Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)
| Autor: | Kerry Barkan, David J. Roberts, Gary B. Willars, Naichang Li, Jing Lu, Timothy M. Skerry, Simon J. Dowell, Christopher A. Reynolds, Meenakshi Pardamwar, Graham Ladds, Gareth O. Richards, David R. Poyner, Cathryn Weston |
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| Rok vydání: | 2015 |
| Předmět: |
endocrine system
G protein-coupled receptor (GPCR) Pharmacology Biology Ligands Receptor Activity-Modifying Protein 2 Biochemistry Glucagon-Like Peptide-1 Receptor Enzyme-linked receptor Humans 5-HT5A receptor signal bias Molecular Biology Coagulation factor II receptor Glucagon-like peptide 1 receptor Receptor activity-modifying protein digestive oral and skin physiology glucagon receptor Cell Biology Glucagon receptor activity-modifying proteins (RAMPs) 3. Good health HEK293 Cells glucagon-like peptide-1 Estrogen-related receptor gamma type 2 diabetes pharmacology Glucagon receptor family Glucagon receptor hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Background: The glucagon and glucagon-like peptide-1 (GLP-1) receptors are important targets for treating type 2 diabetes. Results: We describe novel glucagon receptor pharmacology, through interaction with the receptor activity-modifying protein-2 (RAMP2). Conclusion: RAMP2 regulates both ligand binding and G protein selectivity of the glucagon receptor. Significance: The effect of RAMP2 should be considered when designing anti-diabetic treatments. 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. |
| Databáze: | OpenAIRE |
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