Abstract

Prof. Marc Caron, Department of Cell Biology, Medicine and Neurobiology, Duke University Medical Center, USA.

G protein-coupled receptors (GPCR-7TM) can signal not only through the activation of G proteins but also through the ability of GPCR/beta-arrestin 2 (Barr2) to scaffold intracellular signaling complexes. The brain dopaminergic system is implicated in the control of many physiological functions. Hyperactivity of the dopaminergic system recapitulates symptoms of psychosis. Several classes of antipsychotics have been developed for the treatment of schizophrenia. Despite their complex pharmacological profiles, all clinically effective antipsychotics share the ability to interact with D2 class dopamine receptors (D2R). G protein-coupled receptors (GPCR-7TM) like the D2Rs can signal not only through the activation of G proteins but also through the ability of GPCR/ß-arrestin 2 (βarr2) to scaffold intracellular signaling complexes. Interestingly, D2Rs mediate their physiological effects via both of these pathways but the role of these D2R-mediated signaling events in the actions of antipsychotics remains unclear.

In mice, pharmacological or genetic activation of D2-like receptors (D2R) modulates not only the G protein/cAMP-dependent signaling pathway but also engages an Akt-GSK-3 signaling pathway through the ability of D2R/ßarr2 complex to scaffold the kinase Akt and the phosphatase PP2A. Thus, in mice D2R activation leads to a dephosphorylation (inhibition) of Akt (Thr308) and dephosphorylation of GSK-3 (activation), an effect that is independent of both cAMP and Ca2+ signaling. Behaviorally, inhibition of GSK-3 inhibits dopaminergic responses. ßarr2-KO mice show diminished behavioral responses to D2R activation and loose the ability of D2Rs to regulate Akt/GSK3 phosphorylation with no effects on G protein-mediated responses. Using the two cellular assays, we demonstrate that a large series of antipsychotics including haloperidol, clozapine and aripiprazole, uniformly and potently antagonize the β-arrestin 2 recruitment to D2R induced by agonists. On the other hand, these antipsychotics have complex pharmacological profiles on D2R mediated Gi/o protein/cAMP inhibition with very highly variable efficacies. The higher potency of the drugs at the β-arrestin-2-dependent D2R signaling ranges from 3 to 150 fold. Interestingly, the mood stabilizer lithium can also regulates Akt/GSK-3 signaling and related behaviors in mice by disrupting the signaling complex composed of βarr2/Akt/PP2A.

These results suggest that the Akt/GSK-3 signaling pathway plays an important role in the actions of dopamine and that antagonism at the barr2-dependent signaling is a common property of clinically effective antipsychotics. Thus, βarr2-mediated signaling complexes represent interesting novel pharmacological targets for functionally selective agents.

Host: Prof Neal Copeland