ßarrestin1-biased agonism at human δ-opioid receptor by peptidic and alkaloid ligands

Benjamin Aguila, Laurent Coulbault, Audrey Davis, Nicolas Marie, Ahmed Hasbi, Florian Le bras, Géza Tóth, Anna Borsodi, Vsevolod V. Gurevich, Philippe Jauzac, Stéphane Allouche

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Abstract

We have previously reported on the differential regulation of the human δ-opioid receptor (hDOR) by alkaloid (etorphine) and peptidic (DPDPE and deltorphin I) ligands, in terms of both receptor desensitization and post-endocytic sorting. Since ßarrestins are well known to regulate G protein-coupled receptors (GPCRs) signaling and trafficking, we therefore investigated the role of ßarrestin1 (the only isoform expressed in our cellular model) in the context of the hDOR. We established clonal cell lines of SK-N-BE cells over-expressing ßarrestin1, its dominant negative mutant (ßarrestin1 319-418), and shRNA directed against endogenous ßarrestin1. Interestingly, both binding and confocal microscopy approaches demonstrated that ßarrestin1 is required for hDOR endocytosis only when activated by etorphine. Conversely, functional experiments revealed that ßarrestin1 is exclusively involved in hDOR desensitization promoted by the peptides. Taken together, these results provide substantial evidence for a ßarrestin1-biased agonism at hDOR, where ßarrestin1 is differentially involved during receptor desensitization and endocytosis depending on the ligand.

Original languageEnglish
Pages (from-to)699-707
Number of pages9
JournalCellular Signalling
Volume24
Issue number3
DOIs
Publication statusPublished - Mar 1 2012

Keywords

  • G protein-coupled receptor
  • Peptidic and alkaloid ligands
  • ßarrestin
  • δ-opioid receptor

ASJC Scopus subject areas

  • Cell Biology

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    Aguila, B., Coulbault, L., Davis, A., Marie, N., Hasbi, A., Le bras, F., Tóth, G., Borsodi, A., Gurevich, V. V., Jauzac, P., & Allouche, S. (2012). ßarrestin1-biased agonism at human δ-opioid receptor by peptidic and alkaloid ligands. Cellular Signalling, 24(3), 699-707. https://doi.org/10.1016/j.cellsig.2011.10.018