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Updated: May 1, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast

C Weston1, D Poyner, V Patel

  • 1Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Coventry, UK.

British Journal of Pharmacology
|April 10, 2014
PubMed
Abstract

Insights

A novel yeast assay reveals distinct G protein signaling preferences for GLP-1 receptor drugs, aiding the development of safer type 2 diabetes treatments.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • The glucagon-like peptide 1 (GLP-1) receptor is crucial for glycemic control and a key target for type 2 diabetes therapies.
  • Adverse effects of current GLP-1 receptor agonists suggest a need for deeper understanding of their signaling pathways.

Purpose of the Study:

  • To develop a novel yeast-based assay for studying GLP-1 receptor G protein coupling selectivity.
  • To investigate signaling bias of GLP-1 receptor ligands and allosteric modulators.

Main Methods:

  • Expression of the GLP-1 receptor in modified yeast strains coupled to G protein chimeras.
  • Assessing receptor activation and G protein coupling preferences via cell growth.
  • Quantifying ligand-receptor interactions and G protein selectivity.

Main Results:

  • The GLP-1 receptor functionally coupled to human Gαs, Gαi, and Gαq chimeras.
  • Identified distinct G protein signaling bias for liraglutide and exenatide, with exenatide favoring the Gαi pathway.
  • Validated the system for evaluating allosteric compounds and the glucagon receptor.

Conclusions:

  • The yeast platform provides a robust tool for dissecting GLP-1 receptor pleiotropic signaling.
  • Enables screening for more selective and efficacious GLP-1 receptor agonists and modulators.
  • Facilitates the development of improved therapeutics for type 2 diabetes with reduced side effects.
Keywords:
G proteinsGPCRdiabetesexenatideglucagonglucagon-like peptide-1 (GLP-1)liraglutidesignal bias

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