Shigeri Yasushi, Seal Rebecca P, Shimamoto Keiko
National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorigaoka, Ikeda, Osaka 563-8577, Japan.
Brain Res Brain Res Rev. 2004 Jul;45(3):250-65. doi: 10.1016/j.brainresrev.2004.04.004.
L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.
L-谷氨酸是哺乳动物中枢神经系统（CNS）中的主要兴奋性神经递质，通过依赖质子电化学梯度的摄取系统（囊泡谷氨酸转运体，VGLUTs）储存于突触小泡中。谷氨酸胞吐释放后，激活快速起效的兴奋性离子型受体和起效较慢的代谢型受体，介导神经传递。位于神经元和神经胶质细胞质膜上的钠依赖性谷氨酸转运体（EAATs）迅速终止谷氨酸的作用，并将其细胞外浓度维持在兴奋性毒性水平以下。迄今为止，已鉴定出五种钠依赖性谷氨酸转运体（EAATs 1 - 5）和三种囊泡谷氨酸转运体（VGLUTs 1 - 3）。在脑制备物中以及通过各种克隆亚型的异源表达对EAATs和VGLUTs进行检测，结果表明这两个转运体家族在许多功能特性上存在差异，包括底物特异性和离子需求。这些载体的功能和/或表达改变与一系列精神和神经疾病有关。EAATs与脑卒、癫痫、阿尔茨海默病、HIV相关痴呆、亨廷顿病、肌萎缩侧索硬化症（ALS）和恶性胶质瘤有关，而VGLUTs与精神分裂症有关。为了更详细地研究谷氨酸转运体的生理作用，已开发出几类可转运和不可转运的抑制剂，其中许多是天然氨基酸天冬氨酸和谷氨酸的衍生物。本综述总结了这些不可或缺的药理学工具的发展情况，它们对于我们理解正常和异常突触传递至关重要。
