Systematic analysis of factors influencing observations of biased agonism at the mu-opioid receptor

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• 作者：Georgina L. Thompson^a ; ^b ; J. Robert Lane^a ; Thomas Coudrat^a ; Patrick M. Sexton^a ; Arthur Christopoulos^a ; ^{arthur.christopoulos@monash.edu" class="auth_mail" title="E-mail the corresponding author} ; Meritxell Canals^a ; ^{meri.canals@monash.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AC ; adenylyl cyclase ; α-neo ; α-neoendorphin ; β-arr1 and β-arr2 ; β-arrestin 1 and 2 ; BRET ; bioluminescence resonance energy transfer ; CHO ; Chinese hamster ovary ; DAMGO ; d-Ala2-N-MePhe4-Gly-ol enkephalin ; endo ; endomorphin ; pERK ; extracellular signal regulated kinases 1/2 phosphorylation ; GIRK ; G protein-gated inwardly rectifying K+ channel ; GPCR ; G protein-coupled receptor ; GRK ; G protein-coupled receptor kinase ; enk ; enkephalin ; MOP ; μ-opioid receptor ; PKC ; protein kinase C ; PCA ; principal compo
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 August 2016
• 年：2016
• 卷：113
• 期：Complete
• 页码：70-87
• 全文大小：4191 K

文摘

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.