title: ßarrestin1-biased agonism at human δ-opioid receptor by peptidic and alkaloid ligands.
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.
authors.affiliation: Université de Caen, Laboratoire de biologie moléculaire et cellulaire de la signalisation, UPRES-EA 3919, IFR 146 ICORE, Caen, France. benjamin.aguila@mcgill.ca
authors.forename: Benjamin
authors.initials: B
authors.lastname: Aguila
authors.forename: Laurent
authors.initials: L
authors.lastname: Coulbault
authors.forename: Audrey
authors.initials: A
authors.lastname: Davis
authors.forename: Nicolas
authors.initials: N
authors.lastname: Marie
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hasbi
authors.forename: Florian
authors.initials: F
authors.lastname: Le bras
authors.forename: Géza
authors.initials: G
authors.lastname: Tóth
authors.forename: Anna
authors.initials: A
authors.lastname: Borsodi
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.forename: Philippe
authors.initials: P
authors.lastname: Jauzac
authors.forename: Stéphane
authors.initials: S
authors.lastname: Allouche
mesh_terms: D019390:Arrestins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology*; D005048:Etorphine / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D008024:Ligands; D009842:Oligopeptides; D034741:RNA, Small Interfering; D017465:Receptors, Opioid, delta; D000071557:beta-Arrestins; C060208:deltorphin I, Ala(2)-; D005048:Etorphine; D020881:Enkephalin, D-Penicillamine (2,5)-
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