Metabolism and Physiological functions of endogenous D-serine

为了深入了解内源性D-丝氨酸在高级脑功能中的生理和病理生理作用，我们研究了D-丝氨酸在大鼠和人脑组织中的代谢。通过体内微透析技术，在大鼠额叶皮质和纹状体的细胞外液中检测到大量浓度的D-丝氨酸。无论是钙离子自由的条件下，也不灌注河豚毒素减少细胞外D-丝氨酸含量在额叶皮层和去极化剂，Escherrin，引起谷氨酸的细胞外释放的增加，但不是D-丝氨酸。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。发现[3 H] D-丝氨酸以温度和钠依赖性和可饱和的方式被摄取到皮质和小脑P2神经胶质瘤和C6神经胶质瘤细胞中，表明存在D-丝氨酸的转运系统。除了D-丝氨酸作为有效激动剂的NMDA受体的甘氨酸调节位点外，[3 H] D-丝氨酸还显示与脑组织中的新位点结合。此外，我们已经观察到，在缺乏甘氨酸裂解系统（GCS）活性的非酮症高甘氨酸血症患者和用GCS抑制剂半胱胺治疗的动物中，皮质D-丝氨酸含量显著降低。全身给予大量的L-丝氨酸产生了显着增加皮质D-丝氨酸浓度在幼年大鼠，反之亦然。本研究结果进一步支持了内源性D-丝氨酸可能参与NMDA受体和其他未知受体位点介导的突触传递的观点。D-丝氨酸的合成可能与L-丝氨酸和甘氨酸的代谢密切相关。

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.