Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane
Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane
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DOI：
10.1038/s41598-020-68947-7
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发表时间：
2020-07
影响因子：
4.6
通讯作者：
Y. Moriwaki;N. Kubo;Mizuho Watanabe;Shinsuke Asano;T. Shinoda;Taro Sugino;D. Ichikawa;S. Tsuji;F. Kato;H. Misawa
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文献类型：
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作者：
Y. Moriwaki;N. Kubo;Mizuho Watanabe;Shinsuke Asano;T. Shinoda;Taro Sugino;D. Ichikawa;S. Tsuji;F. Kato;H. Misawa
α7烟碱乙酰胆碱受体（nAChR）在中枢神经系统中广泛表达，并被认为是神经退行性疾病如阿尔茨海默病和精神分裂症的潜在治疗靶点。然而，尽管假定α7 nAChR的病理生理学的重要性，分子生理学的表征仍然很差的进展，因为α7 nAChR不能正确地折叠和分选到质膜在大多数哺乳动物细胞系，从而阻止了异源表达系统中的分析。最近，ER驻留膜蛋白NACHO被发现是非允许细胞中α7 nAChR功能表达的强伴侣。Ly 6 H是一种脑内富集的GPI锚定神经毒素样蛋白，是一种新的调节α7 nAChR胞内转运的蛋白质。在这项研究中，我们通过将α7 nAChR、Ric-3和NACHO cDNA导入HEK 293细胞（Tripleα7 nAChR/RIC-3/NACHO细胞; TARO细胞），建立了稳定和稳健表达表面α7 nAChR的细胞系，并重新评估了Ly 6 H的功能。我们在此报道Ly 6 H与细胞膜上的α7 nAChR结合并调节通道活性，而不影响α7 nAChR的细胞内运输。
α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and regarded as potential therapeutic targets for neurodegenerative conditions, such as Alzheimer’s disease and schizophrenia. Yet, despite the assumed pathophysiological importance of the α7 nAChR, molecular physiological characterization remains poorly advanced because α7 nAChR cannot be properly folded and sorted to the plasma membranes in most mammalian cell lines, thus preventing the analyses in heterologous expression system. Recently, ER-resident membrane protein NACHO was discovered as a strong chaperone for the functional expression of α7 nAChR in non-permissive cells. Ly6H, a brain-enriched GPI-anchored neurotoxin-like protein, was reported as a novel modulator regulating intracellular trafficking of α7 nAChR. In this study, we established cell lines that stably and robustly express surface α7 nAChR by introducing α7 nAChR, Ric-3, and NACHO cDNA into HEK293 cells (Tripleα7 nAChR/RIC-3/NACHOcells; TARO cells), and re-evaluated the function of Ly6H. We report here that Ly6H binds with α7 nAChRs on the cell membrane and modulates the channel activity without affecting intracellular trafficking of α7 nAChR.