EAAC1 Transporter Associated Protein, GABA & Epilepsy

EAAC1 转运蛋白相关蛋白，GABA

• 批准号: 6542839
• 负责人: JEHUDA P SEPKUTY
• 金额: $ 23.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542839
• 关键词: GABA receptor; aminoacid transport; electroencephalography; electrophysiology; epilepsy; gamma aminobutyrate; glutamate transporter; hippocampus; immunocytochemistry; laboratory rat; neural transmission; neurons; neurotransmitter biosynthesis; protein structure function; single cell analysis; synapses; video recording system

Decreasing the expression of the neuronal glutamate transporter, EAAC1, causes epilepsy in adult rats. Recent metabolic studies indicate that this seizure activity may result from a reduced synthesis of GABA, implicating the involvement of EAAC1 in normal GABA metabolism. These results offer new insights about the cellular mechanisms responsible for maintaining the transmitter pool of GABA. We propose to investigate the relationship between glutamate uptake by EAAC1 and epilepsy, by manipulating EAAC1 activity in vivo, and examining the effect that this has on seizures, glutamate uptake, GABA synthesis, and synaptic inhibition. Recently, a novel protein was identified and characterized that is an endogenous negative regulator of EAAC1. This protein, GTRAP3-18 (Glutamate Transporter Associated Protein 3-18), may play a critical role in the regulation of GABA metabolism through its effect on glutamate uptake mediated by EAAC1. The overall goals of this project are to determine, (1) if decreasing EAAC1 expression decreases GABA synthesis and causes epilepsy in adult rat, (2) if interfering with EAAC1 metabolism directly or indirectly through GTRAP3-18 disrupts the synthesis of GABA. These studies of EAAC1 involvement in GABA metabolism may lead to new insights into the causes of epilepsies, and help to develop novel therapeutic approaches for treating a variety of seizure disorders. Significance: The studies proposed in this grant seek to define the relationship between the glutamate transporter EAAC1, GABA metabolism, and epilepsy in the adult brain. We plan to test whether an increase in the level of GTRAP3-18, a negative regulator of EAAC1 activity, causes epilepsy, and alternatively, whether decreasing GTRAP3-18 expression decreases seizure susceptibility. Our hope is that these studies of the links between glutamate uptake by EAAC1 and the efficacy of GABAergic transmission, may help to identify novel approaches for treating epilepsy.

降低神经元谷氨酸转运体EAAC1的表达会导致成年大鼠癫痫。最近的代谢研究表明，这种癫痫活动可能是由于GABA合成减少所致，暗示EAAC1参与了正常的GABA代谢。这些结果为维持GABA递质池的细胞机制提供了新的见解。我们建议通过在体内控制EAAC1的活性来研究EAAC1摄取谷氨酸与癫痫之间的关系，并检测这对癫痫发作、谷氨酸摄取、GABA合成和突触抑制的影响。最近发现并鉴定了一种新的蛋白质，它是EAAC1的内源性负调控因子。该蛋白GTRAP3-18(谷氨酸转运体相关蛋白3-18)可能通过影响EAAC1介导的谷氨酸摄取，在调节GABA代谢中发挥关键作用。该项目的总体目标是确定：(1)EAAC1表达减少是否会减少GABA的合成并导致成年大鼠癫痫；(2)通过GTRAP3-18直接或间接干扰EAAC1代谢是否会扰乱GABA的合成。这些关于EAAC1参与GABA代谢的研究可能会为癫痫的病因带来新的见解，并有助于开发治疗各种癫痫障碍的新疗法。意义：这项拨款中提出的研究试图确定谷氨酸转运体EAAC1、GABA代谢和成人大脑中癫痫之间的关系。我们计划测试EAAC1活性的负调控因子GTRAP3-18水平的增加是否会导致癫痫，或者，GTRAP3-18表达的减少是否会降低癫痫的易感性。我们希望，这些关于EAAC1摄取谷氨酸和GABA能传递有效性之间联系的研究，可能有助于确定治疗癫痫的新方法。