Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics

Abstract

Since the unexpected discovery of the antipsychotic activity of chlorpromazine, a variety of therapeutic agents have been developed for the treatment of schizophrenia. Despite differences in their activities at various neurotransmitter systems, all clinically effective antipsychotics share the ability to interact with D2 class dopamine receptors (D2R). D2R mediate their physiological effects via both G protein-dependent and independent (␤-arrestin 2-dependent) signaling, but the role of these D2R-mediated signaling events in the actions of antipsychotics remains unclear. We demonstrate here that while different classes of antipsychotics have complex pharmacological profiles at G protein-dependent D2R long isoform (D2 LR) signaling, they share the common property of antagonizing dopamine-mediated interaction of D2 LR with ␤-arrestin 2. Using two cellular assays based on a bioluminescence resonance energy transfer (BRET) approach, we demonstrate that a series of antipsychotics including haloperidol, clozapine, aripiprazole, chlorpromazine, quetiapine, olanzapine, risperidone, and ziprasidone all potently antagonize the ␤-arrestin 2 recruitment to D2 LR induced by quinpirole. However, these antipsychotics have various effects on D2 LR mediated Gi/o protein activation ranging from inverse to partial agonists and antagonists with highly variable efficacies and potencies at quinpirole-induced cAMP inhibition. These results suggest that the different classes of clinically effective antipsychotics share a common molecular mechanism involving inhibition of D2 LR/␤-arrestin 2 mediated signaling. Thus, selective targeting of D2LR/␤-arrestin 2 interaction and related signaling pathways may provide new opportunities for antipsychotic development.BRET ͉ schizophrenia ͉ signaling ͉ functional selectivity

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

“…These changes in signal transduction allowed for the elucidation of complex signaling paradigms. MAP kinase cascades have previously been shown to be activated downstream of G proteins and β-arrestins (25,26), but as shown here, [Gprot] D 2 R is responsible for a major component of the ERK signaling cascade with the normal complement of kinases and β-arrestins present in HEK 293T cells. However, overexpression of β-arrestin 2 revealed the ability of [βarr] D 2 R to couple to ERK.…”

“…1 A and B, mutations were predicted and scored by EA according to how likely they would produce a phenotype (Table S1). Each point mutation was tested for G-protein activity by cAMP inhibition and β-arrestin 2 recruitment by bioluminescent resonance energy transfer (BRET) (25) and fidelity of plasma membrane trafficking as well as lack of constitutive activity. These mutants were binned into four categories: (i) β-arrestinbiased, (ii) G protein-biased, (iii) deficient at both pathways, or (iv) unaffected at either pathway ( Table S1 and Fig.…”

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

“…Given the clinical efficacy of antipsychotic medications it is reasonable to expect that these drugs would influence CME. While this has not yet been specifically assessed, it has been shown that these agents influence core members of the CME interactome 109 . Further, lithium and PUFAs also influence CME 115,118 .…”

“…In search of a common mechanism which may explain their clinical effectiveness, Masri and colleagues recently demonstrated that first-and second generation antipsychotics strongly antagonize recruitment of the CME protein -arrestin to D2R's following stimulation with dopamine or quinpirole 109 . The authors further demonstrated that this inhibition effectively prevented -arrestin mediated signaling through the Akt/ Glycogen Synthase Kinase-3 (GSK-3) pathway 110 .…”

Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice

“…These data suggest D2R involvement in olanzapine activity. Although olanzapine displays slightly lower affinity for D2R than risperidone and ziprasidone [5], olanzapine has similar antagonist efficacy in D2R-mediated signaling, such as reversing dopamine D2R-mediated decreases in cAMP accumulation [32] and other signaling [33].…”