ArticleProceedings of the National Academy of Sciences of the United States of America2015
Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 87 citations in OpenAlex.
- Membrane lipid poly-unsaturation selectively affects dopamine D2 receptor endocytosis.Nature communications · 2026Article
- Lost in translation: why don't dopamine D2 antagonists cure addictions?Journal of psychiatry & neuroscience : JPN · 2026Article
- Multidimensional Evaluation of Lisdexamfetamine: Pharmacology, Therapeutic Use, Toxicity and Forensic Implications.Basic & clinical pharmacology & toxicology · 2025Review
- Virtual Compound Screening for Discovery of Dopamine D1 Receptor Biased Allosteric Modulators.Journal of chemical information and modeling · 2025Article
- Mdm2-Mediated Ubiquitination Plays a Pivotal Role in Differentiating the Endocytic Roles of GRK2 and Arrestin3.International journal of molecular sciences · 2025Article
- Myosin VI drives arrestin-independent internalization and signaling of GPCRs.Nature communications · 2024Article
- Biased Signaling Agonists Promote Distinct Phosphorylation and Conformational States of the Dopamine D3 Receptor.International journal of molecular sciences · 2024Article
- Biased Dopamine DBiomolecules & therapeutics · 2024Article
- Review
- Ubiquitination of GRK2 Is Required for the β-Arrestin-Biased Signaling Pathway of Dopamine D2 Receptors to Activate ERK Kinases.International journal of molecular sciences · 2023Article
- Unveiling the Differences in Signaling and Regulatory Mechanisms between Dopamine DInternational journal of molecular sciences · 2023Review
- The histamine H3 receptor modulates dopamine D2 receptor-dependent signaling pathways and mouse behaviors.The Journal of biological chemistry · 2023Article
- Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal.Biomedicines · 2023Review
- The Drosophila dopamine 2-like receptor D2R (Dop2R) is required in the blood brain barrier for male courtship.Genes, brain, and behavior · 2023Article
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- Dopamine, Immunity, and Disease.Pharmacological reviews · 2023Review
- Middle-Down Mass Spectrometry Reveals Activity-Modifying Phosphorylation Barcode in a Class C G Protein-Coupled Receptor.Journal of the American Chemical Society · 2022Article
- Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review.Neurology and therapy · 2022Review
- Genome interpretation using in silico predictors of variant impact.Human genetics · 2022Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The neuromodulator dopamine signals through the dopamine D2 receptor (D2R) to modulate central nervous system functions through diverse signal transduction pathways. D2R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D2R signals through distinct G-protein and β-arrestin pathways, and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D2R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D2R mutants with strongly biased signal transduction for either the G-protein or β-arrestin interactions. These mutants were used to resolve the role of G proteins and β-arrestins in D2R signaling assays. The results show that D2R interactions with the two downstream effectors are dissociable and that G-protein signaling accounts for D2R canonical MAP kinase signaling cascade activation, whereas β-arrestin only activates elements of this cascade under certain conditions. Nevertheless, when expressed in mice in GABAergic medium spiny neurons of the striatum, the β-arrestin-biased D2R caused a significant potentiation of amphetamine-induced locomotion, whereas the G protein-biased D2R had minimal effects. The mutant receptors generated here provide a molecular tool set that should enable a better definition of the individual roles of G-protein and β-arrestin signaling pathways in D2R pharmacology, neurobiology, and associated pathologies.
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