Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Cells. 2019 Feb 20;8(2):184. doi: 10.3390/cells8020184.
Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca release from the astrocytes' intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases.
谷氨酸是中枢神经系统（CNS）中兴奋性神经元释放的最常见的神经递质之一；然而，细胞外间隙中残留的谷氨酸可能具有神经毒性。现在已经明确，星形胶质细胞的基本功能之一是摄取大部分突触释放的谷氨酸，这优化了神经元的功能并防止了谷氨酸兴奋性毒性。在中枢神经系统中，谷氨酸的清除由主要由星形胶质细胞表达的谷氨酸摄取转运体介导。有趣的是，最近的研究表明，细胞外谷氨酸刺激星形胶质细胞细胞内储存的 Ca 释放，这触发谷氨酸从星形胶质细胞释放到相邻神经元，主要通过胞吐作用机制。这种释放的谷氨酸被认为可以协调神经元的发射并调节它们的兴奋或抑制活性。因此，星形胶质细胞通过维持其摄取和释放谷氨酸的相反功能之间的平衡，为中枢神经系统中的谷氨酸稳态做出贡献。星形胶质细胞的这种双重功能代表了与谷氨酸兴奋性毒性相关的中枢神经系统疾病的潜在治疗靶点。在这方面，我们总结了谷氨酸摄取和释放的分子机制、它们的调节以及这两个过程在中枢神经系统中的意义。此外，我们还回顾了谷氨酸代谢和谷氨酸兴奋性毒性的主要特征及其在中枢神经系统疾病中的意义。
