دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: G protein-coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling.
المؤلفون: Tóth AD; Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary.; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.; Department of Internal Medicine and Haematology, Semmelweis University, Szentkirályi utca 46, H-1088 Budapest, Hungary., Szalai B; Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary.; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary., Kovács OT; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary., Garger D; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.; Computational Health Center, Helmholtz Munich, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany., Prokop S; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary., Soltész-Katona E; Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary., Balla A; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.; HUN-REN-SE Laboratory of Molecular Physiology, Hungarian Research Network, Tűzoltó utca 37-47, H-1094 Budapest, Hungary., Inoue A; Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578 Japan., Várnai P; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.; HUN-REN-SE Laboratory of Molecular Physiology, Hungarian Research Network, Tűzoltó utca 37-47, H-1094 Budapest, Hungary., Turu G; Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary.; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary., Hunyady L; Institute of Molecular Life Sciences, Centre of Excellence of the Hungarian Academy of Sciences, HUN-REN Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary.; Department of Physiology, Faculty of Medicine, Semmelweis University, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.
المصدر: Science signaling [Sci Signal] 2024 Jun 25; Vol. 17 (842), pp. eadi0934. Date of Electronic Publication: 2024 Jun 25.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Association for the Advancement of Science
مواضيع طبية MeSH: Endocytosis*/physiology , Signal Transduction* , Receptor, Angiotensin, Type 1*/metabolism , Receptor, Angiotensin, Type 1*/genetics , beta-Arrestins*/metabolism , beta-Arrestins*/genetics, Humans ; HEK293 Cells ; Receptors, Vasopressin/metabolism ; Receptors, Vasopressin/genetics ; Receptors, Adrenergic, beta-2/metabolism ; Receptors, Adrenergic, beta-2/genetics ; Endosomes/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Receptors, G-Protein-Coupled/genetics ; Animals ; Ligands ; Protein Binding ; Protein Transport
مستخلص: 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 (AT 1 R) 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 AT 1 R 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 V 2 vasopressin receptor and a mutant β 2 -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.
المشرفين على المادة: 0 (Receptor, Angiotensin, Type 1)
0 (beta-Arrestins)
0 (Receptors, Vasopressin)
0 (Receptors, Adrenergic, beta-2)
0 (Receptors, G-Protein-Coupled)
0 (AVPR2 protein, human)
0 (Ligands)
0 (ADRB2 protein, human)
تواريخ الأحداث: Date Created: 20240625 Date Completed: 20240625 Latest Revision: 20240625
رمز التحديث: 20240626
DOI: 10.1126/scisignal.adi0934
PMID: 38917219
قاعدة البيانات: MEDLINE
الوصف
تدمد:1937-9145
DOI:10.1126/scisignal.adi0934