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首页> 外文期刊>The European Journal of Neuroscience >Modulation of the trafficking of the human serotonin transporter by human alpha-synuclein.
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Modulation of the trafficking of the human serotonin transporter by human alpha-synuclein.

机译：人α-突触核蛋白对人5-羟色胺转运蛋白运输的调节。

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摘要

alpha-Synuclein (alpha-Syn), a protein primarily localized in the presynaptic compartment of neurons, is known to regulate dopaminergic neurotransmission by negatively modulating dopamine transporter activity and regulating its trafficking to or away from the cell surface. Given the considerable homology between dopamine transporters and the serotonin (5-HT) transporter (SERT), we examined whether alpha-Syn could similarly regulate SERT function. Increasing expression levels of human alpha-Syn gradually decreased [(3)H]5-HT uptake by human SERT in cotransfected Ltk(-) cells, by diminishing its V(max) without changing its K(m), as compared to cells expressing only SERT. Biotinylation studies to label cell-surface proteins showed that alpha-Syn decreased the levels of SERT present at the plasma membrane. alpha-Syn and SERT were able to coimmunoprecipitate (co-IP), suggesting heteromeric complexes between these two proteins through direct protein-protein interactions. The negative modulation of SERT activity by alpha-Syn occurred through the non-Abeta-amyloid component (NAC) domain of alpha-Syn (aa58-107); DNA constructs encoding this region mimicked the full-length alpha-Syn protein by decreasing [(3)H]5-HT uptake by the transporter. Furthermore, only the constructs encoding the NAC domain of alpha-Syn prevented the co-IPs between full-length alpha-Syn and SERT, in both transfected cells and in rat solubilized lysates isolated from the prefrontal cortex. These studies suggest a novel physiological role for alpha-Syn in regulating SERT activity and may be of relevance in certain mental illnesses and in depression, in which SERT function is believed to be dysregulated.
机译：众所周知，α-突触核蛋白（α-Syn）主要位于神经元突触前区，通过负调节多巴胺转运蛋白的活性并调节其向细胞表面或从细胞表面的运输来调节多巴胺能神经传递。鉴于多巴胺转运蛋白和5-羟色胺（5-HT）转运蛋白（SERT）之间存在相当的同源性，我们研究了alpha-Syn是否可以类似地调节SERT功能。与细胞相比，通过减少其V（max）而不改变其K（m），提高人类α-Syn的表达水平可通过降低其V（max）而不改变其K（m）来逐渐降低人SERT在共转染的Ltk（-）细胞中的[（3）H] 5-HT摄取。仅表示SERT。标记细胞表面蛋白的生物素化研究表明，α-Syn降低了质膜上存在的SERT水平。 alpha-Syn和SERT能够共免疫沉淀（co-IP），表明这两种蛋白之间的异聚复合物是通过直接的蛋白-蛋白相互作用而形成的。 α-Syn对SERT活性的负调节是通过α-Syn（aa58-107）的非Aβ-淀粉样蛋白（NAC）域发生的;编码该区域的DNA构建体通过减少转运蛋白对[（3）H] 5-HT的吸收来模仿全长α-Syn蛋白。此外，在从前额叶皮层分离的转染细胞和大鼠溶解的裂解物中，只有编码α-Syn的NAC结构域的构建体才能阻止全长α-Syn和SERT之间的co-IP。这些研究表明，α-Syn在调节SERT活性方面具有新的生理作用，并且可能与某些精神疾病和抑郁症有关，其中认为SERT功能失调。

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