Functional analysis and expression cloning of D-serine uptake site

D-丝氨酸摄取位点的功能分析和表达克隆

• 批准号: 12680761
• 负责人: HASHIMOTO Atsushi
• 金额: $ 2.43万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680761/
• 关键词: D-amino acid; D-serine; uptake site; トランスポーター

Although D-amino acids have been assumed to be unnatural in mammals, a wide variety of studies has demonstrated that free D-serine and serine racemase occur in the mammalian brain. To gain an insight into the uptake site of D-serine, we have investigated the effect of systemic administration of D-serine on the concentrations of D- and L-serine in the several brain areas and periphery of infant and adult rat. Intraperitoneal administration of D-serine caused a drastic increase in the levels of D-serine in all brain areas and periphery of infant and adult rat. The increase in the D-serine levels were higher in the cerebellum and kidney, which D-amino acid oxidase appear during early postnatal development. A systemic injection of D-serine produced a slight but significant increase in the levels of L-serine in almost all brain and peripheral tissues of infant rat. The increase in the L-serine levels might be due to the reverse reaction of serine racemase. Following a systemic injection of D-serine, the D-serine concentrations in all brain areas of adult rat rapidly increased, and peaked at 3 or 6 hours. The D-serine levels in the cortex, striatum, hippocampus, diencephalon gradually decreased and returned to the control levels 7 days after the injection, whereas the D-serine levels in the pons-medulla and cerebellum rapidly decreased and returned to the control levels 3 days after the injection. Because D-serine potentiates the NMDA receptor-mediated neurotransmission via the glycine site with an affinity similar to glycine and because D-serine application ameliorates the positive and negative symptoms of schizophrenia, D-serine administration could be beneficial in treating diseases related to the hypofunction of the NMDA-mediated neurotransmission such as schizophrenia and Alzheimer's disease.

尽管 D-氨基酸被认为在哺乳动物中是非天然的，但大量研究表明，游离的 D-丝氨酸和丝氨酸消旋酶存在于哺乳动物大脑中。为了深入了解 D-丝氨酸的摄取位点，我们研究了全身施用 D-丝氨酸对婴儿和成年大鼠的几个脑区和外周 D-和 L-丝氨酸浓度的影响。腹膜内给予D-丝氨酸导致婴儿和成年大鼠所有脑区和外周的D-丝氨酸水平急剧增加。小脑和肾脏中 D-丝氨酸水平的增加较高，这是 D-氨基酸氧化酶在出生后早期发育过程中出现的。全身注射 D-丝氨酸可使幼鼠几乎所有大脑和外周组织的 L-丝氨酸水平略有增加但显着增加。 L-丝氨酸水平的增加可能是由于丝氨酸消旋酶的逆反应所致。全身注射D-丝氨酸后，成年大鼠所有脑区的D-丝氨酸浓度迅速升高，并在3或6小时达到峰值。注射后7天，皮层、纹状体、海马、间脑的D-丝氨酸水平逐渐下降并恢复至对照水平，而脑桥延髓和小脑的D-丝氨酸水平迅速下降，注射后3天恢复至对照水平。由于 D-丝氨酸通过甘氨酸位点以与甘氨酸相似的亲和力增强 NMDA 受体介导的神经传递，并且由于 D-丝氨酸的应用可改善精神分裂症的阳性和阴性症状，因此 D-丝氨酸给药可能有益于治疗与 NMDA 介导的神经传递功能减退相关的疾病，例如精神分裂症和阿尔茨海默病 疾病。

项目成果

Atsushi Hashimoto: "Effect of the intracerebro-ventricular and systemic administration of L-serine on the concentrations of D- and L-serine in several brain areas and periphery of rat"Brain Research. 955. 214-220 (2002)

Atsushi Hashimoto：“脑室内和全身施用 L-丝氨酸对大鼠几个脑区和外周 D-和 L-丝氨酸浓度的影响”脑研究。

Atsushi Hashimoto: "Effect of the intracerebroventricular and systemic administration of L-serine..."Brain Research. 955. 214-220 (2002)

Atsushi Hashimoto：“L-丝氨酸脑室内和全身给药的效果......”大脑研究。

Atsushi hashimoto: "Effects on N-methyl-D-aspartate, kainate or veratridine on"Brain Research Bulletin. 53. 347-351 (2000)

Atsushi Hashimoto：“对 N-甲基-D-天冬氨酸、红藻氨酸或藜芦定的影响”《脑研究通报》。

Atsushi Hashimoto: "Effects on N-methytl-D-aspartate, kainate or veratridine on"Brain Research Bulletin. 53. 347-351 (2000)

Atsushi Hashimoto：“对 N-甲基-D-天冬氨酸、红藻氨酸或藜芦定的影响”《脑研究通报》。

Atsushi Hashimoto: "Effect of the intracerebroventricular and systemic"Brain Research. 955. 214-220 (2002)

Atsushi Hashimoto：“脑室内和全身的影响”脑研究。