Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Amino Acids. 2012 Nov;43(5):1919-31. doi: 10.1007/s00726-012-1398-4. Epub 2012 Sep 19.
For elucidation of the regulation mechanisms of intrinsic amounts of D-serine (D-Ser) which modulates the neuro-transmission of N-methyl-D-aspartate receptors in the brain, mutant animals lacking serine racemase (SRR) and D-amino acid oxidase (DAO) were established, and the amounts of D-Ser in the tissues and physiological fluids were determined. D-Ser amounts in the frontal brain areas were drastically decreased followed by reduced SRR activity. On the other hand, a moderate but significant decrease in D-Ser amounts was observed in the cerebellum and spinal cord of SRR knock-out (SRR(-/-)) mice compared with those of control mice, although the amounts of D-Ser in these tissues were low. The amounts of D-Ser in the brain and serum were not altered with aging. To clarify the uptake of exogenous D-Ser into the brain tissues, we have determined the D-Ser of SRR(-/-) mice after oral administration of D-Ser for the first time, and a drastic increase in D-Ser amounts in all the tested tissues was observed. Because both DAO and SRR are present in some brain areas, we have established the double mutant mice lacking SRR and DAO for the first time, and the contribution of both enzymes to the intrinsic D-Ser amounts was investigated. In the frontal brain, most of the intrinsic D-Ser was biosynthesized by SRR. On the other hand, half of the D-Ser present in the hindbrain was derived from the biosynthesis by SRR. These results indicate that the regulation of intrinsic D-Ser amounts is different depending on the tissues and provide useful information for the development of treatments for neuronal diseases.
为了阐明内源性 D-丝氨酸 (D-Ser) 的调节机制，这种物质可调节大脑中 N-甲基-D-天冬氨酸受体的神经传递，研究人员建立了缺乏丝氨酸消旋酶 (SRR) 和 D-氨基酸氧化酶 (DAO) 的突变动物模型，并测定了组织和生理体液中的 D-Ser 含量。结果发现，在前脑区域 D-Ser 含量明显减少，随后 SRR 活性降低。另一方面，与对照小鼠相比，SRR 敲除 (SRR(-/-)) 小鼠小脑和脊髓中的 D-Ser 含量中度但显著降低，尽管这些组织中的 D-Ser 含量较低。在衰老过程中，大脑和血清中的 D-Ser 含量没有变化。为了阐明外源性 D-Ser 进入脑组织的摄取情况，我们首次测定了 SRR(-/-) 小鼠口服 D-Ser 后的 D-Ser 含量，结果发现所有测试组织中的 D-Ser 含量均明显增加。由于 DAO 和 SRR 都存在于一些脑区，我们首次建立了同时缺乏 SRR 和 DAO 的双突变小鼠，并研究了这两种酶对内源性 D-Ser 含量的贡献。在前脑，大部分内源性 D-Ser 是由 SRR 生物合成的。另一方面，后脑中存在的 D-Ser 有一半来源于 SRR 的生物合成。这些结果表明，内源性 D-Ser 含量的调节因组织而异，为神经元疾病的治疗方法的开发提供了有用的信息。
