ArticleThe Journal of biological chemistry2015
Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 79 citations in OpenAlex.
- Design of a metabolically-stable peptide therapeutic with triple-hormone-receptor agonist activity.Journal of computer-aided molecular design · 2026Article
- Specific Glucagon Assay System Using a Receptor-Derived Glucagon-Binding Peptide Probe.International journal of molecular sciences · 2026Article
- Receptor activity-modifying protein 3 enhances GLP-1-mediated insulin secretion.The Journal of biological chemistry · 2025Article
- GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion.Diabetologia · 2024Article
- Article
- Receptor activity-modifying protein modulation of parathyroid hormone-1 receptor function and signaling.Frontiers in pharmacology · 2024Article
- Review
- Article
- Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins.Pharmacological reviews · 2023Review
- Multi-biological functions of intermedin in diseases.Frontiers in physiology · 2023Review
- Glucagon receptor-mediated regulation of gluconeogenic gene transcription is endocytosis-dependent in primary hepatocytes.Molecular biology of the cell · 2022Article
- Functional modulation of PTH1R activation and signaling by RAMP2.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Receptor activity-modifying protein 1 regulates mouse skin fibroblast proliferation via the Gαi3-PKA-CREB-YAP axis.Cell communication and signaling : CCS · 2022Article
- Modulating effects of RAMPs on signaling profiles of the glucagon receptor family.Acta pharmaceutica Sinica. B · 2022Article
- CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells.Communications biology · 2021Article
- Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling.The Journal of biological chemistry · 2020Article
- Agonist bias and agonist-dependent antagonism at corticotrophin releasing factor receptors.Pharmacology research & perspectives · 2020Article
- Dawn of a New RAMPage.Trends in pharmacological sciences · 2020Review
- Engineering G protein-coupled receptor signalling in yeast for biotechnological and medical purposes.FEMS yeast research · 2020Review
- The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a.Science signaling · 2020Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 1 country.
Funding
Abstract
The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.
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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.