Oxyntomodulin differentially affects glucagon-like peptide-1 receptor β-arrestin recruitment and signaling through Gαs

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(2) assays to measure agonist- induced recruitment of beta 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 beta arrestins and GRK2 to the GLP- 1 receptor. We suggest that oxyntomodulin and glucagon are biased ligands on the GLP- 1 receptor.