title: The Akt-GSK-3 signaling cascade in the actions of dopamine.
abstract: 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.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. m.caron@cellbio.duke.edu
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Beaulieu
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism*; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D014150:Antipsychotic Agents; D019390:Arrestins; D011954:Receptors, Dopamine; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine