ArticleProceedings of the National Academy of Sciences of the United States of America2016
Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 136 citations in OpenAlex.
- Dopamine D2 receptors bypass canonical signaling to directly tune NMDA receptor function and aversive learning.Science advances · 2026Article
- Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.JCI insight · 2026Article
- Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism.The Journal of biological chemistry · 2026Article
- Lost in translation: why don't dopamine D2 antagonists cure addictions?Journal of psychiatry & neuroscience : JPN · 2026Article
- Article
- The clinical implication of β-arrestins-mediated signaling in memory and cognition.Molecular and cellular biochemistry · 2025Review
- Stabilized DNature communications · 2025Article
- Virtual Compound Screening for Discovery of Dopamine D1 Receptor Biased Allosteric Modulators.Journal of chemical information and modeling · 2025Article
- Biased agonism in psychopharmacology: an opportunity to improve efficacy and safety of treatments.CNS spectrums · 2025Review
- Molecular mechanism of β-arrestin 2 interaction with phosphorylated intracellular loop 3 of dopamine receptor D2.Communications biology · 2025Article
- Cannabinoid CB1 receptor-sensitive neurodevelopmental processes and trajectories.Molecular psychiatry · 2025Review
- Opioid Analgesics: Rise and Fall of Ligand Biased Signaling and Future Perspectives in the Quest for the Holy Grail.CNS drugs · 2025Review
- Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission.Nature communications · 2024Article
- Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral sensitization.Cell reports. Medicine · 2024Article
- The multifaceted functions of β-arrestins and their therapeutic potential in neurodegenerative diseases.Experimental & molecular medicine · 2024Review
- Arrestin-3 Agonism at Dopamine DBiological psychiatry · 2023Article
- Review
- Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures.Neuropharmacology · 2023Review
- Article
- The G protein biased serotonin 5-HT2A receptor agonist lisuride exerts anti-depressant drug-like activities in mice.Frontiers in molecular biosciences · 2023Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 7 institutions in 1 country.
Funding
Abstract
The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.
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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.