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

  1. Rasmus Jorgensen,
  2. Valentina Kubale,
  3. Milka Vrecl,
  4. Thue W. Schwartz and
  5. Christian E. Elling
  1. 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.)
  1. Address correspondence to:
    Dr. Christian E. Elling, 7TM Pharma A/S, 2970 Horsholm, Denmark. E-mail: cee{at}7tm.com

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 transfer2 assays to measure agonist-induced recruitment of βarrestins 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 βarrestins and GRK2 to the GLP-1 receptor. We suggest that oxyntomodulin and glucagon are biased ligands on the GLP-1 receptor.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.120006.

  • ABBREVIATIONS: 7TM, seven transmembrane; GLP, glucagon-like peptide; GRK, G-protein-coupled receptor kinase; GFP, green fluorescent protein; βarr, β-arrestin; RLuc, Renilla luciferase; BRET, bioluminescence resonance energy transfer; wt, wild type; PTH, parathyroid hormone; MAP, mitogen-activated protein.

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received January 16, 2007.
    • Accepted March 28, 2007.
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  1. doi: 10.1124/jpet.107.120006 JPET July 2007 vol. 322 no. 1 148-154
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