TY - JOUR
T1 - GRK specificity and Gβγ dependency determines the potential of a GPCR for arrestin-biased agonism
AU - Matthees, Edda S.F.
AU - Filor, Jenny C.
AU - Jaiswal, Natasha
AU - Reichel, Mona
AU - Youssef, Noureldine
AU - D’Uonnolo, Giulia
AU - Szpakowska, Martyna
AU - Drube, Julia
AU - König, Gabriele M.
AU - Kostenis, Evi
AU - Chevigné, Andy
AU - Godbole, Amod
AU - Hoffmann, Carsten
N1 - Grants and funding
EFRE HSB 2018 0019/EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj), JSMM/Carl-Zeiss-Stiftung (Carl Zeiss Foundation) 290847012/FOR2372/Deutsche Forschungsgemeinschaft (German Research Foundation)
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/7/3
Y1 - 2024/7/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85197423605
UR - https://pubmed.ncbi.nlm.nih.gov/38956302/
U2 - 10.1038/s42003-024-06490-1
DO - 10.1038/s42003-024-06490-1
M3 - Article
C2 - 38956302
AN - SCOPUS:85197423605
SN - 2399-3642
VL - 7
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 802
ER -