Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum

G protein-coupled receptors (GPCR) signal not only through heterotrimeric G proteins, but also through alternate pathways. Thus, dopamine D2 receptors in the striatum signal through Gi/o and also by promoting formation of a multi-protein complex containing ?-arrestin2, protein phosphatase 2A (PP2A), and Akt in order to dephosphorylate Akt. Lithium, on the other hand, disrupts this complex to increase Akt phosphorylation. Rhes is a striatally enriched GTP-binding protein that has been shown to inhibit dopamine receptor-mediated behavior and signaling through heterotrimeric G proteins. Therefore, our objective was to test whether Rhes similarly affects signaling through the Akt/GSK3 pathway in the striatum. Rhes mice showed basally increased Akt and GSK3? phosphorylation relative to rhes mice that was not further enhanced by lithium treatment. Furthermore, they responded to the D1/D2 agonist apomorphine with increased Akt and GSK3 phosphorylation. Co-immunoprecipitation experiments revealed that apomorphine treatment recruits PP 2A-C to Akt in both rhes and rhes mice. Lithium did not disrupt their interaction in rhes mice as there was little basal interaction. Rhes co-immunoprecipitated with ?-arrestins, suggesting that it is integral to the multi-protein complex. Thus, Rhes is necessary for Akt dephosphorylation by the striatal multi-protein complex, and in its absence, a lithium-treated phenotype results. © 2013 IBRO.