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.
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
- G protein-coupled receptor
- signal transduction
- type 2 diabetes
- glucagon receptor
- glucagon-like peptide-1
- receptor activity modifying proteins
- signal bias