G蛋白偶联受体的内吞作用在β-arrestin信号传导中产生时空偏差。

IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
András D. Tóth, Bence Szalai, Orsolya T. Kovács, Dániel Garger, Susanne Prokop, Eszter Soltész-Katona, András Balla, Asuka Inoue, Péter Várnai, Gábor Turu, László Hunyady
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引用次数: 0

摘要

G蛋白偶联受体不同活性构象的稳定被认为是偏性和平衡性激动剂不同功效的基础。在这里,通过分析血管紧张素 II 1 型受体(AT1R)激动剂对信号转换器的激活发现,β-阿司匹林结合的程度和动力学表现出很大的配体依赖性差异,当受体内化受到抑制时,这种差异就消失了。当阻止 AT1R 内吞时,即使β-阿司匹林通路的弱部分激动剂也能发挥完全或接近完全激动剂的作用,这表明受体构象并不完全决定β-阿司匹林的招募。β-阿restin转运中配体依赖性的差异在内膜上比在质膜上要大得多,这表明配体在β-阿restin通路中的效力是由时空决定的。实验研究和数学建模证明了多种因素如何同时影响激动剂对内体受体-β-阿司匹林结合的作用,从而决定了功能选择性的程度。配体解离率和G蛋白活性对受体-β-阿瑞斯汀相互作用的影响尤为强烈,并具有内化依赖性。我们还发现,内吞作用调节了另外两种与β-阿司匹林持续结合的受体的激动剂效力:V2血管加压素受体和一种突变型β2肾上腺素能受体。在没有内吞作用的情况下,β-arrestin2 结合的激动剂依赖性变化明显减弱。我们的研究结果表明,内吞作用决定了 GPCR 信号传导的时空偏差,有助于开发更有效的功能选择性化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
G protein–coupled receptor endocytosis generates spatiotemporal bias in β-arrestin signaling
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.
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来源期刊
Science Signaling
Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
9.50
自引率
0.00%
发文量
148
审稿时长
3-8 weeks
期刊介绍: "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.
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