ReviewThe Journal of biological chemistry2022
G protein-coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias.
Review in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 63 citations in OpenAlex.
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- Factors modulating the assembly of human βNature structural & molecular biology · 2026Article
- β-arrestin recruitment facilitates a direct association with G proteins.Nature communications · 2026Article
- GPCR kinases shape ACKR4 functions via differential C-terminal phosphorylation.Nature communications · 2026Article
- Decoding GPCR signaling reprogramming in cancer: molecular mechanisms and therapeutic implications.Molecular medicine (Cambridge, Mass.) · 2026Review
- Structural mechanism for noncanonical GPCR signaling in the Hedgehog pathway.Nature structural & molecular biology · 2026Article
- Cooperative Control of Arrestin Activation By Membrane Lipids And Phosphorylation Barcodes.bioRxiv : the preprint server for biology · 2026Article
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants.Cell reports · 2026Article
- Activated protein C drives β-arrestin-2- and c-Src-dependent phosphorylation of Cav1 and modulates Cav1 association with PAR1 and GRK5.The Journal of biological chemistry · 2026Article
- Local GPCR density tips the balance of μ-opioid receptor trafficking.bioRxiv : the preprint server for biology · 2026Article
- Distinct membrane binding properties of the two non-visual arrestins.Communications biology · 2026Article
- Decoding GPCR signaling in living cells to advance early therapeutic discovery for neurological disorders.Frontiers in molecular neuroscience · 2026Review
- β-arrestin2: an emerging player and potential therapeutic target in inflammatory immune diseases.Acta pharmacologica Sinica · 2025Review
- Molecular basis of β-arrestin coupling to the metabotropic glutamate receptor mGlu3.Nature chemical biology · 2025Article
- Differential Role of Phosphorylation in Glucagon Family Receptor Signaling Revealed by Mass Spectrometry.Journal of proteome research · 2025Article
- Article
- GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner.Communications biology · 2025Article
- Genetic variants of accessory proteins and G proteins in human genetic disease.Critical reviews in clinical laboratory sciences · 2025Review
- Biased activation of the vasopressin V2 receptor probed by molecular dynamics simulations, NMR and pharmacological studies.Computational and structural biotechnology journal · 2024Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
G protein-coupled receptor (GPCR) kinases (GRKs) and arrestins interact with agonist-bound GPCRs to promote receptor desensitization and downregulation. They also trigger signaling cascades distinct from those of heterotrimeric G proteins. Biased agonists for GPCRs that favor either heterotrimeric G protein or GRK/arrestin signaling are of profound pharmacological interest because they could usher in a new generation of drugs with greatly reduced side effects. One mechanism by which biased agonism might occur is by stabilizing receptor conformations that preferentially bind to GRKs and/or arrestins. In this review, we explore this idea by comparing structures of GPCRs bound to heterotrimeric G proteins with those of the same GPCRs in complex with arrestins and GRKs. The arrestin and GRK complexes all exhibit high conformational heterogeneity, which is likely a consequence of their unusual ability to adapt and bind to hundreds of different GPCRs. This dynamic behavior, along with the experimental tactics required to stabilize GPCR complexes for biophysical analysis, confounds these comparisons, but some possible molecular mechanisms of bias are beginning to emerge. We also examine if and how the recent structures advance our understanding of how arrestins parse the "phosphorylation barcodes" installed in the intracellular loops and tails of GPCRs by GRKs. In the future, structural analyses of arrestins in complex with intact receptors that have well-defined native phosphorylation barcodes, such as those installed by the two nonvisual subfamilies of GRKs, will be particularly illuminating.
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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.