Klein Herenbrink Carmen, Sykes David A, Donthamsetti Prashant, Canals Meritxell, Coudrat Thomas, Shonberg Jeremy, Scammells Peter J, Capuano Ben, Sexton Patrick M, Charlton Steven J, Javitch Jonathan A, Christopoulos Arthur, Lane J Robert
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Nat Commun. 2016 Feb 24;7:10842. doi: 10.1038/ncomms10842.
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.
偏向性激动作用描述了配体稳定与不同功能结果相关的G蛋白偶联受体（GPCR）不同构象的能力，并为设计避免脱靶副作用的通路特异性药物提供了前景。这种机制通常是从药理学数据中推断出来的，前提是通过实验设计和分析排除了观察性（即检测依赖性）和系统性（即细胞背景依赖性）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所决定的“动力学背景”，可对一系列多巴胺D2受体激动剂的表观偏向性产生深远影响，甚至可导致偏向性方向的逆转。我们建议在偏向性激动作用的研究设计和解释中必须考虑动力学背景。
