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Submitted on August 4, 2004
Accepted on October 28, 2004
arrestin2 Interaction: A high Affinity Receptor Phenotype
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Horsholm, Denmark; Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2100, Denmark
* To whom correspondence should be addressed. E-mail: cee{at}7tm.com.
To dissect the interaction between 
arrestin and family B G-protein coupled receptors, we constructed fusion proteins between the Glucagon Like Peptide-1 receptor and arrestin2. The fusion constructs had an increase in apparent affinity selectively for glucagon suggesting that arrestin2 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 arrestin2 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 co-expressing wild type receptor with arrestin2. However, when the wild type receptor was co-expressed with both arrestin2 and G-protein coupled receptor kinase 5, a phenotype similar to that observed for the fusion constructs was observed. We conclude that the GLP-1 fusion construct mimics the natural interaction of the receptor with arrestin2 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 arrestin interaction between family A and -B receptors also at the molecular level.
arrestin •
BRET •
G-protein coupled receptor kinase
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