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Elucidation of the mechanism of membrane transport of metal ions in the central nervous system and the relation to brain function

阐明中枢神经系统金属离子膜转运机制及其与脑功能的关系

基本信息

批准号：
10470093
负责人：
SAITO Takeshi
金额：
$ 9.02万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470093/
关键词：
metal ion transporter ATP7B Copper CNS Neurological function metabolism of trace elements

项目摘要

In the present study, we intended to evaluate the mechanism of membrane transport of metal ions in the central nervous system and its relation to the brain function. Results obtained in the present investigations are as follows;1. Localization of copper-transporting P-type ATPase (ATP7B), a gene product responsible for Wilson disease, was visualized in the brain, kidney, small intestine and liver of the Long-Evans agouti rat using immunohistochemical technique. The ATP7B was intensely detected in neuronal cells of the hippocampal formation, olfactory bulbs, cerebellum, cerebral cortex and nuclei in the brain stem of the rat brain, the cortex and the outer stripe of the outer medulla in the kidney, Paneth cells of the small intestine, and hepatocytes. ATP7B was observed predominantly in the regions in which high amounts of copper and copper-binding proteins such as Cu-ZnSOD and metallothionein and NO synthase were detected. Thus, in normal tissue, ATP7B was considered to regulate not only copper homeostasis and biosynthesis of holo copper-binding proteins but also NO synthesis in CNS.2.. Changes in concentrations of trace elements and neurotransmitters by aging were determined in the brain of Senescence-Accelerated Mouse P10(SAMP10), which showed brain atrophy and deficits in learning and memory. Zn, Cu and Mn concentrations in most regions of SAM-P10, were significantly lower than those in the control rat. Mo concentration in the brain of SAM-P10 was significantly higher than that in the control. The excess amount of glutamate and glycine release from the hippocampal CA3 regions of SAM-P10 aged 12 months was observed as compared to that in the control. These results suggest that abnormal membrane transports of metal ions in CNS induce senescence-acceleration of the brain of SAMP10.

在本研究中，我们旨在评估中枢神经系统中金属离子的膜转运机制及其与脑功能的关系。本次调查取得的结果如下： 1．使用免疫组织化学技术，在 Long-Evans 刺豚鼠的大脑、肾脏、小肠和肝脏中观察到了铜转运 P 型 ATP 酶 (ATP7B)（一种导致威尔逊病的基因产物）的定位。 ATP7B 在海马结构、嗅球、小脑、大脑皮层和大鼠脑干细胞核、肾脏外髓质的皮层和外条纹、小肠潘氏细胞和肝细胞的神经元细胞中强烈检测到。 ATP7B 主要在检测到大量铜和铜结合蛋白（例如 Cu-ZnSOD、金属硫蛋白和 NO 合酶）的区域中观察到。因此，在正常组织中，ATP7B被认为不仅调节铜稳态和全铜结合蛋白的生物合成，还调节中枢神经系统中的一氧化氮合成。2.在衰老加速小鼠P10（SAMP10）的大脑中测定了随衰老引起的微量元素和神经递质浓度的变化，该小鼠显示出脑萎缩以及学习和记忆缺陷。 SAM-P10 大部分区域的 Zn、Cu 和 Mn 浓度显着低于对照大鼠。 SAM-P10脑内Mo浓度显着高于对照组。与对照组相比，观察到 12 个月龄 SAM-P10 的海马 CA3 区域释放过量的谷氨酸和甘氨酸。这些结果表明，中枢神经系统中金属离子的异常膜转运会导致 SAMP10 大脑加速衰老。