Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Tokyo 113-8519, Japan.
J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Nov 1;879(29):3169-83. doi: 10.1016/j.jchromb.2011.08.030. Epub 2011 Aug 30.
D-Serine is a unique endogenous substance enriched in the brain at the exceptionally high concentrations as a free D-amino acid in mammals throughout their life. Peripheral tissues and blood contain low or trace levels of the D-amino acid. In the nervous systems, D-serine appears to act as an intrinsic coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDA receptor) based upon the following characteristics: (i) D-serine stereoselectively binds to and stimulates the glycine-regulatory site of the NMDA receptor consisting of GRIN1/GRIN2 subunits more potently than glycine with an affinity and ED50 at high nanomolar ranges, (ii) the selective elimination of D-serine in brain tissues attenuates the NMDA receptor functions, indicating an indispensable role in physiological activation of the glutamate receptor, and (iii) the distribution of D-serine is uneven and closely correlated with that of the binding densities of the various NMDA receptor sites, and especially of the GRIN2B subunit in the brain. Moreover, d-serine exerts substantial influence on the GRIN1/GRIN3-NMDA and δ2 glutamate receptor. In the brain and retina, metabolic processes of D-serine, such as biosynthesis, extracellular release, uptake, and degradation, are observed and some candidate molecules that mediate these processes have been isolated. The fact that the mode of extracellular release of D-serine in the brain differs from that of classical neurotransmitters is likely to be related to the detection of D-serine in both glial cells and neurons, suggesting that d-serine signals could be required for the glia-synapse interaction. Moreover, the findings from the basic experiments and clinical observations support the views that the signaling system of endogenous free D-serine plays important roles, at least, through the action on the NMDA receptors in the brain wiring development and the regulation of higher brain functions, including cognitive, emotional and sensorimotor function. Based upon these data, aberrant D-serine-NMDA receptor interactions have been considered to be involved in the pathophysiology of a variety of neuropsychiatric disorders including schizophrenia and ischemic neuronal cell death. The molecular and cellular mechanisms for regulating the D-serine signals in the nervous system are, therefore, suitable targets for studies aiming to elucidate the causes of neuropsychiatric disorders and for the development of new treatments for intractable neuropsychiatric symptoms.
D-丝氨酸是一种独特的内源性物质，在哺乳动物的整个生命过程中，以游离 D-氨基酸的形式在大脑中高度富集，浓度极高。外周组织和血液中 D-氨基酸的含量较低或检测不到。在神经系统中，D-丝氨酸似乎作为 N-甲基-D-天冬氨酸型谷氨酸受体（NMDA 受体）的内源性共激动剂发挥作用，基于以下特征：（i）D-丝氨酸对 NMDA 受体的甘氨酸调节部位具有立体选择性结合和刺激作用，GRIN1/GRIN2 亚基组成，与甘氨酸相比，亲和力和 ED50 处于高纳摩尔范围，（ii）脑组织中 D-丝氨酸的选择性消除会减弱 NMDA 受体的功能，表明其在谷氨酸受体的生理激活中不可或缺，（iii）D-丝氨酸的分布不均匀，与各种 NMDA 受体部位的结合密度密切相关，尤其是大脑中的 GRIN2B 亚基。此外，D-丝氨酸对 GRIN1/GRIN3-NMDA 和 δ2 谷氨酸受体也有很大的影响。在大脑和视网膜中，观察到 D-丝氨酸的代谢过程，如生物合成、细胞外释放、摄取和降解，并且已经分离出一些介导这些过程的候选分子。D-丝氨酸在大脑中的细胞外释放方式不同于经典神经递质的事实，可能与 D-丝氨酸在神经胶质细胞和神经元中的检测有关，这表明 D-丝氨酸信号可能是胶质突触相互作用所必需的。此外，基础实验和临床观察的结果支持这样的观点，即内源性游离 D-丝氨酸的信号系统通过作用于大脑连接发育和调节认知、情绪和感觉运动功能等高级脑功能中的 NMDA 受体，至少发挥重要作用。基于这些数据，异常的 D-丝氨酸-NMDA 受体相互作用被认为与包括精神分裂症和缺血性神经元细胞死亡在内的多种神经精神疾病的病理生理学有关。因此，调节神经系统中 D-丝氨酸信号的分子和细胞机制是研究神经精神疾病病因和开发治疗难治性神经精神症状新方法的合适靶点。
