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Modulation of glucagon receptor pharmacology by receptor activity-modifying protein-2 (RAMP2)

Weston, C and Lu, J and Li, N and Barkan, K and Richards, GO and Roberts, DJ and Skerry, TM and Poyner, D and Pardamwar, M and Reynolds, CA and Dowell, SJ and Willars, GB and Ladds, G (2015) 'Modulation of glucagon receptor pharmacology by receptor activity-modifying protein-2 (RAMP2).' Journal of Biological Chemistry, 290 (38). 23009 - 23022. ISSN 0021-9258

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Abstract

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. 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.

Item Type: Article
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Christopher Reynolds
Date Deposited: 24 Feb 2016 17:01
Last Modified: 09 Aug 2019 11:15
URI: http://repository.essex.ac.uk/id/eprint/16097

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