Metabolism and Physiological functions of endogenous D-serine

内源性D-丝氨酸的代谢和生理功能

基本信息

批准号：
07557242
负责人：
NISHIKAWA Toru
金额：
$ 3.01万
依托单位：
National Institute of Neuroscience, NCNP
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

To obtain an insight into physiological and pathophysiological role of endogenous D-serine in higher brain functions, we have investigated the metabolism of D-serine in the rat and human brain tissues. Substantial concentration of D-serine has been detected in the extracellular fluid of the frontal cortex and striatum of the rat by an in vivo microdialysis technique. Neither calcium ion-free condition nor perfusion of tetrodotoxin reduced extracellular D-serine content in the frontal cortex and a depolarization agent, veratrin, caused an increase in the extracellular release of glutamate, but not D-serine. These data suggest that extracellular D-serine could be liberated from glial cells. [3H]D-Serine was found to be taken up into the cortical and cerebellar P2 franction and the C6 glioma cells in a temperature-and sodium-dependent and saturable manner, indicating the presence a transport system for D-serine. In addition to the glycine modulatory site of the NMDA receptor at which D-serine acts as a potent agonist, [3H]D-serine has also been shown to bind to a novel site in the brain tissues. Moreover, we have observed a profound reduction of cortical D-serine contents in the patients with non-ketotic hyperglycinemia lacking activity of glycine cleavage system (GCS) and in the animal treated with an inhibitor of GCS,cysteamine. Systemic administration of a high amount of L-serine produced a marked increase in cortical D-serine concentrations in the infant rats, vice versa. The present findings further support the view that endogenous D-serine may be involved in the synaptic transmission mediated by the NMDA receptor and other unknown receptor sites. The synthesis of D-serine might be closely related to the metabolism of L-serine and glycine.

为了了解内源性D-丝氨酸在较高脑功能中的生理和病理生理学作用，我们研究了大鼠和人脑组织中D-丝氨酸的代谢。通过体内微透析技术，已经在额叶皮层和大鼠纹状体的细胞外流体和大鼠纹状体的细胞外流体中检测到了大量的D-丝氨酸。额叶皮质中的细胞外D-丝氨酸含量和去极化剂Veratrin均未导致细胞外释放的谷氨酸盐释放增加，但没有D-丝氨酸的增加。这些数据表明，细胞外D-丝氨酸可以从神经胶质细胞中释放出来。 [3H]发现D-塞林以温度依赖性且可饱和的方式被带入皮质和小脑P2骨骼和C6胶质瘤细胞中，表明存在D-丝氨酸的传输系统。除了NMDA受体的甘氨酸调节位点，在该甘氨酸受体中，D丝氨酸充当有效的激动剂，[3H] D丝氨酸也已被证明与脑组织中的新位点结合。此外，我们已经观察到缺乏甘氨酸裂解系统（GCS）活性的非菠萝高血糖患者以及用GCS抑制剂CySteamine治疗的动物中，皮质D-丝氨酸含量的大幅降低。全身给药大量的L-塞琳在婴儿大鼠的皮质D-丝氨酸浓度显着增加，反之亦然。目前的发现进一步支持了以下观点：内源性D-丝氨酸可能参与由NMDA受体和其他未知受体部位介导的突触传播。 D丝氨酸的合成可能与L塞林和甘氨酸的代谢密切相关。