title: 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, 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.
authors.affiliation: From the Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom, caw38@leicester.ac.uk.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Weston
authors.affiliation: the Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: the Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Naichang
authors.initials: N
authors.lastname: Li
authors.affiliation: From the Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Kerry
authors.initials: K
authors.lastname: Barkan
authors.affiliation: the Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors.forename: Gareth O
authors.initials: GO
authors.lastname: Richards
authors.affiliation: the Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Roberts
authors.affiliation: the Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Skerry
authors.affiliation: the School of Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Poyner
authors.affiliation: the School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom, and.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Pardamwar
authors.affiliation: the School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom, and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reynolds
authors.affiliation: the Department of Biological Sciences, Molecular Discovery Research, GlaxoSmithKline, Hertfordshire SG1 2NY, United Kingdom, and.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dowell
authors.affiliation: the Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Willars
authors.affiliation: From the Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom, the Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom grl30@cam.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Ladds
mesh_terms: D005934:Glucagon / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; C545503:RAMP2 protein, human; D058263:Receptor Activity-Modifying Protein 2; D005934:Glucagon; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: G protein-coupled receptor (GPCR); glucagon; glucagon receptor; glucagon-like peptide-1; pharmacology; receptor activity-modifying proteins (RAMPs); signal bias; signal transduction; type 2 diabetes