Glutamate transporter blockers for elucidation of the function of excitatory neurotransmission systems
Glutamate transporter blockers for elucidation of the function of excitatory neurotransmission systems
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DOI：
10.1002/tcr.20145
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发表时间：
2008-01-01
期刊：
影响因子：
6.6
通讯作者：
Shimamoto, Keiko
中科院分区：
文献类型：
--
作者：
Shimamoto, Keiko
谷氨酸是哺乳动物中枢神经系统中主要的兴奋性神经递质。谷氨酸受体激活的终止和细胞外低谷氨酸浓度的维持主要通过位于神经末梢和周围神经胶质细胞中的谷氨酸转运蛋白[兴奋性氨基酸转运蛋白1-5（EAAT 1 -5）]来实现。长期以来，人们一直需要选择性和有效的抑制剂来研究转运蛋白在突触传递调节和神经疾病发病机制中的生理意义。非转运阻断剂是理想的，因为与竞争性底物不同，它们不会引起离子通量和异源交换。经过一系列可能的候选分子，我们合成了苏式-β-苄氧基天冬氨酸（TBOA），第一个非转运阻滞剂的所有亚型的EAAT。此外，TBOA类似物与庞大的取代基上的苯环显示出增强的抑制标记谷氨酸摄取。比较底物和非转运阻断剂的作用，揭示了EAAT的生理作用。我们还开发了一种新的结合分析系统，使用氚标记的TBOA类似物。在这篇综述中，我们描述了这些阻断剂的设计和合成，以及与它们一起阐明的EAAT功能。(c)2008日本化学杂志论坛和Wiley Periodicals，Inc.
L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Termination of glutamate receptor activation and maintenance of low extracellular glutamate concentrations are mainly achieved by glutamate transporters [excitatory amino acid transporters 1-5 (EAAT1-5)] located in nerve endings and surrounding glial cells. Selective and potent inhibitors have long been required to investigate the physiological significance of transporters in the regulation of synaptic transmission and the pathogenesis of neurological diseases. Non-transportable blockers are desirable because, unlike competitive substrates, they do not cause ion flux and heteroexchange. After a series of possible candidate molecules, we synthesized threo-beta-benzyloxyaspartate (TBOA), the first non-transportable blocker for all subtypes of EAATs. In addition, TBOA analogs with a bulky substituent on their benzene ring showed enhanced inhibition of labeled glutamate uptake. Comparing the effects of substrates and non-transportable blockers revealed the physiological roles of EAATs. We also developed a novel binding assay system using a tritium-labeled TBOA analog. In this review, we describe the design and synthesis of these blockers and the functions of the EAATs elucidated with them. (c) 2008 The Japan Chemical journal Forum and Wiley Periodicals, Inc.