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. and Ladds, Graham (2015). Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2). Journal of Biological Chemistry, 290 (38), pp. 23009-23022.

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: Life & Health Sciences
Life & Health Sciences > Pharmacy
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
Full Text Link: http://www.jbc. ... nt/290/38/23009
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2015-09-18
Authors: Weston, Cathryn
Lu, Jing
Li, Naichang
Barkan, Kerry
Richards, Gareth O.
Roberts, David J.
Skerry, Timothy M.
Poyner, David ( 0000-0003-1590-112X)
Pardamwar, Meenakshi
Reynolds, Christopher A.
Dowell, Simon J.
Willars, Gary B.
Ladds, Graham

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