PDF(Pubmed)
Abstract：
Impaired ion channels regulating Golgi pH lead to structural alterations in the Golgi apparatus, such as fragmentation, which is found, along with cognitive impairment, in Alzheimer\'s disease. However, the causal relationship between altered Golgi structure and cognitive impairment remains elusive due to the lack of understanding of ion channels in the Golgi apparatus of brain cells. Here, we identify that a transmembrane protein TMEM87A, renamed Golgi-pH-regulating cation channel (GolpHCat), expressed in astrocytes and neurons that contributes to hippocampus-dependent memory. We find that GolpHCat displays unique voltage-dependent currents, which is potently inhibited by gluconate. Additionally, we gain structural insights into the ion conduction through GolpHCat at the molecular level by determining three high-resolution cryogenic-electron microscopy structures of human GolpHCat. GolpHCat-knockout mice show fragmented Golgi morphology and altered protein glycosylation and functions in the hippocampus, leading to impaired spatial memory. These findings suggest a molecular target for Golgi-related diseases and cognitive impairment.
摘要：
调节高尔基体pH值的离子通道受损会导致高尔基体的结构改变，比如碎片化，被发现，伴随着认知障碍，在阿尔茨海默病中。然而,由于缺乏对高尔基体中脑细胞离子通道的了解，高尔基体结构改变与认知障碍之间的因果关系仍然难以捉摸。这里,我们确定了跨膜蛋白TMEM87A，更名为高尔基pH调节阳离子通道(GolpHCat)，在星形胶质细胞和神经元中表达，有助于海马依赖性记忆。我们发现GolpHcat显示出独特的电压相关电流，被葡萄糖酸盐有效抑制。此外,通过确定人类GolpHCat的三种高分辨率低温电子显微镜结构，我们在分子水平上获得了对通过GolpHCat的离子传导的结构见解。GolpHcat基因敲除小鼠在海马中表现出断裂的高尔基体形态和改变的蛋白质糖基化和功能，导致空间记忆受损。这些发现提示了高尔基体相关疾病和认知障碍的分子靶标。
