Flavors of GPCR signaling bias

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Mohammad Seyedabadi , Vsevolod V. Gurevich
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引用次数: 0

Abstract

GPCRs are inherently flexible molecules existing in an equilibrium of multiple conformations. Binding of GPCR agonists shifts this equilibrium. Certain agonists can increase the fraction of active-like conformations that predispose the receptor to coupling to a particular signal transducer or a select group of transducers. Such agonists are called biased, in contrast to balanced agonists that facilitate signaling via all transducers the receptor couples to. These biased agonists preferentially channel the signaling of a GPCR to particular G proteins, GRKs, or arrestins. Preferential activation of particular G protein or arrestin subtypes can be beneficial, as it would reduce unwanted on-target side effects, widening the therapeutic window. However, biasing GPCRs has two important limitations: a) complete bias is impossible due to inherent flexibility of GPCRs; b) receptor-independent functions of signal transducer proteins cannot be directly affected by GPCR ligands or differential receptor barcoding by GRK phosphorylation.
GPCR 信号偏差的味道。
GPCR 本身是一种灵活的分子,处于多种构象的平衡状态。GPCR 激动剂的结合会改变这种平衡。某些激动剂可以增加活性构象的比例,从而使受体与特定的信号转导物或一组特定的信号转导物发生耦合。这种激动剂被称为偏性激动剂,与之相反的是,平衡激动剂会促进受体通过与之偶联的所有转换器发出信号。这些偏性激动剂会优先将 GPCR 的信号传递给特定的 G 蛋白、GRK 或抑制素。优先激活特定的 G 蛋白或抑制素亚型可能是有益的,因为这样可以减少不必要的靶向副作用,扩大治疗窗口。然而,偏向 GPCR 有两个重要的局限性:a) 由于 GPCR 固有的灵活性,不可能完全偏向;b) 信号转导蛋白与受体无关的功能不能直接受到 GPCR 配体或 GRK 磷酸化的不同受体条码的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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