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Characterization of Glucagon-Like Peptide-1 Receptor ß-Arrestin 2 Interaction: A High-Affinity Receptor Phenotype

7TM Pharma A/S (R.J., L.M., T.W.S., C.E.E.), Horsholm, DK-2970, Denmark; and Laboratory for Molecular Pharmacology (T.W.S.), The Panum Institute, University of Copenhagen, DK-2100, Denmark

Address all correspondence and requests for reprints to: Christian E. Elling, Ph.D., 7TM Pharma A/S, 2970 Horsholm, Denmark. E-mail: cee{at}7tm.com.

To dissect the interaction between ß-arrestin (ßarr) and family B G protein-coupled receptors, we constructed fusion proteins between the glucagon-like peptide 1 receptor and ßarr2. The fusion constructs had an increase in apparent affinity selectively for glucagon, suggesting that ßarr2 interaction locks the receptor in a high-affinity conformation, which can be explored by some, but not all, ligands. The fusion constructs adopted a signaling phenotype governed by the tethered ßarr2 with an attenuated G protein-mediated cAMP signal and a higher maximal internalization compared with wild-type receptors. This distinct phenotype of the fusion proteins can not be mimicked by coexpressing wild-type receptor with ßarr2. However, when the wild-type receptor was coexpressed with both ßarr2 and G protein-coupled receptor kinase 5, a phenotype similar to that observed for the fusion constructs was observed. We conclude that the glucagon-like peptide 1 fusion construct mimics the natural interaction of the receptor with ßarr2 with respect to binding peptide ligands, G protein-mediated signaling and internalization, and that this distinct molecular phenotype is reminiscent of that which has previously been characterized for family A G protein-coupled receptors, suggesting similarities in the effect of ßarr interaction between family A and B receptors also at the molecular level.

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