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Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast
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Weston, Cathryn, Poyner, David R., Patel, Vanlata H., Dowell, Scott F. and Ladds, Graham (2014) Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast. British Journal of Pharmacology, 171 (15). pp. 3651-3665. doi:10.1111/bph.12716 ISSN 1476-5381.
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Official URL: http://dx.doi.org/10.1111/bph.12716
Abstract
BACKGROUND AND PURPOSE
The glucagon-like peptide 1 (GLP-1) receptor performs an important role in glycaemic control, stimulating the release
of insulin. It is an attractive target for treating type 2 diabetes. Recently, several reports of adverse side effects following
prolonged use of GLP-1 receptor therapies have emerged: most likely due to an incomplete understanding of signalling
complexities.
EXPERIMENTAL APPROACH
We describe the expression of the GLP-1 receptor in a panel of modified yeast strains that couple receptor activation to cell
growth via single Gα/yeast chimeras. This assay enables the study of individual ligand–receptor G protein coupling
preferences and the quantification of the effect of GLP-1 receptor ligands on G protein selectivity.
KEY RESULTS
The GLP-1 receptor functionally coupled to the chimeras representing the human Gαs, Gαi and Gαq subunits. Calculation of
the dissociation constant for a receptor antagonist, exendin-3 revealed no significant difference between the two systems. We
obtained previously unobserved differences in G protein signalling bias for clinically relevant therapeutic agents, liraglutide
and exenatide; the latter displaying significant bias for the Gαi pathway. We extended the use of the system to investigate
small-molecule allosteric compounds and the closely related glucagon receptor.
CONCLUSIONS AND IMPLICATIONS
These results provide a better understanding of the molecular events involved in GLP-1 receptor pleiotropic signalling and
establish the yeast platform as a robust tool to screen for more selective, efficacious compounds acting at this important class
of receptors in the future.
Item Type: | Journal Article | ||||||||||||||||||
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Subjects: | Q Science > QP Physiology R Medicine > RA Public aspects of medicine R Medicine > RB Pathology |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | G proteins , G proteins -- Receptors, Cellular signal transduction, Diabetes -- Treatment -- Complications, Glucagon-like peptide 1, Glucagon-like peptide 1 -- Effectiveness | ||||||||||||||||||
Journal or Publication Title: | British Journal of Pharmacology | ||||||||||||||||||
Publisher: | John Wiley & Sons Ltd. | ||||||||||||||||||
ISSN: | 1476-5381 | ||||||||||||||||||
Official Date: | August 2014 | ||||||||||||||||||
Dates: |
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Volume: | 171 | ||||||||||||||||||
Number: | 15 | ||||||||||||||||||
Page Range: | pp. 3651-3665 | ||||||||||||||||||
DOI: | 10.1111/bph.12716 | ||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
RIOXX Funder/Project Grant: |
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