EAAC1 Transporter Associated Protein, GABA & Epilepsy

EAAC1 转运蛋白相关蛋白，GABA

• 批准号: 6640148
• 负责人: JEHUDA P SEPKUTY
• 金额: $ 23.99万
• 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/6640148
• 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蛋白 EAAC1 的表达会导致成年大鼠癫痫。最近的代谢研究表明，这种癫痫发作活动可能是由于 GABA 合成减少所致，这表明 EAAC1 参与了正常的 GABA 代谢。这些结果提供了关于负责维持 GABA 递质库的细胞机制的新见解。我们建议通过操纵体内 EAAC1 活性来研究 EAAC1 谷氨酸摄取与癫痫之间的关系，并检查这对癫痫发作、谷氨酸摄取、GABA 合成和突触抑制的影响。最近，一种新的蛋白质被鉴定和表征，它是 EAAC1 的内源性负调节因子。这种蛋白质 GTRAP3-18（谷氨酸转运蛋白相关蛋白 3-18）可能通过影响 EAAC1 介导的谷氨酸摄取，在 GABA 代谢的调节中发挥关键作用。该项目的总体目标是确定：(1) 降低 EAAC1 表达是否会降低成年大鼠的 GABA 合成并导致癫痫，(2) 直接或通过 GTRAP3-18 间接干扰 EAAC1 代谢是否会破坏 GABA 的合成。这些关于 EAAC1 参与 GABA 代谢的研究可能会带来对癫痫病因的新见解，并有助于开发治疗各种癫痫疾病的新治疗方法。意义：本次资助提出的研究旨在明确成人大脑中谷氨酸转运蛋白 EAAC1、GABA 代谢和癫痫之间的关系。我们计划测试 GTRAP3-18（EAAC1 活性的负调节因子）水平的增加是否会导致癫痫，以及降低 GTRAP3-18 的表达是否会降低癫痫易感性。我们希望这些关于 EAAC1 谷氨酸摄取与 GABA 能传输功效之间联系的研究可能有助于确定治疗癫痫的新方法。