Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations

Area of Science:

• Pharmacology
• Molecular Biology
• Endocrinology

Background:

• The glucagon-like peptide-1 receptor (GLP-1R) is a key target for type 2 diabetes and obesity.
• Biased agonists, favoring G protein over β-arrestin signaling, show clinical efficacy.
• Previous studies faced challenges due to ligand property variations.

Purpose of the Study:

• To investigate G protein-biased GLP-1R agonism using receptor mutations instead of modified ligands.
• To mimic G protein-biased signaling by inhibiting GLP-1R C-tail phosphorylation.

Main Methods:

• Mutated human and mouse GLP-1R C-tails (serine to alanine) to inhibit phosphorylation.
• Assessed β-arrestin recruitment, internalisation, and Gαs activation in HEK293 cells and pancreatic β-cells.
• Compared wild-type and mutant receptors using native GLP-1 and biased ligands (ExF1, ExD3).

Main Results:

• Reduced C-terminal phosphorylation decreased GLP-1R internalisation and β-arrestin recruitment.
• Phosphodeficient GLP-1R exhibited preferential Gαs activation and increased cAMP generation.
• Specific phosphorylation sites differentially regulated β-arrestin recruitment, internalisation, and cAMP production.

Conclusions:

• Genetic modifications reducing β-arrestin recruitment and internalisation can enhance GLP-1R signaling.
• This provides evidence supporting G protein bias as a strategy to improve GLP-1R agonist efficacy.
• The findings offer a novel approach to developing more effective GLP-1R-based therapeutics.