Human Glutamate Transporter Structure

人类谷氨酸转运蛋白结构

• 批准号: 8699001
• 负责人: MICHAEL PATRICK KAVANAUGH
• 金额: $ 28.28万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699001
• 关键词: Affinity; Alkalies; Alzheimer' s Disease; Amino Acid Transporter; Brain; Buffers; Cations; Cells; Chronic; Coupled; Crystallization; Crystallography; Detection; Detergents; Development; Diagnostic; Diffusion; Disulfides; EAAT3; Engineering; Excitatory Amino Acids; Fab Immunoglobulins; Fluorescence; Frequencies; Functional disorder; Glutamate Transporter; Glutamates; Goals; Homologous Gene; Human; Image; Impairment; Injury; Insecta; Ions; Ligands; Lipids; Mediating; Metabolic; Molecular Conformation; Molecular Sieve Chromatography; Mutagenesis; Neuraxis; Neurons; Neurotransmitters; Oxidants; Pathology; Pharmaceutical Preparations; Physiology; Play; Positioning Attribute; Proteins; Reagent; Research; Resolution; Role; Signal Transduction; Stroke; Structure; Surface; Synapses; Testing; Therapeutic; Time; Traumatic Brain Injury; Work; X-Ray Crystallography; crosslink; density; excitotoxicity; mutant; neuron loss; postsynaptic; presynaptic; prevent; public health relevance; receptor; reuptake; screening; uptake

DESCRIPTION (provided by applicant): Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system. Glutamate is released by presynaptic neurons and signals primarily through postsynaptic ionotropic and metabotropic receptors. Excitatory amino acid transporters (EAATs) play critical roles in neuronal physiology and pathophysiology. In order for high frequency signaling to occur, neurotransmitter must be removed from the synapse soon after release. Additionally, low levels of ambient glutamate are required to prevent chronic excitotoxic activity of high-affinity receptors. In pathological circumstances, changes in glutamate transporter function and/or surface density can occur. Disruption of alkali ion gradients caused by metabolic impairment after stroke or traumatic brain injury cause transporter slowing or reversal, contributing to glutamate elevation and excitotoxicity. Bidirectional changes in transporter surface expression occur in both normal and pathophysiological conditions, causing ambient glutamate levels to change. Development of selective new ligands for modulating and imaging glutamate transporter density changes is an important goal. We propose to determine the first high-resolution atomic structure of a human neuronal glutamate transporter. This will provide new understanding of transporter function and facilitate development of selective and high- affinity EAAT ligands for potential therapeutic and diagnostic uses.

描述(申请人提供)：谷氨酸是哺乳动物中枢神经系统中的主要兴奋性神经递质。谷氨酸由突触前神经元释放，信号主要通过突触后离子受体和代谢性受体释放。兴奋性氨基酸转运体(EAATs)在神经生理学和病理生理学中发挥着重要作用。为了使高频信号发生，神经递质必须在释放后不久从突触中移除。此外，环境中低水平的谷氨酸是防止高亲和力受体的慢性兴奋毒性活动所必需的。在病理情况下，谷氨酸转运体功能和/或表面密度可能发生变化。中风或创伤性脑损伤后代谢障碍引起的碱性离子梯度的破坏会导致转运体减慢或逆转，导致谷氨酸升高和兴奋性毒性。转运蛋白表面表达的双向变化在正常和病理生理条件下都会发生，导致环境中谷氨酸水平的变化。发展选择性的新型配体来调节和成像谷氨酸转运体的密度变化是一个重要的目标。我们建议确定人类神经元谷氨酸转运体的第一个高分辨率原子结构。这将提供对转运蛋白功能的新理解，并促进选择性和高亲和力的EAAT配体的开发，以用于潜在的治疗和诊断用途。

项目成果

D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures.

• DOI: 10.1371/journal.pone.0156551
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Foster AC;Farnsworth J;Lind GE;Li YX;Yang JY;Dang V;Penjwini M;Viswanath V;Staubli U;Kavanaugh MP
• 通讯作者: Kavanaugh MP

Novel dicarboxylate selectivity in an insect glutamate transporter homolog.

昆虫谷氨酸转运蛋白同系物中的新型二羧酸选择性。

• DOI: 10.1371/journal.pone.0070947
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang,Hui;Rascoe,AviM;Holley,DavidC;Gouaux,Eric;Kavanaugh,MichaelP
• 通讯作者: Kavanaugh,MichaelP