Neuronal Activity-Regulated Glutamine Transporter

神经元活动调节的谷氨酰胺转运蛋白

• 批准号: 9888453
• 负责人: JEFFREY D ERICKSON
• 金额: $ 18.45万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888453
• 关键词: Acute; Adrenergic alpha-Antagonists; Affinity; Animals; Astrocytes; Bilateral; Brain; Cerebral Ischemia; Cerebrum; Chronic; Common carotid artery; Complementary DNA; Electrophysiology (science); Evaluation; Family; Fluorescence; Gene Family; Glutamates; Glutamine; Goals; Hippocampus (Brain); Hypotension; Impaired cognition; In Vitro; Ischemia; Measures; Mediating; Molecular; Neurobiology; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Neurotransmitters; Outcome; Pathologic; Pathologic Processes; Patients; Penetration; Pharmaceutical Preparations; Physiological; Presynaptic Terminals; Prevention strategy; Rattus; Resistance; Riluzole; Risk; Rodent; Role; Stains; Subfamily lentivirinae; Synapses; System; Testing; Therapeutic; Work; artery occlusion; cell injury; cognitive function; cresyl violet; excitotoxicity; experimental study; hippocampal pyramidal neuron; improved; in vitro Assay; in vivo; inhibitor/antagonist; knock-down; member; neuron loss; new therapeutic target; novel; novel therapeutics; postnatal period; presynaptic; prevent; relating to nervous system; small hairpin RNA; therapeutic target; transmission process

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.

抽象的。兴奋性毒性是神经细胞受损的病理过程 被神经递质谷氨酸过度刺激致死如此兴奋毒性 神经元死亡与全脑缺血有关， 突触前谷氨酸释放过多据信谷氨酸传输 需要从星形胶质细胞将谷氨酰胺输入轴突末端以补充细胞质 谷氨酸水平和囊泡存储损失后，过量的突触谷氨酸 release.因此，阻断谷氨酰胺的突触输入代表了一种潜在的治疗方法， 目标是限制兴奋性毒性条件下持续的谷氨酸释放。我们有 最近在功能上鉴定了一种新的活性调节的谷氨酰胺转运蛋白， 被抗组胺药利鲁唑有效抑制。取得进展的关键障碍 了解突触前机制参与过量谷氨酸释放是1） 表达的神经活性调节的谷氨酰胺转运蛋白的分子特性 在突触中的作用尚不清楚，2）利鲁唑衍生物，其选择性地阻断神经元 活性调节的谷氨酰胺转运蛋白，并具有改善的脑渗透， 没有，和3）神经元活性调节的谷氨酰胺转运蛋白的作用， vivo尚未确定。阿曲唑阻断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，包括全身性神经元损伤。 啮齿类动物的脑缺血我们已经鉴定了具有上级 脑渗透，有效地阻断神经元活性调节的谷氨酰胺转运，但 那些可能不干扰Na+（即，NaV）或K+（即，KV）通道，相比之下， 利鲁唑。利鲁唑敏感、神经元活动调节的功能鉴定 海马突触中的谷氨酰胺转运在海马神经系统中具有重要的分支， 神经生物学的突触谷氨酸释放，谷氨酸/谷氨酰胺循环，和 谷氨酸诱导的兴奋性毒性我们的总体目标是改善治疗选择， 条件过量谷氨酸释放从突触提供的理由， 开发药物以限制轴突末端中活性驱动的谷氨酰胺输入， 维持兴奋性毒性谷氨酸所需的细胞质谷氨酸水平的补充 release.