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Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

journal contribution
posted on 08.01.2016, 12:22 by C. Weston, Jing Lu, Naichang Li, K. Barkan, G. O. Richards, D. J. Roberts, T. M. Skerry, D. Poyner, M. Pardamwar, C. A. Reynolds, S. J. Dowell, Gary Brian Willars, G. Ladds
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.

History

Citation

Journal of Biological Chemistry, 2015, 290 (38), pp. 23009-23022

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Journal of Biological Chemistry

Publisher

American Society for Biochemistry and Molecular Biology

eissn

1083-351X

Acceptance date

15/07/2015

Copyright date

2015

Available date

08/01/2016

Publisher version

http://www.jbc.org/content/290/38/23009

Language

en