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

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.

Publication DOI: https://doi.org/10.1074/jbc.M114.624601
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: © 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
Uncontrolled 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,Biochemistry,Cell Biology,Molecular Biology
Publication ISSN: 1083-351X
Last Modified: 23 Feb 2024 18:51
Date Deposited: 19 Aug 2019 09:36
Full Text Link: http://www.jbc. ... nt/290/38/23009
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-09-18
Published Online Date: 2015-07-21
Authors: Weston, Cathryn
Lu, Jing
Li, Naichang
Barkan, Kerry
Richards, Gareth O.
Roberts, David J.
Skerry, Timothy M.
Poyner, David (ORCID Profile 0000-0003-1590-112X)
Pardamwar, Meenakshi
Reynolds, Christopher A.
Dowell, Simon J.
Willars, Gary B.
Ladds, Graham

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