi: 10.1016/ Epub 2007 Mar 8.


Drugs that act on dopamine neurotransmission are important tools for the management of multiple neuropsychiatric disorders. Classically, dopamine receptors have been shown to regulate cAMP-PKA (protein kinase A) and Ca(2+) pathways through G-protein-mediated signaling. However, it has become apparent that, in addition to this canonical action, D(2)-class dopamine receptors can function through a protein kinase B (Akt)-GSK-3 (glycogen synthase kinase 3) signaling cascade. This novel signaling mode involves the multifunctional scaffolding protein beta-arrestin 2, which has a role in G-protein-coupled receptor (GPCR) desensitization. In this article, we provide an overview of how this dual function of components of the GPCR desensitization machinery relates to dopamine-receptor-mediated responses and we summarize recent insights into the relevance of the Akt-GSK-3 signaling cascade for the expression of dopamine-associated behaviors and the actions of dopaminergic drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Arrestins / metabolism
  • Cyclic AMP / metabolism
  • Dopamine / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Dopamine / metabolism*
  • Signal Transduction
  • beta-Arrestin 2
  • beta-Arrestins


  • ARRB2 protein, human
  • Antipsychotic Agents
  • Arrestins
  • Receptors, Dopamine
  • beta-Arrestin 2
  • beta-Arrestins
  • Cyclic AMP
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Dopamine