TY - JOUR

T1 - Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics

AU - Masri, Bernard

AU - Salahpour, Ali

AU - Didriksen, Michael

AU - Ghisi, Valentina

AU - Beaulieu, Jean Martin

AU - Gainetdinov, Raul R.

AU - Caron, Marc G.

PY - 2008/9/9

Y1 - 2008/9/9

N2 - 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 (β-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 D2LR with β-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 β-arrestin 2 recruitment to D2LR induced by quinpirole. However, these antipsychotics have various effects on D2LR 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 D2LR/β- arrestin 2 mediated signaling. Thus, selective targeting of D2 LR/β-arrestin 2 interaction and related signaling pathways may provide new opportunities for antipsychotic development.

AB - 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 (β-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 D2LR with β-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 β-arrestin 2 recruitment to D2LR induced by quinpirole. However, these antipsychotics have various effects on D2LR 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 D2LR/β- arrestin 2 mediated signaling. Thus, selective targeting of D2 LR/β-arrestin 2 interaction and related signaling pathways may provide new opportunities for antipsychotic development.

KW - BRET

KW - Functional selectivity

KW - Schizophrenia

KW - Signaling

UR - http://www.scopus.com/inward/record.url?scp=51649084026&partnerID=8YFLogxK

U2 - 10.1073/pnas.0803522105

DO - 10.1073/pnas.0803522105

M3 - Article

C2 - 18768802

AN - SCOPUS:51649084026

VL - 105

SP - 13656

EP - 13661

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 36

ER -