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 G(alpha)i/o and also by promoting formation of a multi-protein complex containing beta-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 GSK beta 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 beta-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. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.