Neuronal Activity-Regulated Glutamine Transporter

抽象的。兴奋性毒性是神经细胞受损的病理过程。 并被神经递质谷氨酸过度刺激致死。如此具有兴奋性毒性 神经元死亡与全脑缺血有关，是由 突触前谷氨酸释放过多。人们认为谷氨酸的传递 需要将谷氨酰胺从星形胶质细胞导入轴突终末以补充细胞质 突触谷氨酸过量导致谷氨酸水平和囊泡丢失 放手。因此，阻止谷氨酰胺的突触输入是一种潜在的治疗方法 目标是限制兴奋性毒性条件下谷氨酸的持续释放。我们有 最近从功能上发现了一种新的活性调节谷氨酰胺转运体，它是 被抗谷氨酸能药物利鲁唑有效抑制。取得进展的关键障碍 了解涉及谷氨酸过度释放的突触前机制1) 神经元活性调节的谷氨酰胺转运蛋白表达的分子同源性 在突触中的作用尚不清楚，2)利鲁唑衍生物选择性地阻断神经元 活动调节的谷氨酰胺转运体，并提高了大脑的渗透率，是 不可用，以及3)神经元活动调节的谷氨酰胺转运体在 活体还没有确定。利鲁唑阻止过度的突触谷氨酸释放 可以阻断在兴奋性毒性条件下发生的神经元损伤，包括 啮齿动物的脑缺血。我们已经鉴定出新的利鲁唑衍生物具有更好的 大脑穿透有效地阻止神经元活动调节的谷氨酰胺运输，但 那些可能不干扰Na+(即NAV)或K+(即KV)通道的通道，与 利鲁唑。利鲁唑敏感、神经元活动调节的功能鉴定 海马区突触的谷氨酰胺转运在 突触谷氨酸释放、谷氨酸/谷氨酰胺循环的神经生物学 谷氨酸诱导的兴奋性毒性。我们的总体目标是改善治疗方案 从突触过度释放谷氨酸的条件 开发药物以限制轴突终末和细胞内活性驱动的谷氨酰胺进口 维持兴奋性谷氨酸所需的细胞质谷氨酸水平的补充 放手。

Abstract. Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by the neurotransmitter glutamate. Such excitotoxic neuronal death has been implicated in cerebral global ischemia and is a result of excessive presynaptic glutamate release. It is believed that glutamate transmission requires import of glutamine into axon terminals from astrocytes to replenish cytoplasmic glutamate levels and vesicular stores lost following excessive synaptic glutamate release. Thus, blocking synaptic import of glutamine represents a potential therapeutic target to limit continued glutamate release under conditions of excitotoxicity. We have recently functionally identified a novel activity-regulated glutamine transporter, which is potently inhibited by the anti-glutamatergic drug riluzole. Critical barriers to progress in understanding presynaptic mechanisms involved in excessive glutamate release are 1) the molecular identity of the neuronal activity-regulated glutamine transporter expressed in synapses is not known, 2) riluzole derivatives that selectively block the neuronal activity-regulated glutamine transporter, and that have improved brain penetration, are not available, and 3) the role of the neuronal activity-regulated glutamine transporter in vivo has not been determined. Riluzole blocks excessive synaptic glutamate release and can block neuronal damage that occurs in conditions of excitotoxicity, including global cerebral ischemia in rodents. We have identified novel riluzole derivatives with superior brain penetration that potently block neuronal activity-regulated glutamine transport, but those likely do not interfere with Na+ (i.e., NaV) or K+ (i.e., KV) channels, compared to riluzole. The functional identification of riluzole-sensitive, neuronal activity-regulated glutamine transport in hippocampal synapses has important ramifications in the neurobiology of synaptic glutamate release, the glutamate/glutamine cycle, and glutamate-induced excitotoxicity. Our overall goal is to improve therapeutic options in conditions of excessive glutamate release from synapses by providing rationale for developing drugs to limit activity-driven glutamine import in axon terminals and replenishment of cytoplasmic glutamate levels required to sustain excitotoxic glutamate release.