ArticlePloS one2014
The GIP receptor displays higher basal activity than the GLP-1 receptor but does not recruit GRK2 or arrestin3 effectively.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 53 citations in OpenAlex.
- Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations.Molecular metabolism · 2026Article
- A metabolic comparison of GIPR agonism versus GIPR antagonism in male mice.Diabetes, obesity & metabolism · 2026Article
- Systematic metabolite screening identifies functional regulators of the adenosine A2A receptor.Communications chemistry · 2025Article
- Glucagon-like Peptide-1 Receptor (GLP-1R) Signaling: Making the Case for a Functionally GInternational journal of molecular sciences · 2025Review
- Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling.Nature communications · 2025Article
- The C-terminal regions of the GLP-1 and GIP receptors are not the key determinants of their differential arrestin recruitment but modulate the rate of receptor endocytosis.Frontiers in pharmacology · 2025Article
- Lipid regulation of the glucagon receptor family.The Journal of endocrinology · 2024Review
- Enhanced Endosomal Signaling and Desensitization of GLP-1R vs GIPR in Pancreatic Beta Cells.Endocrinology · 2023Article
- Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process.International journal of molecular sciences · 2022Review
- Differential effects of glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor heteromerization on cell signaling when expressed in HEK-293 cells.Pharmacology research & perspectives · 2022Article
- A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor.Journal of medicinal chemistry · 2022Article
- Functionality of Melatonin Receptors: Recruitment of β-Arrestin at MT1.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1.Biochemical pharmacology · 2021Article
- Glucose-induced cAMP elevation in β-cells involves amplification of constitutive and glucagon-activated GLP-1 receptor signalling.Acta physiologica (Oxford, England) · 2021Article
- GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.BMC biology · 2021Article
- GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action.Frontiers in endocrinology · 2021Article
- Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.British journal of pharmacology · 2020Article
- Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors.ACS pharmacology & translational science · 2020Review
- Article
- The Effect of Cell Surface Expression and Linker Sequence on the Recruitment of Arrestin to the GIP Receptor.Frontiers in pharmacology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
BACKGROUND AND
objectivesGlucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of insulin secretion, and their functional loss is an early characteristic of type 2 diabetes mellitus (T2DM). Pharmacological levels of GLP-1, but not GIP, can overcome this loss. GLP-1 and GIP exert their insulinotropic effects through their respective receptors expressed on pancreatic β-cells. Both the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR) are members of the secretin family of G protein-coupled receptors (GPCRs) and couple positively to adenylate cyclase. We compared the signalling properties of these two receptors to gain further insight into why GLP-1, but not GIP, remains insulinotropic in T2DM patients.
methodsGLP-1R and GIPR were transiently expressed in HEK-293 cells, and basal and ligand-induced cAMP production were investigated using a cAMP-responsive luciferase reporter gene assay. Arrestin3 (Arr3) recruitment to the two receptors was investigated using enzyme fragment complementation, confocal microscopy and fluorescence resonance energy transfer (FRET).
resultsGIPR displayed significantly higher (P<0.05) ligand-independent activity than GLP-1R. Arr3 displayed a robust translocation to agonist-stimulated GLP-1R but not to GIPR. These observations were confirmed in FRET experiments, in which GLP-1 stimulated the recruitment of both GPCR kinase 2 (GRK2) and Arr3 to GLP-1R. These interactions were not reversed upon agonist washout. In contrast, GIP did not stimulate recruitment of either GRK2 or Arr3 to its receptor. Interestingly, arrestin remained at the plasma membrane even after prolonged (30 min) stimulation with GLP-1. Although the GLP-1R/arrestin interaction could not be reversed by agonist washout, GLP-1R and arrestin did not co-internalise, suggesting that GLP-1R is a class A receptor with regard to arrestin binding.
conclusionsGIPR displays higher basal activity than GLP-1R but does not effectively recruit GRK2 or Arr3.
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