PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Tóth, A.D.* ; Szalai, B.* ; Kovács, O.T.* ; Garger, D. ; Prokop, S.* ; Soltész-Katona, E.* ; Balla, A.* ; Inoue, A.* ; Várnai, P.* ; Turu, G.* ; Hunyady, L.*

G protein-coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling.

Sci. Signal. 17:eadi0934 (2024)
Publ. Version/Full Text DOI PMC
Closed
Open Access Green as soon as Postprint is submitted to ZB.
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.
Impact Factor
Scopus SNIP
Altmetric
6.800
0.000
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Phosphatidylinositol 4-phosphate; Functional Selectivity; Mediated Endocytosis; Angiotensin; Phosphorylation; Activation; Agonist; Dephosphorylation; Sequestration; Clathrin
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 1945-0877
e-ISSN 1937-9145
Journal Science Signaling
Quellenangaben Volume: 17, Issue: 842, Pages: , Article Number: eadi0934 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-501900-382
Grants Japan Agency for Medical Research and Development
Ministry for National Economy
Janos Bolyai Research Scholarship
Janos Bolyai Research Scholarship Plus of the Hungarian Academy of Sciences
Japan Society for the Promotion of Science
Japan Science and Technology Agency
Hungarian National Research, Development and innovation Fund
DOI 10.1126/scisignal.adi0934
WOS ID 001253566900001
PubMed ID 38917219
Erfassungsdatum 2024-07-22
[➜Report correction]