GRK specificity and Gβγ dependency determines the potential of a GPCR for arrestin-biased agonism.

Autor: Matthees ESF; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Filor JC; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Jaiswal N; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany.; Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Reichel M; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Youssef N; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., D'Uonnolo G; Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg.; Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Szpakowska M; Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg., Drube J; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., König GM; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115, Bonn, Germany., Kostenis E; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115, Bonn, Germany., Chevigné A; Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29 rue Henri Koch, L-4354, Esch-sur-Alzette, Luxembourg., Godbole A; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Hoffmann C; Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine; Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany. carsten.hoffmann@med.uni-jena.de.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 Jul 03; Vol. 7 (1), pp. 802. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1038/s42003-024-06490-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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