Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast

C. Weston, D. Poyner, V. Patel, S. Dowell, G. Ladds

Research output: Contribution to journalArticle

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.

LanguageEnglish
Pages3651-3665
Number of pages15
JournalBritish Journal of Pharmacology
Volume171
Issue number15
Early online date17 Jul 2014
DOIs
Publication statusPublished - Aug 2014

Fingerprint

GTP-Binding Proteins
Yeasts
Glucagon Receptors
Ligands
Type 2 Diabetes Mellitus
Glucagon-Like Peptide-1 Receptor
Insulin
Therapeutics
Growth

Bibliographical note

© 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Funding: Warwick Impact Fund (C. W., G. L.), the University Hospitals of Coventry and Warwickshire NHS Trust (G. L.), the BBSRC (G. L.) grant number (BB/G01227X/1), Warwick Research Development Fund (C. W., G. L.) grant number (RD13301) and the Birmingham Science City Research Alliance (G. L).

Keywords

  • diabetes
  • exenatide
  • G proteins
  • glucagon
  • glucagon-like peptide-1 (GLP-1)
  • GPCR
  • liraglutide
  • signal bias

Cite this

Weston, C. ; Poyner, D. ; Patel, V. ; Dowell, S. ; Ladds, G. / Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 15. pp. 3651-3665.
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Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast. / Weston, C.; Poyner, D.; Patel, V.; Dowell, S.; Ladds, G.

In: British Journal of Pharmacology, Vol. 171, No. 15, 08.2014, p. 3651-3665.

Research output: Contribution to journalArticle

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AU - Poyner, D.

AU - Patel, V.

AU - Dowell, S.

AU - Ladds, G.

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