Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO
Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO
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DOI：
10.1016/j.neuron.2016.01.018
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发表时间：
2016-03-02
期刊：
影响因子：
16.2
通讯作者：
Bredt, David S.
中科院分区：
文献类型：
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作者：
Gu, Shenyan;Matta, Jose A.;Bredt, David S.
尼古丁通过大脑烟碱型乙酰胆碱受体(NAChRs)家族发挥其行为和相加作用。增强α7型nAChR信号可改善阿尔茨海默病和精神分裂症的症状。阿尔法7受体的药学研究受到阻碍，因为这些受体在细胞系中不形成其功能性的五聚体结构，而且在神经元中组装阿尔法7受体的机制尚不清楚。在这里，基因组筛选策略解决了这个长期存在的难题，并确定了Nacho，一种神经内质网的跨膜蛋白，介导阿尔法7受体的组装。Nacho通过高尔基复合体促进α7蛋白折叠、成熟，并在细胞表面表达。在培养的海马神经元中敲除Nacho或在小鼠中敲除Nacho选择性地完全扰乱α7受体组装并取消α7通道功能。这项工作确定Nacho是nAChRs的关键的、客户特定的伴侣，并对与这些广泛分布的神经递质受体相关的生理学和疾病有影响。
Nicotine exerts its behavioral and additive actions through a family of brain nicotinic acetylcholine receptors (nAChRs). Enhancing alpha 7-type nAChR signaling improves symptoms in Alzheimer's disease and schizophrenia. The pharmaceutical study of alpha 7 receptors is hampered because these receptors do not form their functional pentameric structure in cell lines, and mechanisms that underlie alpha 7 receptor assembly in neurons are not understood. Here, a genomic screening strategy solves this long-standing puzzle and identifies NACHO, a transmembrane protein of neuronal endoplasmic reticulum that mediates assembly of alpha 7 receptors. NACHO promotes alpha 7 protein folding, maturation through the Golgi complex, and expression at the cell surface. Knockdown of NACHO in cultured hippocampal neurons or knockout of NACHO in mice selectively and completely disrupts alpha 7 receptor assembly and abolishes alpha 7 channel function. This work identifies NACHO as an essential, client-specific chaperone for nAChRs and has implications for physiology and disease associated with these widely distributed neurotransmitter receptors.