Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s)

TY - JOUR

T1 - Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s)

AU - Jorgensen, Rasmus

AU - Kubale, Valentina

AU - Vrecl, Milka

AU - Schwartz, Thue W

AU - Elling, Christian E

N1 - Keywords: Animals; Arrestins; COS Cells; Cercopithecus aethiops; Cyclic AMP; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinase 5; GTP-Binding Protein alpha Subunits, Gs; Glucagon; Glucagon-Like Peptide 1; Humans; Luminescent Measurements; Oxyntomodulin; Protein-Serine-Threonine Kinases; Receptors, Glucagon; Signal Transduction; beta-Adrenergic Receptor Kinases

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1124/jpet.107.120006

DO - 10.1124/jpet.107.120006

M3 - Journal article

C2 - 17395766

SN - 0022-3565

VL - 322

SP - 148

EP - 154

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

IS - 1

ER -