Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

• DOI: 10.1074/jbc.m114.624601
• Publication Date: 2015-07-21T23:58:53Z
• Authors: Cathryn Weston; Jing Lu; Naichang Li; Kerry Barkan; Gareth O. Richards; David J. Roberts; Timothy M. Skerry; David Poyner; Meenakshi Pardamwar; Christopher A. Re...; Simon J. Dowell; Gary B. Willars; Graham Ladds
• Keywords: Glucagon receptor

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, associated with severe adverse side-effects, targeting of receptor has yet to be successful. Here we use a combination yeast reporter assays mammalian systems provide more complete understanding signaling, considering effect multiple ligands, association receptor-interacting protein activity-modifying protein-2 (RAMP2), role individual G α-subunits. We demonstrate that RAMP2 alters both ligand selectivity preference receptor. Importantly, also uncover cross-reactivity therapeutically used ligands is abolished by interaction. This study reveals previously unidentified target agonists highlights its pharmacology. Such unrecognized functions RAMPs highlight need consider all proteins future drug development.