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- Title
G protein–coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling.
- Authors
Tóth, András D.; Szalai, Bence; Kovács, Orsolya T.; Garger, Dániel; Prokop, Susanne; Soltész-Katona, Eszter; Balla, András; Inoue, Asuka; Várnai, Péter; Turu, Gábor; Hunyady, László
- Abstract
The stabilization of different active conformations of G protein–coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (AT1R) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When AT1R endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor–β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor–β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V2 vasopressin receptor and a mutant β2-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds. Editor's summary: Biased agonists of GPCRs stimulate signaling through either G proteins or β-arrestins, which is clinically relevant if one pathway is therapeutic and the other produces side effects. Tóth et al. found that the endocytosis of the angiotensin II receptor AT1R and other GPCRs determined signaling strength through the β-arrestin pathway. Blocking endocytosis elicited responses from weak β-arrestin–biased agonists that resembled those generated by full agonists. As a result, ligand efficacy in β-arrestin signaling may be determined more by spatiotemporal regulation than by the induction of different receptor conformations at the plasma membrane by distinct agonists. These findings may guide the development of GPCR-targeting drugs that more effectively produce only the desired therapeutic response. —John F. Foley
- Subjects
ARRESTINS; G protein coupled receptors; ENDOCYTOSIS; ANGIOTENSIN receptors; ANGIOTENSIN II; CELL membranes; G proteins
- Publication
Science Signaling, 2024, Vol 17, Issue 842, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adi0934