Human Glutamate Transporter Structure

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，主要通过突触后离子型和代谢型受体传递信号。兴奋性氨基酸转运蛋白（EAAT）在神经元生理和病理生理中起着重要作用。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，需要低水平的环境谷氨酸来防止高亲和力受体的慢性兴奋性毒性活性。在病理情况下，谷氨酸转运蛋白功能和/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离子梯度破坏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，引起周围谷氨酸水平的变化。开发用于调节和成像谷氨酸转运体密度变化的选择性新配体是一个重要目标。我们建议确定人类神经元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，并促进用于潜在治疗和诊断用途的选择性和高亲和力EAAT配体的开发。

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.