G protein–receptor kinases 5/6 are the key regulators of G protein–coupled receptor 35–arrestin interactions

Ganguly, Amlan; Quon, Tezz; Jenkins, Laura; Joseph, Babu; Al-awar, Rima; Chevigne, Andy; Tobin, Andrew B.; Uehling, David E.; Hoffmann, Carsten; Drube, Julia; Milligan, Graeme

doi:10.1016/j.jbc.2023.105218

Cited by 2 publications

(1 citation statement)

References 39 publications

(88 reference statements)

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“…In this case, the same ligand induced active conformations of the receptors, which might have enabled GRK2/3 to phosphorylate also the atypical ACKR3 even though the recruitment to the membrane was mediated via CXCR4. Recently, the GPR35 has also been described as a GRK5/6-regulated GPCR 46 . Since this receptor has been shown to be Gi-, G12/13-coupled, this implies that additional factors might contribute to GRK specificity in this group of receptors.…”

Section: Discussionmentioning

confidence: 99%

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

Matthees,

Filor,

Jaiswal

et al. 2024

Commun Biol

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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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Section: Discussionmentioning

confidence: 99%