Beyond cAMP: The Regulation of Akt and GSK3 by Dopamine Receptors

Abstract

Brain dopamine receptors have been preferred targets for numerous pharmacological compounds developed for the treatment of various neuropsychiatric disorders. Recent discovery that D2 dopamine receptors, in addition to cAMP pathways, can engage also in Akt/GSK3 signaling cascade provided a new framework to understand intracellular signaling mechanisms involved in dopamine-related behaviors and pathologies. Here we review a recent progress in understanding the role of Akt, GSK3, and related signaling molecules in dopamine receptor signaling and functions. Particularly, we focus on the molecular mechanisms involved, interacting partners, role of these signaling events in the action of antipsychotics, psychostimulants, and antidepressants as well as involvement in pathophysiology of schizophrenia, bipolar disorder, and Parkinson's disease. Further understanding of the role of Akt/GSK3 signaling in dopamine receptor functions could provide novel targets for pharmacological interventions in dopamine-related disorders.

Keywords: Akt; G protein coupled receptor; arrestin; catecholamines; dopamine; glycogen synthase kinase 3; protein kinase B; receptor tyrosine kinase.

Figure 1

Dual role of beta-arrestin 2 in D2R desensitization and Akt/GSK3 signaling. (A) GPCR activation/desensitization cycle. Following the activation of dopamine receptors (DAR), the receptor is phosphorylated by G protein receptor kinases (GRK), which leads to the recruitment of beta-arrestins. The recruitment of beta-arrestins to the receptors results in clatrin-mediated endocytosis that is followed either by receptor degradation of cell surface recycling. (B) G protein-dependent and G protein-independent beta-arrestin-mediated signaling of D2R. Receptor activation leads to both classical G protein mediated signaling and to the formation of complexes of signaling molecules that are associated together by beta-arrestins. In the specific case of striatal D2R beta-arrestin 2 has been shown to enhance the interaction between Akt and protein phosphatase 2A (PP2A) therefore resulting in Akt inactivation and increased activation of GSK3.

Figure 2

Regulation of dopamine and D2R-dependent Akt:βArr2:PP2A signaling complex by lithium and GSK3. (A) Under basal condition, the activation of D2R stimulates the formation of a signaling complex composed by beta-arrestin 2, PP2A, and Akt. The formation of this complex results in increased inactivation of Akt by PP2A. Furthermore enhanced activation of GSK3 that results from Akt inhibition would act as a positive feedback loop that further stabilizes the signaling complex. Finally, the formation of this complex also appears to be dependent on Mg²⁺ to allow the interaction of Akt and beta-arrestin 2. (B) Following treatment with lithium, the formation of this signaling complex can be destabilized by two overlapping mechanisms. First a competition between Li⁺ and Mg²⁺ ions can disrupt the complex directly by preventing the interaction of Akt and beta-arrestin 2. Second direct inhibition of GSK3 by lithium prevents the stabilization of the complex by activated GSK3.

Figure 3

Putative signaling pathways downstream of dopamine receptors with different potential outcomes on Akt/GSK3 signaling. Dopamine receptors can regulate Akt and GSK3 signaling by acting through at least two signaling mechanisms that have an opposite effect on the activity of these two kinases. Activation of D2R leads to a regulated deactivation of Akt by PP2A that is mediated by beta-arrestin 2. In contrast activation of either D1R or D2R can also activate Akt via receptor tyrosine kinase (RTK) transactivation leading to enhancement of Pi3K signaling.