Skip to main content
. 2024 Jul 3;7:802. doi: 10.1038/s42003-024-06490-1

Fig. 6. The GRK-dependency of each GPCR determines its potential in biased agonism.

Fig. 6

GPCRs can be grouped based on the GRKs involved in their regulation into GRK2/3-dependent, GRK5/6-dependent or GRK2/3/5/6-dependent receptors. As the membrane-localization of GRK2/3 is mediated via the interaction with Gβγ, the phosphorylation of the receptor and hence, the β-arrestin recruitment, are in fact G protein-dependent. Therefore, it will likely be mechanistically unattainable or difficult to achieve for this group of receptors to create β-arrestin-biased ligands that do not activate G proteins, because the phosphorylation by GRK2/3 is dependent on the availability of free Gβγ-subunits. This is not the case for GRK5/6-regulated receptors, as these GRKs are already membrane-tethered and not dependent on Gβγ for the recruitment to this receptor group. For receptors that are found to be GRK2/3/5/6-regulated, β-arrestin-biased ligands would convey their effects only via GRK5/6-induced receptor phosphorylation.