Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
Amino Acids. 2013 Jul;45(1):133-42. doi: 10.1007/s00726-013-1481-5. Epub 2013 Mar 6.
Extracellular glutamate should be maintained at low levels to conserve optimal neurotransmission and prevent glutamate neurotoxicity in the brain. Excitatory amino acid transporters (EAATs) play a pivotal role in removing extracellular glutamate in the central nervous system (CNS). Excitatory amino acid carrier 1 (EAAC1) is a high-affinity Na⁺-dependent neuronal EAAT that is ubiquitously expressed in the brain. However, most glutamate released in the synapses is cleared by glial EAATs, but not by EAAC1 in vivo. In the CNS, EAAC1 is widely distributed in somata and dendrites but not in synaptic terminals. The contribution of EAAC1 to the control of extracellular glutamate levels seems to be negligible in the brain. However, EAAC1 can transport not only extracellular glutamate but also cysteine into the neurons. Cysteine is an important substrate for glutathione (GSH) synthesis in the brain. GSH has a variety of neuroprotective functions, while its depletion induces neurodegeneration. Therefore, EAAC1 might exert a critical role for neuroprotection in neuronal GSH metabolism rather than glutamatergic neurotransmission, while EAAC1 dysfunction would cause neurodegeneration. Despite the potential importance of EAAC1 in the brain, previous studies have mainly focused on the glutamate neurotoxicity induced by glial EAAT dysfunction. In recent years, however, several studies have revealed regulatory mechanisms of EAAC1 functions in the brain. This review will summarize the latest information on the EAAC1-regulated neuroprotective functions in the CNS.
细胞外谷氨酸应保持在低水平，以维持最佳的神经递质传递并防止大脑中的谷氨酸神经毒性。兴奋性氨基酸转运体（EAATs）在中枢神经系统（CNS）中去除细胞外谷氨酸中起着关键作用。兴奋性氨基酸载体 1（EAAC1）是一种高亲和力的 Na⁺依赖性神经元 EAAT，在大脑中广泛表达。然而，突触中释放的大多数谷氨酸是由神经胶质 EAATs 而不是 EAAC1 在体内清除的。在中枢神经系统中，EAAC1 广泛分布于神经元的胞体和树突中，但不在突触末端。EAAC1 对控制细胞外谷氨酸水平的贡献在大脑中似乎可以忽略不计。然而，EAAC1 不仅可以转运细胞外谷氨酸，还可以转运半胱氨酸进入神经元。半胱氨酸是大脑中谷胱甘肽（GSH）合成的重要底物。GSH 具有多种神经保护功能，而其耗竭会诱导神经退行性变。因此，EAAC1 可能在神经元 GSH 代谢的神经保护中发挥关键作用，而不是在谷氨酸能神经传递中，而 EAAC1 功能障碍会导致神经退行性变。尽管 EAAC1 在大脑中具有潜在的重要性，但以前的研究主要集中在神经胶质 EAAT 功能障碍引起的谷氨酸神经毒性上。然而，近年来，几项研究揭示了 EAAC1 功能在大脑中的调节机制。本综述将总结 CNS 中 EAAC1 调节的神经保护功能的最新信息。
