Differential Effects of Glucose-dependent Insulinotropic Polypeptide Receptor/glucagon-like Peptide-1 Receptor Heteromerization on Cell Signaling when Expressed in HEK-293 Cells

The incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP-1R) are closely related members of the secretin class of G-protein-coupled receptors. As both receptors are expressed on pancreatic β-cells there is at least the hypothetical possibility that they may form heteromers. In the present study, we investigated GIPR/GLP-1R heteromerization and the impact of GIPR on GLP-1R-mediated signaling and vice versa in HEK-293 cells. Real-time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) saturation experiments confirm that GLP-1R and GIPR form heteromers. Stimulation with 1 μM GLP-1 caused an increase in both FRET and BRET ratio, whereas stimulation with 1 μM GIP caused a decrease. The only other ligand tested to cause a significant change in BRET signal was the GLP-1 metabolite, GLP-1 (9-36). GIPR expression had no significant effect on mini-G recruitment to GLP-1R but significantly inhibited GLP-1 stimulated mini-G and arrestin recruitment. In contrast, the presence of GLP-1R improved GIP stimulated mini-G and mini-G recruitment to GIPR. These data support the hypothesis that GIPR and GLP-1R form heteromers with differential consequences on cell signaling.