Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)
| Autor: | Weston, Cathryn, Lu, Jing, Li, Naichang, Barkan, Kerry, Richards, Gareth O, Roberts, David J, Skerry, Timothy M, Poyner, David, Pardamwar, Meenakshi, Reynolds, Christopher A, Dowell, Simon J, Willars, Gary B, Ladds, Graham |
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| Přispěvatelé: | Ladds, Graham [0000-0001-7320-9612], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
endocrine system
digestive oral and skin physiology G protein-coupled receptor (GPCR) glucagon receptor receptor activity-modifying proteins (RAMPs) Glucagon Ligands Receptor Activity-Modifying Protein 2 Glucagon-Like Peptide-1 Receptor HEK293 Cells glucagon-like peptide-1 Humans type 2 diabetes pharmacology signal bias signal transduction hormones hormone substitutes and hormone antagonists |
| ISSN: | 1083-351X |
| Popis: | 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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