The role of kinetic context in apparent biased agonism at GPCRs
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 a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2016
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| Online Access: | https://eprints.nottingham.ac.uk/38578/ |
| _version_ | 1848795644366422016 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Klein Herenbrink, Carmen |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:35:22Z |
| format | Article |
| id | nottingham-38578 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:35:22Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-385782020-05-04T17:35:50Z https://eprints.nottingham.ac.uk/38578/ The role of kinetic context in apparent biased agonism at GPCRs 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 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. Nature Publishing Group 2016-02-24 Article PeerReviewed 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 and Lane, J. Robert (2016) The role of kinetic context in apparent biased agonism at GPCRs. Nature Communications, 7 . 10842/1-10842/14. ISSN 2041-1723 http://www.nature.com/articles/ncomms10842 doi:10.1038/ncomms10842 doi:10.1038/ncomms10842 |
| spellingShingle | 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 The role of kinetic context in apparent biased agonism at GPCRs |
| title | The role of kinetic context in apparent biased
agonism at GPCRs |
| title_full | The role of kinetic context in apparent biased
agonism at GPCRs |
| title_fullStr | The role of kinetic context in apparent biased
agonism at GPCRs |
| title_full_unstemmed | The role of kinetic context in apparent biased
agonism at GPCRs |
| title_short | The role of kinetic context in apparent biased
agonism at GPCRs |
| title_sort | role of kinetic context in apparent biased
agonism at gpcrs |
| url | https://eprints.nottingham.ac.uk/38578/ https://eprints.nottingham.ac.uk/38578/ https://eprints.nottingham.ac.uk/38578/ |