Piroli Gerardo G, Grillo Claudia A, Hoskin Elena K, Znamensky Vladimir, Katz Ellen B, Milner Teresa A, McEwen Bruce S, Charron Maureen J, Reagan Lawrence P
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10021, USA.
J Comp Neurol. 2002 Oct 14;452(2):103-14. doi: 10.1002/cne.10368.
The expression and localization of glucose transporter isoforms play essential roles in the glucoregulatory activities of the hippocampus and ultimately contribute to cognitive status in physiological and pathophysiological settings. The recently identified glucose transporter GLUT8 is uniquely expressed in neuronal cell bodies in the rat hippocampus and therefore may contribute to hippocampal glucoregulatory activities. We show here that GLUT8 has a novel intracellular distribution in hippocampal neurons and is translocated to intracellular membranes following glucose challenge. Immunoblot analysis revealed that GLUT8 is expressed in high-density microsomes (HDM), suggesting that GLUT8 is associated with intracellular organelles under basal conditions. Immunogold electron microscopic analysis confirmed this observation, in that GLUT8 immunogold particles were associated with the rough endoplasmic reticulum (ER) and cytoplasm. Peripheral glucose administration produced a rapid twofold increase in GLUT8 levels in the HDM fraction while decreasing GLUT8 levels in low-density microsomes. Similarly, peripheral glucose administration significantly increased GLUT8 association with the rough ER in the hippocampus. Conversely, under hyperglycemic/insulinopenic conditions, namely, in streptozotocin (STZ) diabetes, hippocampal GLUT8 protein levels were decreased in the HDM fraction. These results demonstrate that GLUT8 undergoes rapid translocation to the rough ER in the rat hippocampus following peripheral glucose administration, trafficking that is impaired in STZ diabetes, suggesting that insulin serves as a stimulus for GLUT8 translocation in hippocampal neurons. Because glucose is liberated from oligosaccharides during N-linked glycosylation events in the rough ER, we propose that GLUT8 may serve to transport glucose out of the rough ER into the cytosol and in this manner contribute to glucose homeostasis in hippocampal neurons.
葡萄糖转运蛋白异构体的表达和定位在海马体的葡萄糖调节活动中发挥着重要作用，并最终在生理和病理生理环境中对认知状态产生影响。最近发现的葡萄糖转运蛋白GLUT8在大鼠海马体的神经元细胞体中独特表达，因此可能有助于海马体的葡萄糖调节活动。我们在此表明，GLUT8在海马神经元中具有一种新的细胞内分布，并且在葡萄糖刺激后会转运至细胞内膜。免疫印迹分析显示GLUT8在高密度微粒体（HDM）中高表达，这表明在基础条件下GLUT8与细胞内细胞器相关。免疫金电子显微镜分析证实了这一观察结果，即GLUT8免疫金颗粒与粗面内质网（ER）和细胞质相关。外周给予葡萄糖使HDM组分中GLUT8水平迅速增加两倍，同时降低低密度微粒体中GLUT8水平。同样，外周给予葡萄糖显著增加了海马体中GLUT8与粗面内质网的结合。相反，在高血糖/胰岛素缺乏条件下，即链脲佐菌素（STZ）诱导的糖尿病中，HDM组分中海马体GLUT8蛋白水平降低。这些结果表明，外周给予葡萄糖后，GLUT8会迅速转运至大鼠海马体的粗面内质网，而在STZ糖尿病中这种转运受损，这表明胰岛素是海马神经元中GLUT8转运的刺激因素。由于在粗面内质网的N-连接糖基化过程中葡萄糖从寡糖中释放出来，我们推测GLUT8可能用于将葡萄糖从粗面内质网转运至细胞质中，从而有助于海马神经元中的葡萄糖稳态。
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