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

Br J Pharmacol. 2014 Aug;171(15):3651-65. doi: 10.1111/bph.12716.


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.

Keywords: G proteins; GPCR; diabetes; exenatide; glucagon; glucagon-like peptide-1 (GLP-1); liraglutide; signal bias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • GTP-Binding Proteins / metabolism*
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • HEK293 Cells
  • Humans
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Signal Transduction


  • Glucagon-Like Peptide-1 Receptor
  • GTP-Binding Proteins