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

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.

LanguageEnglish
Pages23009-23022
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number38
Early online date21 Jul 2015
DOIs
Publication statusPublished - 18 Sep 2015

Fingerprint

Receptor Activity-Modifying Protein 2
Glucagon Receptors
Modulation
Pharmacology
Receptor-Interacting Protein Serine-Threonine Kinases
Ligands
GTP-Binding Protein alpha Subunits
Medical problems
Glucagon
GTP-Binding Proteins
Pharmaceutical Preparations
Yeast
Blood Glucose
Assays
Yeasts
Association reactions
Glucagon-Like Peptide-1 Receptor

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

Cite this

Weston, C., Lu, J., Li, N., Barkan, K., Richards, G. O., Roberts, D. J., ... 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
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. / Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2). In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 38. pp. 23009-23022.
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Weston, C, Lu, J, Li, N, Barkan, K, Richards, GO, Roberts, DJ, Skerry, TM, Poyner, D, Pardamwar, M, Reynolds, CA, Dowell, SJ, Willars, GB & Ladds, G 2015, 'Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)' Journal of Biological Chemistry, vol. 290, no. 38, pp. 23009-23022. https://doi.org/10.1074/jbc.M114.624601

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

In: Journal of Biological Chemistry, Vol. 290, No. 38, 18.09.2015, p. 23009-23022.

Research output: Contribution to journalArticle

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T1 - Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

AU - Weston, Cathryn

AU - Lu, Jing

AU - Li, Naichang

AU - Barkan, Kerry

AU - Richards, Gareth O.

AU - Roberts, David J.

AU - Skerry, Timothy M.

AU - Poyner, David

AU - Pardamwar, Meenakshi

AU - Reynolds, Christopher A.

AU - Dowell, Simon J.

AU - Willars, Gary B.

AU - Ladds, Graham

N1 - © 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

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