title: Lateral allosterism in the glucagon receptor family: glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation.
abstract: Activation of G-protein-coupled receptors (GPCRs) results in a variety of cellular responses, such as binding to the same receptor of different ligands that activate distinct downstream cascades. Additional signaling complexity is achieved when two or more receptors are integrated into one signaling unit. Lateral receptor interactions can allosterically modulate the receptor response to a ligand, which creates a mechanism for tissue-specific fine tuning, depending on the cellular receptor coexpression pattern. GPCR homomers or heteromers have been explored widely for GPCR classes A and C but to lesser extent for class B. In the present study, we used bioluminescence resonance energy transfer (BRET) techniques, calcium flux measurements, and microscopy to study receptor interactions within the glucagon receptor family. We found basal BRET interactions for some of the receptor combinations tested that decreased upon ligand binding. A BRET increase was observed exclusively for the gastric inhibitory peptide (GIP) receptor and the glucagon-like peptide 1 (GLP-1) receptor upon binding of GLP-1 that could be reversed with GIP addition. The interactions of GLP-1 receptor and GIP receptor were characterized with BRET donor saturation studies, shift experiments, and tests of glucagon-like ligands. The heteromer displayed specific pharmacological characteristics with respect to GLP-1-induced β-arrestin recruitment and calcium flux, which suggests a form of allosteric regulation between the receptors. This study provides the first example of ligand-induced heteromer formation in GPCR class B. In the body, the receptors are functionally related and coexpressed in the same cells. The physiological evidence for this heteromerization remains to be determined.
authors: Addex Pharmaceuticals, Geneva, Switzerland. dominik.schelshorn@addexpharma.com
authors: Dominik
authors: D
authors: Schelshorn
authors: Fanny
authors: F
authors: Joly
authors: Sophie
authors: S
authors: Mutel
authors: Cornelia
authors: C
authors: Hampe
authors: Billy
authors: B
authors: Breton
authors: Vincent
authors: V
authors: Mutel
authors: Robert
authors: R
authors: Lütjens
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D002460:Cell Line; D004705:Endocytosis; D004735:Energy Transfer; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1