Abstract
The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer assays to measure agonist-induced recruitment of betaarrestins and G-protein-coupled receptor kinase (GRK) 2 to the GLP-1 receptor in addition to traditional measurements of second messenger generation. The peptide hormone oxyntomodulin is described in the literature as a full agonist on the glucagon and GLP-1 receptors. Surprisingly, despite being full agonists in GLP-1 receptor-mediated cAMP accumulation, oxyntomodulin and glucagon were observed to be partial agonists in recruiting betaarrestins and GRK2 to the GLP-1 receptor. We suggest that oxyntomodulin and glucagon are biased ligands on the GLP-1 receptor.
MeSH terms
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Animals
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Arrestins / metabolism*
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COS Cells
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Chlorocebus aethiops
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Cyclic AMP / metabolism
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G-Protein-Coupled Receptor Kinase 2
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G-Protein-Coupled Receptor Kinase 5
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GTP-Binding Protein alpha Subunits, Gs / physiology*
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Glucagon / pharmacology
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Glucagon-Like Peptide 1 / pharmacology
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Glucagon-Like Peptide-1 Receptor
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Humans
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Luminescent Measurements
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Oxyntomodulin / pharmacology*
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Protein Serine-Threonine Kinases / physiology
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Receptors, Glucagon / drug effects*
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Receptors, Glucagon / physiology
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Signal Transduction / physiology*
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beta-Adrenergic Receptor Kinases / physiology
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beta-Arrestins
Substances
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Arrestins
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GLP1R protein, human
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Glucagon-Like Peptide-1 Receptor
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Oxyntomodulin
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Receptors, Glucagon
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beta-Arrestins
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Glucagon-Like Peptide 1
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Glucagon
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Cyclic AMP
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Protein Serine-Threonine Kinases
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GRK2 protein, human
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beta-Adrenergic Receptor Kinases
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G-Protein-Coupled Receptor Kinase 2
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G-Protein-Coupled Receptor Kinase 5
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GRK5 protein, human
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GTP-Binding Protein alpha Subunits, Gs