Human Glutamate Transporter Structure

人类谷氨酸转运蛋白结构

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：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。谷氨酸是通过突触前神经元释放的，主要是通过突触后离子型和代谢型受体释放的。兴奋性氨基酸转运蛋白（EAAT）在神经元生理学和病理生理学中起关键作用。为了使高频信号发生，必须在释放后立即从突触中删除神经递质。另外，需要低水平的环境谷氨酸以防止高亲和力受体的慢性兴奋性活性。在病理情况下，可能会发生谷氨酸转运蛋白功能和/或表面密度的变化。中风后代谢损伤引起的碱离子梯度的破坏会导致转运蛋白减慢或逆转，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发生在正常和病理生理条件下，导致环境谷氨酸水平发生变化。开发选择性的新配体用于调节和成像谷氨酸转运蛋白密度变化是一个重要目标。我们建议确定人神经谷氨酸转运蛋白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，并促进对潜在的治疗和诊断用途的选择性和高亲和力EAAT配体的开发。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。