title: Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking.
abstract: Agonist-induced activation of the δ-opioid receptor (δOR) was recently shown to augment β- and γ-secretase activities, which increased the production of β-amyloid peptide (Aβ), known to accumulate in the brain tissues of Alzheimer's disease (AD) patients. Previously, the δOR variant with a phenylalanine at position 27 (δOR-Phe27) exhibited more efficient receptor maturation and higher stability at the cell surface than did the less common cysteine (δOR-Cys27) variant. For this study, we expressed these variants in human SH-SY5Y and HEK293 cells expressing exogenous or endogenous amyloid precursor protein (APP) and assessed the effects on APP processing. Expression of δOR-Cys27, but not δOR-Phe27, resulted in a robust accumulation of the APP C83 C-terminal fragment and the APP intracellular domain, while the total soluble APP and, particularly, the β-amyloid 40 levels were decreased. These changes upon δOR-Cys27 expression coincided with decreased localization of APP C-terminal fragments in late endosomes and lysosomes. Importantly, a long-term treatment with a subset of δOR-specific ligands or a c-Src tyrosine kinase inhibitor suppressed the δOR-Cys27-induced APP phenotype. These data suggest that an increased constitutive internalization and/or concurrent signaling of the δOR-Cys27 variant affects APP processing through altered endocytic trafficking of APP.
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, FI-70211 Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.forename: Jussi T
authors.initials: JT
authors.lastname: Tuusa
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.forename: Jarkko J
authors.initials: JJ
authors.lastname: Lackman
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.forename: Johannes T
authors.initials: JT
authors.lastname: Roehr
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Parrado
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Ulla E
authors.initials: UE
authors.lastname: Petäjä-Repo
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D004705:Endocytosis; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C529706:OPRD1 protein, human; D017465:Receptors, Opioid, delta