Institute of Biological Information Processing, Molekular- und Zellphysiologie (IBI-1), Forschungszentrum Jülich, Jülich, Germany.
Institute of Clinical Pharmacology, RWTH Aachen University, Aachen, Germany.
Neurochem Res. 2022 Jan;47(1):9-22. doi: 10.1007/s11064-021-03252-x. Epub 2021 Feb 15.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. After its release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by excitatory amino acid transporters (EAATs) 1-5, a subfamily of glutamate transporters. The five proteins utilize a complex transport stoichiometry that couples glutamate transport to the symport of three Na ions and one H in exchange with one K to accumulate glutamate against up to 10-fold concentration gradients. They are also anion-selective channels that open and close during transitions along the glutamate transport cycle. EAATs belong to a larger family of secondary-active transporters, the SLC1 family, which also includes purely Na- or H-coupled prokaryotic transporters and Na-dependent neutral amino acid exchangers. In recent years, molecular cloning, heterologous expression, cellular electrophysiology, fluorescence spectroscopy, structural approaches, and molecular simulations have uncovered the molecular mechanisms of coupled transport, substrate selectivity, and anion conduction in EAAT glutamate transporters. Here we review recent findings on EAAT transport mechanisms, with special emphasis on the highly conserved hairpin 2 gate, which has emerged as the central processing unit in many of these functions.
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。谷氨酸从突触前神经末梢释放后，被谷氨酸转运体（EAATs）1-5 迅速从突触间隙中清除，EAATs 是谷氨酸转运体的一个亚家族。这五种蛋白利用复杂的转运计量关系，将谷氨酸转运与三个 Na 离子和一个 H 的共转运偶联，以交换一个 K，从而在高达 10 倍的浓度梯度下积累谷氨酸。它们也是阴离子选择性通道，在谷氨酸转运循环的转变过程中打开和关闭。EAATs 属于更大的 SLC1 家族的二级主动转运体家族，该家族还包括纯 Na 或 H 偶联的原核转运体和 Na 依赖性中性氨基酸交换体。近年来，分子克隆、异源表达、细胞电生理学、荧光光谱学、结构方法和分子模拟揭示了 EAAT 谷氨酸转运体的偶联转运、底物选择性和阴离子传导的分子机制。本文综述了 EAAT 转运机制的最新发现，特别强调了高度保守的发夹 2 门，它已成为许多这些功能的核心处理单元。
