GABA TRANSPORTER INTERACTING DOMAINS

GABA 转运蛋白相互作用域

• 批准号: 6742495
• 负责人: MICHAEL W. QUICK
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-10 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6742495
• 关键词: animal tissue; biological signal transduction; chemical association; chloride channels; density gradient ultracentrifugation; gamma aminobutyrate; gene deletion mutation; gene expression; glia; immunoprecipitation; intermolecular interaction; membrane transport proteins; mutant; neurons; neuroregulation; neurotransmitter transport; protein binding; protein folding; protein protein interaction; protein structure function; syntaxin; tissue /cell culture

DESCRIPTION: (Applicant's Abstract) Neurotransmitter levels in brain are critical for normal brain function. Abnormal levels of neurotransmitter, resulting in inappropriate neural signaling, underlie a diverse list of brain disorders. For example, epilepsy, excitotoxic cell death, depression, and a number of conditions related to drug abuse are all related to abnormal transmitter levels in brain. Neurotransmitter transporters are proteins, located on neurons and glia, that function in part to transport transmitter from the extracellular milieu into cells. As such, they play a central role in regulating synaptic signaling. While much is being learned about the permeation properties of various neurotransmitter transporters (e.g., transport rates, substrate affinities, conducting states), little is known about how particular structural domains of the transporter participate in the permeation process. Furthermore, while it is known that transporter function can be regulated, the extent to which the regulation occurs through manipulation of the domains involved in permeation is not known. The major goal of this application is to define the role of intra-molecular and inter-molecular interactions in regulation of the GABA transporter GAT1. Specific Aim 1 is to test the hypothesis that the amino terminal cytoplasmic tail of the GABA transporter GAT1 positively regulates GABA transport through interactions with internal cytoplasmic loops of the transporter. Specific Aim 2 is to test the hypothesis that proteins that physically interact with the amino terminal tail of GAT1 negatively regulate GAT1 function by preventing the N-terminal tail from interacting with the internal cytoplasmic loops of the transporter. Specific Aim 3 is to test the hypothesis that intermolecular interactions that negatively regulate transporter function can be modulated by physiologically relevant factors. These studies are important because they will (i) define a new regulatory role in permeation for intracellular transporter domains; (ii) elucidate a novel mechanism for the cellular regulation of transporter function through protein-protein interactions; and (iii) provide data that could be useful in strategies aimed at regulating transporter function in the treatment of disorders related to abnormal transmitter levels.

描述：（申请人的摘要） 大脑中的神经递质水平对于正常的大脑功能至关重要。 神经递质的异常水平，导致不适当的神经 信号传导，是脑部疾病的多样化列表。例如，癫痫， 兴奋性细胞死亡，抑郁症以及与药物有关的许多疾病 滥用都与大脑中异常发射器水平有关。神经递质 转运蛋白是位于神经元和神经胶质上的蛋白质，部分作用 将发射机从细胞外环境传输到细胞中。像这样， 它们在调节突触信号传导中起着核心作用。虽然有很多 了解各种神经递质的渗透特性 转运蛋白（例如，运输速率，底物亲和力，指示状态）， 关于转运蛋白的特定结构域知之甚少 参加渗透过程。此外，众所周知 可以调节转运蛋白功能的调节程度 通过操纵参与渗透的域而发生的情况是不清楚的。 该应用的主要目的是定义分子内和 GABA转运蛋白GAT1调节中的分子间相互作用。 具体目的1是检验氨基末端细胞质的假设 GABA转运蛋白GAT1的尾巴正积极调节GABA通过 与转运蛋白的内部细胞质环相互作用。具体目标2 是测试与氨基物理相互作用的蛋白质的假设 GAT1的末端尾巴通过防止 N末端与与内部细胞质环相互作用 转运蛋白。特定目的3是检验分子间的假设 负调控转运蛋白函数的相互作用可以通过 生理上相关的因素。 这些研究很重要，因为它们将（i）定义新的调节作用 在细胞内转运蛋白结构域的渗透中； （ii）阐明小说 通过转运蛋白功能的细胞调节机制 蛋白质蛋白质相互作用； （iii）提供可能有用的数据 旨在调节转运蛋白功能的策略 与异常发射器水平有关的疾病。

项目成果

A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity.

突触融合蛋白 1A 与抗抑郁药敏感的去甲肾上腺素转运蛋白的受调节相互作用建立了儿茶酚胺清除能力。

• DOI: 10.1523/jneurosci.23-05-01697.2003
• 发表时间: 2003
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Sung,Uhna;Apparsundaram,Subramaniam;Galli,Aurelio;Kahlig,KristopherM;Savchenko,Valentina;Schroeter,Sally;Quick,MichaelW;Blakely,RandyD
• 通讯作者: Blakely,RandyD

Syntaxin 1A inhibits GABA flux, efflux, and exchange mediated by the rat brain GABA transporter GAT1.

Syntaxin 1A 抑制大鼠脑 GABA 转运蛋白 GAT1 介导的 GABA 流动、流出和交换。

• DOI: 10.1124/mol.64.4.905
• 发表时间: 2003
• 期刊: Molecular pharmacology.
• 作者: Wang,Dan;Deken,ScottL;Whitworth,TerriL;Quick,MichaelW
• 通讯作者: Quick,MichaelW