逮捕
内化
内吞作用
功能选择性
细胞生物学
受体
G蛋白偶联受体
兴奋剂
内体
G蛋白
酶联受体
生物
化学
内吞循环
信号转导
生物物理学
生物化学
作者
A. Tóth,Bence Szalai,Orsolya Tünde Kovács,Dániel Garger,Susanne Prokop,Eszter Soltész‐Katona,András Balla,Asuka Inoue,Péter Várnai,Gábor Turu,László Hunyady
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2024-06-25
卷期号:17 (842)
被引量:1
标识
DOI:10.1126/scisignal.adi0934
摘要
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.
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