Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s).
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.
Jorgensen
Rasmus
R
7TM Pharma A/S, 2970 Horsholm, Denmark.
Kubale
Valentina
V
Vrecl
Milka
M
Schwartz
Thue W
TW
Elling
Christian E
CE
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008163:Luminescent Measurements; D053772:Oxyntomodulin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D018027:Receptors, Glucagon / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases / Q000502:physiology; D000071557:beta-Arrestins
D019390:Arrestins; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D000071557:beta-Arrestins; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs