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首页> 外文期刊>Molecular and Cellular Biology >Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking
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Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

机译：δ阿片受体的半胱氨酸27变体通过改变内吞贩运影响淀粉样前体蛋白加工。

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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.
机译：激动剂诱导的δ阿片受体（δOR）激活可增强β和γ分泌酶活性，从而增加β淀粉样肽（Aβ）的产生，已知该蛋白会在阿尔茨海默氏病的脑组织中蓄积（ AD）患者。以前，与位置较不常见的半胱氨酸（δOR-Cys27）变体相比，在27位带有苯丙氨酸的δOR变体（δOR-Phe27）在细胞表面表现出更有效的受体成熟和更高的稳定性。对于这项研究，我们在表达外源或内源性淀粉样前体蛋白（APP）的人SH-SY5Y和HEK293细胞中表达了这些变异，并评估了对APP加工的影响。 δOR-Cys27而非δOR-Phe27的表达导致APP C83 C端片段和APP细胞内结构域的强劲积累，而总可溶性APP尤其是β-淀粉样蛋白40的水平降低。 δOR-Cys27表达的这些变化与晚期内体和溶酶体中APP C末端片段的定位减少有关。重要的是，长期使用δOR特异性配体或c-Src酪氨酸激酶抑制剂子集抑制了δOR-Cys27诱导的APP表型。这些数据表明，δOR-Cys27变体的组成性内在化和/或同时信号转导增加，通过改变APP的胞吞运输影响了APP的加工。

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