Dringen Ralf, Arend Christian
Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany.
Center for Environmental Research and Sustainable Technologies, University of Bremen, Bremen, Germany.
J Neurochem. 2025 May;169(5):e70073. doi: 10.1111/jnc.70073.
Astrocytes have essential functions in the brain as partners of neurons in many metabolic and homeostatic processes. The metabolism of the tripeptide GSH (γ-L-glutamyl-L-cysteinyl-glycine) is an important example of a metabolic interaction between astrocytes and neurons. GSH is present in brain cells in millimolar concentrations and has essential functions as an antioxidant and as a substrate for detoxification reactions. A high GSH content protects astrocytes against oxidative stress and toxins and is therefore beneficial for the astrocytic self-defense that helps to maintain the essential functions of astrocytes in the brain and will enable astrocytes to eliminate potential toxins before they may reach other brain cells. In addition, astrocytes provide neurons with the amino acids required for GSH synthesis in a process that involves the export of GSH from astrocytes by the multidrug resistance protein 1, the extracellular processing of GSH via the astrocytic γ-glutamyl transpeptidase to generate the dipeptide cysteinyl-glycine, and the extracellular cleavage of this dipeptide by the neuronal ectopeptidase aminopeptidase N. As GSH export from astrocytes strongly depends on the cytosolic GSH concentration, a high astrocytic GSH content will also facilitate GSH release and thereby the supply of GSH precursors to neighboring neurons. In this article, we will give an overview of the current knowledge on the GSH metabolism of astrocytes, address how a high astrocytic GSH content can help to maintain brain functions, and discuss open questions and future perspectives of research on the functions of astrocytes in the GSH metabolism of the healthy and diseased brain.
星形胶质细胞在大脑中具有重要功能，在许多代谢和体内平衡过程中作为神经元的伙伴。三肽谷胱甘肽（γ-L-谷氨酰-L-半胱氨酰-甘氨酸）的代谢是星形胶质细胞与神经元之间代谢相互作用的一个重要例子。谷胱甘肽以毫摩尔浓度存在于脑细胞中，具有抗氧化剂和解毒反应底物的重要功能。高谷胱甘肽含量可保护星形胶质细胞免受氧化应激和毒素的侵害，因此有利于星形胶质细胞的自我防御，有助于维持星形胶质细胞在大脑中的基本功能，并使星形胶质细胞能够在潜在毒素到达其他脑细胞之前将其清除。此外，星形胶质细胞通过多药耐药蛋白1将谷胱甘肽从星形胶质细胞中输出、通过星形胶质细胞γ-谷氨酰转肽酶对谷胱甘肽进行细胞外加工以生成二肽半胱氨酰-甘氨酸、以及通过神经元外肽酶氨肽酶N对该二肽进行细胞外裂解等过程，为神经元提供谷胱甘肽合成所需的氨基酸。由于谷胱甘肽从星形胶质细胞中的输出强烈依赖于胞质谷胱甘肽浓度，高星形胶质细胞谷胱甘肽含量也将促进谷胱甘肽的释放，从而为邻近神经元提供谷胱甘肽前体。在本文中，我们将概述目前关于星形胶质细胞谷胱甘肽代谢的知识，阐述高星形胶质细胞谷胱甘肽含量如何有助于维持大脑功能，并讨论关于星形胶质细胞在健康和患病大脑谷胱甘肽代谢中功能的研究中的开放性问题和未来展望。
