Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

Cathryn Weston*, Jing Lu, Naichang Li, Kerry Barkan, Gareth O. Richards, David J. Roberts, Timothy M. Skerry, David Poyner, Meenakshi Pardamwar, Christopher A. Reynolds, Simon J. Dowell, Gary B. Willars, Graham Ladds

*Corresponding author for this work

Research output: Contribution to journalArticle

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, whilst 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 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.

Original languageEnglish
Pages (from-to)23009-23022
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number38
Early online date21 Jul 2015
DOIs
Publication statusPublished - 18 Sep 2015

Bibliographical note

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Final version free via Creative Commons CC-BY licence.

Funding: Warwick Impact Fund; BBSRC (BB/G01227X/1; BB/F008392/1, BB/M007529/1 and BB/M000176/1); Warwick Research Development Fund (RD13301) and the Birmingham Science City Research Alliance

Keywords

  • G protein-coupled receptor
  • glucagon
  • pharmacology
  • signal transduction
  • type 2 diabetes
  • glucagon receptor
  • glucagon-like peptide-1
  • receptor activity modifying proteins
  • RAMPs
  • GPCR
  • signal bias

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    Weston, C., Lu, J., Li, N., Barkan, K., Richards, G. O., Roberts, D. J., Skerry, T. M., Poyner, D., Pardamwar, M., Reynolds, C. A., Dowell, S. J., Willars, G. B., & Ladds, G. (2015). Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2). Journal of Biological Chemistry, 290(38), 23009-23022. https://doi.org/10.1074/jbc.M114.624601