The Akt-GSK-3 signaling cascade in the actions of dopamine.
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.
Beaulieu
Jean-Martin
JM
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. m.caron@cellbio.duke.edu
Gainetdinov
Raul R
RR
Caron
Marc G
MG
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
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