Thompson Georgina L, Lane J Robert, Coudrat Thomas, Sexton Patrick M, Christopoulos Arthur, Canals Meritxell
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Defence Science and Technology Organisation, Department of Defence, Fishermans Bend, VIC 3207, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Biochem Pharmacol. 2016 Aug 1;113:70-87. doi: 10.1016/j.bcp.2016.05.014. Epub 2016 Jun 7.
Biased agonism describes the ability of distinct G protein-coupled receptor (GPCR) ligands to stabilise distinct receptor conformations leading to the activation of different cell signalling pathways that can deliver different physiologic outcomes. This phenomenon is having a major impact on modern drug discovery as it offers the potential to design ligands that selectively activate or inhibit the signalling pathways linked to therapeutic effects with minimal activation or blockade of signalling pathways that are linked to the development of adverse on-target effects. However, the explosion in studies of biased agonism at multiple GPCR families in recombinant cell lines has revealed a high degree of variability on descriptions of biased ligands at the same GPCR and raised the question of whether biased agonism is a fixed attribute of a ligand in all cell types. The current study addresses this question at the mu-opioid receptor (MOP). Here, we have systematically assessed the impact of differential cellular protein complement (and cellular background), signalling kinetics and receptor species on our previous descriptions of biased agonism at MOP by several opioid peptides and synthetic opioids. Our results show that all these factors need to be carefully determined and reported when considering biased agonism. Nevertheless, our studies also show that, despite changes in overall signalling profiles, ligands that previously showed distinct bias profiles at MOP retained their uniqueness across different cell backgrounds.
偏向性激动作用描述了不同的G蛋白偶联受体（GPCR）配体稳定不同受体构象的能力，这种构象变化会导致不同细胞信号通路的激活，进而产生不同的生理结果。这一现象对现代药物研发产生了重大影响，因为它为设计配体提供了可能，即选择性激活或抑制与治疗效果相关的信号通路，同时将与不良靶标效应产生相关的信号通路的激活或阻断降至最低。然而，重组细胞系中多个GPCR家族的偏向性激动作用研究激增，结果显示对于同一GPCR的偏向性配体的描述存在高度变异性，这也引发了一个问题，即偏向性激动作用是否是配体在所有细胞类型中的固定属性。当前的研究以μ-阿片受体（MOP）为对象探讨了这一问题。在此，我们系统评估了细胞蛋白组成差异（以及细胞背景）、信号动力学和受体种类对我们之前关于几种阿片肽和合成阿片类药物对MOP偏向性激动作用描述的影响。我们的结果表明，在考虑偏向性激动作用时，所有这些因素都需要仔细确定并报告。尽管如此，我们的研究还表明，尽管整体信号谱有所变化，但之前在MOP上表现出不同偏向性谱的配体在不同细胞背景下仍保持其独特性。
