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|Title:||Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)|
Richards, G. O.
Roberts, D. J.
Skerry, T. M.
Reynolds, C. A.
Dowell, S. J.
Willars, Gary Brian
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Citation:||Journal of Biological Chemistry, 2015, 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, although 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 the role of 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.|
|Rights:||Copyright © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license ( http://creativecommons.org/licenses/by/3.0 ).|
|Appears in Collections:||Published Articles, College of Medicine, Biological Sciences and Psychology|
Files in This Item:
|Weston JBC Maintext_final1.pdf||Post-review (final submitted)||2.4 MB||Adobe PDF||View/Open|
|J. Biol. Chem.-2015-Weston-23009-22.pdf||Published (publisher PDF)||3.47 MB||Adobe PDF||View/Open|
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