ArticleProceedings of the National Academy of Sciences of the United States of America2012
Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
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- Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.Cellular & molecular biology letters · 2026Article
- Dynamic monomer-dimer transition in ligand-induced apelin receptor activation.Nature communications · 2026Article
- Characterizing ghrelin's role in dysregulating GLP-1-mediated function and promoting the development of alcohol-associated liver disease.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Extracellular ATP increases agonist potency and reduces latency at class B G protein-coupled receptors.Molecular pharmacology · 2025Article
- Prolonged signaling of backbone-modified glucagon-like peptide-Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart.Comprehensive Physiology · 2025Review
- Structure-activity relationships of thiadiazole agonists of the human secretin receptor.SLAS discovery : advancing life sciences R & D · 2024Article
- Highly biased agonism for GPCR ligands via nanobody tethering.Nature communications · 2024Article
- Impact of secretin receptor homo-dimerization on natural ligand binding.Nature communications · 2024Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- Discovery of a functionally selective ghrelin receptor (GHSRProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Type 2 Diabetes Complicated With Heart Failure: Research on Therapeutic Mechanism and Potential Drug Development Based on Insulin Signaling Pathway.Frontiers in pharmacology · 2022Review
- The Emerging Role of Dual GLP-1 and GIP Receptor Agonists in Glycemic Management and Cardiovascular Risk Reduction.Diabetes, metabolic syndrome and obesity : targets and therapy · 2022Review
- Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment.Life (Basel, Switzerland) · 2021Review
- Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking.Molecular pharmacology · 2021Article
- Manipulating oligodendrocyte intrinsic regeneration mechanism to promote remyelination.Cellular and molecular life sciences : CMLS · 2021Review
- Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.British journal of pharmacology · 2020Article
- The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide-1 Receptor Biased Agonists.ACS pharmacology & translational science · 2020Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.