Functional analysis and expression cloning of D-serine uptake site

虽然D-氨基酸在哺乳动物中被认为是非自然的，但大量的研究表明，哺乳动物的大脑中存在游离的D-丝氨酸和丝氨酸外消旋酶。为了深入了解D-丝氨酸的摄取部位，我们研究了全身给药对幼年和成年大鼠几个脑区和外周D-丝氨酸和L-丝氨酸浓度的影响。腹腔注射D-丝氨酸可使幼鼠和成年大鼠各脑区和外周的D-丝氨酸水平显著升高。D-丝氨酸水平在小脑和肾脏中升高较高，D-氨基酸氧化酶出现在出生后早期。全身注射D-丝氨酸后，幼鼠几乎所有脑组织和外周组织中的L-丝氨酸水平均有轻微但显著的升高。L-丝氨酸水平的升高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，成年大鼠各脑区D-丝氨酸浓度迅速升高，并在3或6小时达到高峰。皮质区、纹状体、海马区、间脑的D-丝氨酸水平在注射后7d逐渐下降，并恢复到对照水平，而脑桥和小脑的D-丝氨酸水平在注射后3d迅速下降，并恢复到对照水平。由于D-丝氨酸以与甘氨酸相似的亲和力通过甘氨酸部位增强NMDA受体介导的神经传递，而且D-丝氨酸的应用可以改善精神分裂症的阳性和阴性症状，因此D-丝氨酸的应用可能有助于治疗与NMDA介导的神经传递功能低下有关的疾病，如精神分裂症和阿尔茨海默病。

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.