Differential effects of glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor heteromerization on cell signaling when expressed in HEK-293 cells

Bashaier Al-Zaid, Siby Chacko, Charles Ifeamalume Ezeamuzie, Moritz Bünemann, Cornelius Krasel, Tina Karimian, Peter Lanzerstorfer, Suleiman Al-Sabah

Research output: Contribution to journalArticlepeer-review

Abstract

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 s recruitment to GLP-1R but significantly inhibited GLP-1 stimulated mini-G q and arrestin recruitment. In contrast, the presence of GLP-1R improved GIP stimulated mini-G s and mini-G q recruitment to GIPR. These data support the hypothesis that GIPR and GLP-1R form heteromers with differential consequences on cell signaling.

Translated title of the contributionDifferential effects of glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor heteromerization on cell signaling when expressed in HEK-293 cells
Original languageEnglish
Article numbere01013
JournalPharmacology Research and Perspectives
Volume10
Issue number5
DOIs
Publication statusPublished - Oct 2022

Keywords

  • Arrestins/metabolism
  • Gastric Inhibitory Polypeptide/metabolism
  • Glucagon-Like Peptide 1/metabolism
  • Glucagon-Like Peptide-1 Receptor/genetics
  • Glucose/pharmacology
  • HEK293 Cells
  • Humans
  • Incretins
  • Ligands
  • Peptides
  • Receptors, G-Protein-Coupled/metabolism
  • Receptors, Gastrointestinal Hormone
  • Secretin/metabolism
  • Signal Transduction
  • BRET
  • GLP-1
  • G-protein-coupled receptor
  • heteromerization
  • GIP
  • FRET
  • Glucagon-Like Peptide-1 Receptor/metabolism
  • Receptors, Gastrointestinal Hormone/metabolism

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