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 Ca2+ pathways through G-protein-mediated signaling. However, it has become apparent that, in addition to this canonical action, D2-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 β-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.