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Nat Commun. 2016 Feb 24;7:10842. doi: 10.1038/ncomms10842.

The role of kinetic context in apparent biased agonism at GPCRs.

Author information

1
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
2
Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
3
Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
4
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
5
Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
6
Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA.

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.

PMID:
26905976
PMCID:
PMC4770093
DOI:
10.1038/ncomms10842
[Indexed for MEDLINE]
Free PMC Article

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