The role of kinetic context in apparent biased agonism at GPCRs.
The role of kinetic context in apparent biased agonism at GPCRs.
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DOI：
10.1038/ncomms10842
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发表时间：
2016-02-24
影响因子：
16.6
通讯作者：
Lane JR
中科院分区：
文献类型：
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作者：
Klein Herenbrink C;Sykes DA;Donthamsetti P;Canals M;Coudrat T;Shonberg J;Scammells PJ;Capuano B;Sexton PM;Charlton SJ;Javitch JA;Christopoulos A;Lane JR
偏倚激动作用描述了配体稳定与不同功能结果相关的GPCR不同构象的能力，并为设计避免靶侧副作用的途径特异性药物提供了前景。这种机制通常是从药理学数据推断出来的，并假设通过实验设计和分析排除了观察（即依赖于测定）和系统（即依赖于细胞背景）偏差的混杂影响。在这里，我们揭示了由配体结合动力学和受体信号传导过程的时间模式决定的“动力学背景”，可以对一系列多巴胺D2受体激动剂的明显偏倚产生深远的影响，甚至可以导致偏倚方向的逆转。我们建议在设计和解释偏倚激动作用的研究时必须承认动力学背景。偏置激动剂作用于受体，优先诱导不同的细胞内信号反应。在这里，作者展示了配体结合和信号反应的动力学如何极大地影响观察到的偏倚概况，因此在研究偏倚激动剂时必须考虑。
Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism. Biased agonists act at a receptor to preferentially induce distinct intracellular signalling responses over others. Here the authors show how kinetics of ligand binding and signaling responses greatly influence observed bias profiles, and hence must be considered when studying biased agonists.