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

Autor: Klein Herenbrink C; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Sykes DA; Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK., Donthamsetti P; Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.; Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA., Canals M; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Coudrat T; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Shonberg J; Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Scammells PJ; Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Capuano B; Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Sexton PM; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Charlton SJ; Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK., Javitch JA; Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.; Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA., Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Lane JR; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2016 Feb 24; Vol. 7, pp. 10842. Date of Electronic Publication: 2016 Feb 24.
DOI: 10.1038/ncomms10842
Abstrakt: 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.
Databáze: MEDLINE