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CELLULAR AND MOLECULAR

Oxyntomodulin Differentially Affects Glucagon-Like Peptide-1 Receptor -Arrestin Recruitment and Signaling through G

7TM Pharma A/S, Horsholm, Denmark (R.J., T.W.S., C.E.E.); Institute of Anatomy, Histology, and Embryology, Veterinary Faculty, University of Ljubljana, Ljubljana, Slovenia (V.K., M.V.); Laboratory for Molecular Pharmacology, Panum Institute, University of Copenhagen, Blegdamsvej, Denmark (T.W.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 transfer² assays to measure agonist-induced recruitment of arrestins 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 arrestins and GRK2 to the GLP-1 receptor. We suggest that oxyntomodulin and glucagon are biased ligands on the GLP-1 receptor.

Address correspondence to: Dr. Christian E. Elling, 7TM Pharma A/S, 2970 Horsholm, Denmark. E-mail: cee{at}7tm.com

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