Elucidation of the mechanism of membrane transport, metallochaperone of essential trace metals related to central nervous activities

在本研究中，我们打算阐明影响中枢神经系统活动的微量金属代谢。在不同的培养细胞中，我们检测了铜金属伴侣、CCS、Cu、从CCS接收铜的Zn-SOD和铜转运体Ctr1在缺铜和多铜状态下的变化。在缺铜状态下，CCS蛋白和Cu、Zn-SOD蛋白含量增加。另一方面，在铜含量过高的状态下，CCS和Cu、Zn-SOD的蛋白质含量显著下降。此外，我制造了一只锌摄入量过高的动物。在含锌过多的情况下，发生肠道铜吸收障碍。提示肠道细胞内铜含量下降，铜转运蛋白ATP7A含量下降。当在神经细胞来源的培养细胞中添加铜螯合物时，很明显花生四烯酸的代谢在细胞中发生了变化。缺铜导致Cu、Zn-SOD活性下降，导致NO和活性氧含量升高，影响细胞内花生四烯酸代谢。我们检测了金属硫蛋白-3 （MT-3）的金属结合能力，它专门出现在中枢神经系统。与其他金属硫蛋白相比，MT-3的铜结合亲和力明显更高。采用目视观察神经传递的方法，阐明了三丁基锡对神经传递的影响。结果表明，三丁基锡阻碍了与学习记忆有关的长时程增强。此外，我把金属结合蛋白，引起中枢神经障碍和检查障碍爆发机制的活性氧。

In the present study, we intended to clarify a metabolism of trace metals, which affected central nervous system activity. With various cultured cells, we examined changes of a metallochaperone of copper, CCS, Cu,Zn-SOD, which received copper from CCS, and Ctr1, which was copper transporter in a copper lack and too much states. In a copper lack state, the quantity of protein of CCS and Cu,Zn-SOD increased. On the other hand, in a state having too much copper, the quantity of protein of CCS and Cu,Zn-SOD showed a significant fall. Furthermore, I made an animal having too much a zinc intake. In a state having too much zinc, a copper absorption obstruction in an intestinal tract was occurred. It was suggested that the copper in intestinal tract cell decreased, and a copper transporter protein ATP7A decreased as well.When it added copper chelate in a cultured cell of a nerve cell origin, it became clear that arachidonic acid metabolism changed in a cell. A fall of Cu,Zn-SOD activity by copper lack caused rises of NO and active oxygen species as the cause and affected arachidonic acid metabolism in a cell.We examined metal binding ability of metallothionein-3 (MT-3), which specifically emerged to a central nervous system. It became clear that copper-binding affinity of MT-3 is very much higher in comparison with other metallothioneins.With a visual observation method of neurotransmission, we clarified influence of tributyltin on the neurotransmission. As a result, tributyltin obstructed the long-term potentiation, which was related to learning and memory.Furthermore, I put the metal-binding protein, which caused the central nervous disorder and examination of obstacle outbreak mechanism of active oxygen species.