The role of kinetic context in apparent biased agonism at GPCRs

Carmen Klein Herenbrink, David A. Sykes, Prashant Donthamsetti, Meritxell Canals, Thomas Coudrat, Jeremy Shonberg, Peter J. Scammells, Ben Capuano, Patrick M. Sexton, Steven J. Charlton, Jonathan A Javitch, Arthur Christopoulos, J. Robert Lane

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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 D 2 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.

Original languageEnglish
Article number10842
Number of pages14
JournalNature Communications
Publication statusPublished - 24 Feb 2016

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