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 () and J. Robert Lane ()
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Carmen Klein Herenbrink: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
David A. Sykes: Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre
Prashant Donthamsetti: College of Physicians and Surgeons, Columbia University
Meritxell Canals: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Thomas Coudrat: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Jeremy Shonberg: Monash Institute of Pharmaceutical Sciences, Monash University
Peter J. Scammells: Monash Institute of Pharmaceutical Sciences, Monash University
Ben Capuano: Monash Institute of Pharmaceutical Sciences, Monash University
Patrick M. Sexton: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Steven J. Charlton: Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre
Jonathan A. Javitch: College of Physicians and Surgeons, Columbia University
Arthur Christopoulos: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
J. Robert Lane: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10842

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