ArticleThe Journal of biological chemistry2018
The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 52 citations in OpenAlex.
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- 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
- GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization.Science signaling · 2024Article
- Neuromodulator regulation and emotions: insights from the crosstalk of cell signaling.Frontiers in molecular neuroscience · 2024Review
- G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the DBiomolecules · 2023Article
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- 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
- Phosphorylation barcodes direct biased chemokine signaling at CXCR3.Cell chemical biology · 2023Article
- Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2.Frontiers in pharmacology · 2023Article
- Location bias contributes to functionally selective responses of biased CXCR3 agonists.Nature communications · 2022Article
- BRET-Based Biosensors to Measure Agonist Efficacies in Histamine HInternational journal of molecular sciences · 2022Article
- Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties.Frontiers in molecular biosciences · 2022Article
- Noncanonical scaffolding of GScience (New York, N.Y.) · 2021Article
- Receptor-Arrestin Interactions: The GPCR Perspective.Biomolecules · 2021Review
- Targeting G protein-coupled receptor kinases (GRKs) to G protein-coupled receptors.Current opinion in endocrine and metabolic research · 2021Article
- Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.Frontiers in systems neuroscience · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
Abstract
The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways. Therefore, βarr recruitment appears to be intimately tied to G protein activation via GRKs. Here we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on βarr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or βarrs as well as a βarr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the βarr-preferring D2R achieves βarr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the βarr-preferring D2R and also contributes to βarr recruitment at the WT D2R. Additionally, we found an additive interaction between the βarr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving βarr-biased signaling.
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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.