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
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.120006.
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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.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material. - Received January 16, 2007.
- Accepted March 28, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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