ArticleNature communications2022
Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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65 citing papers in PubMed, 103 citations in OpenAlex.
- Molecular basis of diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptor C3aR.Nature communications · 2026Article
- Factors modulating the assembly of human βNature structural & molecular biology · 2026Article
- Mechanistic insight into signal bias by the agonist-dependent conformational dynamics of GPR84.Nature communications · 2026Article
- Biased signaling of β2-adrenergic receptor in physiological and pathological states.Cellular & molecular biology letters · 2026Review
- GPCR kinases shape ACKR4 functions via differential C-terminal phosphorylation.Nature communications · 2026Article
- CXCR1 and CXCR2 display receptor bias for shared chemokine agonists.Molecular pharmacology · 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
- Mast cell-specific CysLT2 receptor signaling inhibits cysteinyl leukotriene-dependent mast cell activation and type 2 allergic lung inflammation.Cell reports · 2026Article
- Distinct membrane binding properties of the two non-visual arrestins.Communications biology · 2026Article
- Assessing the limitations of paraformaldehyde fixation for accurate cell surface receptor measurement.Frontiers in pharmacology · 2026Article
- Membrane-domain compartmentalization of active GPCRs by β-arrestins through PtdIns(4,5)PNature chemical biology · 2025Article
- Single-molecule methods for characterizing receptor dimers reveal metastable opioid receptor homodimers that induce functional modulation.Nature communications · 2025Article
- Biased Agonists of the Type 1 Angiotensin II Receptor Promote Distinct Subcellular β-Arrestin Conformations.Biochemistry · 2025Article
- CXCR1 and CXCR2 display receptor bias for shared chemokine agonists.bioRxiv : the preprint server for biology · 2025Article
- A genetically encoded nanobody sensor reveals conformational diversity in β-arrestins orchestrated by distinct seven transmembrane receptors.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Distinct Phosphorylation Patterns of AT1R by Biased Ligands and GRK Subtypes.International journal of molecular sciences · 2025Article
- Article
- Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.Nature cell biology · 2025Article
- Luciferase complementation for cellular assays beyond protein-protein interactions.Analytical sciences : the international journal of the Japan Society for Analytical Chemistry · 2025Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signaling-biased ligands acting on G-protein-coupled receptors (GPCRs) differentially activate heterotrimeric G proteins and β-arrestins. Although a wealth of structural knowledge about signaling bias at the GPCR level exists (preferential engagement of a specific transducer), little is known about the bias at the transducer level (different functions mediated by a single transducer), partly due to a poor understanding of GPCR kinase (GRK)-mediated GPCR phosphorylation. Here, we reveal a unique role of the Gq heterotrimer as a determinant for GRK-subtype selectivity that regulates subsequent β-arrestin conformation and function. Using the angiotensin II (Ang II) type-1 receptor (AT1R), we show that β-arrestin recruitment depends on both GRK2/3 and GRK5/6 upon binding of Ang II, but solely on GRK5/6 upon binding of the β-arrestin-biased ligand TRV027. With pharmacological inhibition or genetic loss of Gq, GRK-subtype selectivity and β-arrestin functionality by Ang II is shifted to those of TRV027. Single-molecule imaging identifies relocation of AT1R and GRK5, but not GRK2, to an immobile phase under the Gq-inactive, AT1R-stimulated conditions. These findings uncover a previously unappreciated Gq-regulated mechanism that encodes GRK-subtype selectivity and imparts distinct phosphorylation-barcodes directing downstream β-arrestin functions.
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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.