ArticleCommunications biology2024
GRK specificity and Gβγ dependency determines the potential of a GPCR for arrestin-biased agonism.
Article in Communications biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Steric control of signaling bias in the immunometabolic receptor GPR84.Nature communications · 2026Article
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts.Journal of cellular and molecular medicine · 2026Article
- Docking of virtual libraries identifies small-molecule agonists of neurotensin receptors with analgesic activity.Nature communications · 2026Article
- G-protein regulatory network governs receptor internalization dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- GPCR kinases shape ACKR4 functions via differential C-terminal phosphorylation.Nature communications · 2026Article
- Article
- Cytoplasmic tail diversity determines the effector bias of the adhesion GPCR ADGRL2.Cell chemical biology · 2026Article
- mPFC Synaptosome Proteomics Reveals Novel Pathways and Muscarinic Receptor Changes in a Learned Helplessness Mouse Model.bioRxiv : the preprint server for biology · 2026Article
- The Role of Intrinsically Disordered Domains in Regulating G Protein-Coupled Receptor Signaling.Journal of the American Chemical Society · 2026Article
- The role of intrinsically disordered domains in regulating G protein coupled receptor signaling.bioRxiv : the preprint server for biology · 2025Article
- Novel atypical G protein-coupled receptor (GPCR)-arrestin complexes: a structural snapshot of the barcode hypothesis.Signal transduction and targeted therapy · 2025Article
- Helix-bundle and C-terminal GPCR domains differentially influence GRK-specific functions and β-arrestin-mediated regulation.Nature communications · 2025Article
- GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner.Communications biology · 2025Article
- Isoprenaline shows unique kinase dependencies in stimulating βMolecular pharmacology · 2025Article
- G protein-coupled receptor kinase 3 couples atypical chemokine receptor 4 independent of G proteins.Molecular pharmacologyArticle
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Authors and funding
13 authors.
Funding
Abstract
G protein-coupled receptors (GPCRs) are mainly regulated by GPCR kinase (GRK) phosphorylation and subsequent β-arrestin recruitment. The ubiquitously expressed GRKs are classified into cytosolic GRK2/3 and membrane-tethered GRK5/6 subfamilies. GRK2/3 interact with activated G protein βγ-subunits to translocate to the membrane. Yet, this need was not linked as a factor for bias, influencing the effectiveness of β-arrestin-biased agonist creation. Using multiple approaches such as GRK2/3 mutants unable to interact with Gβγ, membrane-tethered GRKs and G protein inhibitors in GRK2/3/5/6 knockout cells, we show that G protein activation will precede GRK2/3-mediated β-arrestin2 recruitment to activated receptors. This was independent of the source of free Gβγ and observable for Gs-, Gi- and Gq-coupled GPCRs. Thus, β-arrestin interaction for GRK2/3-regulated receptors is inseparably connected with G protein activation. We outline a theoretical framework of how GRK dependence on free Gβγ can determine a GPCR's potential for biased agonism. Due to this inherent cellular mechanism for GRK2/3 recruitment and receptor phosphorylation, we anticipate generation of β-arrestin-biased ligands to be mechanistically challenging for the subgroup of GPCRs exclusively regulated by GRK2/3, but achievable for GRK5/6-regulated receptors, that do not demand liberated Gβγ. Accordingly, GRK specificity of any GPCR is foundational for developing arrestin-biased ligands.
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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.