ArticleProceedings of the National Academy of Sciences of the United States of America2008
Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 175 papers.
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Who cites it
175 citing papers in PubMed, 318 citations in OpenAlex.
- Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2010Trial
- Subcellular Localization of Dopamine D1 and D2 Receptors in the Mouse Hippocampus.The Journal of comparative neurology · 2026Article
- Lost in translation: why don't dopamine D2 antagonists cure addictions?Journal of psychiatry & neuroscience : JPN · 2026Article
- The clinical implication of β-arrestins-mediated signaling in memory and cognition.Molecular and cellular biochemistry · 2025Review
- Stabilized DNature communications · 2025Article
- Molecular mechanism of β-arrestin 2 interaction with phosphorylated intracellular loop 3 of dopamine receptor D2.Communications biology · 2025Article
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- Effects of positive mGlu5 modulation on DJournal of psychopharmacology (Oxford, England) · 2025Article
- Haloperidol dopamine receptor occupancy and antagonism correspond to delirium agitation scores and EPS risk: A PBPK-PD modeling analysis.Journal of psychopharmacology (Oxford, England) · 2025Article
- Proteomic signatures of retinal pigment epithelium-derived exosomes in myopic and non-myopic tree shrew eyes.Frontiers in medicine · 2025Article
- Essential strategies for the detection of constitutive and ligand-dependent Gi-directed activity of 7TM receptors using bioluminescence resonance energy transfer.bioRxiv : the preprint server for biology · 2024Article
- Combination of Haloperidol With UNC9994, β-arrestin-Biased Analog of Aripiprazole, Ameliorates Schizophrenia-Related Phenotypes Induced by NMDAR Deficit in Mice.The international journal of neuropsychopharmacology · 2024Article
- Adenylyl cyclase isoforms 5 and 6 in the cardiovascular system: complex regulation and divergent roles.Frontiers in pharmacology · 2024Review
- Arrestin-3 Agonism at Dopamine DBiological psychiatry · 2023Article
- Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility.Biomolecules · 2023Article
- Neighborhood socioeconomic deprivation and individual-level socioeconomic status are associated with dopamine-mediated changes to monocyte subset CCR2 expression via a cAMP-dependent pathway.Brain, behavior, & immunity - health · 2023Article
- Towards Novel Potential Molecular Targets for Antidepressant and Antipsychotic Pharmacotherapies.International journal of molecular sciences · 2023Review
- G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders.Signal transduction and targeted therapy · 2023Review
- Unique effect of clozapine on adenosine ABiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Article
- Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal.Biomedicines · 2023Review
115 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
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 (beta-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(L)R) signaling, they share the common property of antagonizing dopamine-mediated interaction of D2(L)R with beta-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 beta-arrestin 2 recruitment to D2(L)R induced by quinpirole. However, these antipsychotics have various effects on D2(L)R mediated G(i/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(L)R/beta-arrestin 2 mediated signaling. Thus, selective targeting of D2(L)R/beta-arrestin 2 interaction and related signaling pathways may provide new opportunities for antipsychotic development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.