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The role of kinetic context in apparent biased agonism at GPCRs

Javitch, Jonathan A.; 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; Christopoulos, Arthur; Lane, J. Robert


Jonathan A. Javitch

Carmen Klein Herenbrink

David A. Sykes

Prashant Donthamsetti

Thomas Coudrat

Jeremy Shonberg

Peter J. Scammells

Ben Capuano

Patrick M. Sexton

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Professor of Molecular Pharmacology and Drug Discovery

Jonathan Javitch

Arthur Christopoulos

Associate Professor


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.


Javitch, J. A., Klein Herenbrink, C., Sykes, D. A., Donthamsetti, P., Canals, M., Coudrat, T., …Lane, J. R. (2016). The role of kinetic context in apparent biased agonism at GPCRs. Nature Communications, 7, Article 10842.

Journal Article Type Article
Acceptance Date Jan 27, 2016
Online Publication Date Feb 24, 2016
Publication Date Feb 24, 2016
Deposit Date Apr 5, 2017
Publicly Available Date Apr 5, 2017
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 7
Article Number 10842
Keywords angiotensin receptor; aripiprazole; beta arrestin 2; bifeprunox; cariprazine; cyclic AMP; dopamine; dopamine 2 receptor stimulating agent; G protein coupled receptor; mitogen activated protein kinase 1; mitogen activated protein kinase 3; pardoprunox; pre
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