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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Role of glutamine and neuronal glutamate uptake in glutamate homeostasis and synthesis during vesicular release in cultured glutamatergic neurons.
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Role of glutamine and neuronal glutamate uptake in glutamate homeostasis and synthesis during vesicular release in cultured glutamatergic neurons.

机译：谷氨酰胺和神经元谷氨酸摄取在培养的谷氨酸能神经元水泡释放过程中谷氨酸稳态和合成中的作用。

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摘要

Glutamate exists in a vesicular as well as a cytoplasmic pool and is metabolically closely related to the tricarboxylic acid (TCA) cycle. Glutamate released during neuronal activity is most likely to a large extent accumulated by astrocytes surrounding the synapse. A compensatory flux from astrocytes to neurons of suitable precursors is obligatory as neurons are incapable of performing a net synthesis of glutamate from glucose. Glutamine appears to play a major role in this context. Employing cultured cerebellar granule cells, as a model system for glutamatergic neurons, details of the biosynthetic machinery have been investigated during depolarizing conditions inducing vesicular release. [U-13C]Glucose and [U-13C]glutamine were used as labeled precursors for monitoring metabolic pathways by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) technologies. To characterize release mechanisms and influence of glutamate transporters on maintenance of homeostasis in the glutamatergic synapse, a quantification was performed by HPLC analysis of the amounts of glutamate and aspartate released in response to depolarization by potassium (55 mM) in the absence and presence of DL-threo-beta-benzyloxyaspartate (TBOA) and in response to L-trans-pyrrolidine-2,4-dicarboxylate (t-2,4-PDC), a substrate for the glutamate transporter. Based on labeling patterns of glutamate the biosynthesis of the intracellular pool of glutamate from glutamine was found to involve the TCA cycle to a considerable extent (approximately 50%). Due to the mitochondrial localization of PAG this is unlikely only to reflect amino acid exchange via the cytosolic aspartate aminotransferase reaction. The involvement of the TCA cycle was significantly lower in the synthesis of the released vesicular pool of glutamate. However, in the presence of TBOA, inhibiting glutamate uptake, the difference between the intracellular and the vesicular pool with regard to the extent of involvement of the TCA cyclein glutamate synthesis from glutamine was eliminated. Surprisingly, the intracellular pool of glutamate was decreased after repetitive release from the vesicular pool in the presence of TBOA indicating that neuronal reuptake of released glutamate is involved in the maintenance of the neurotransmitter pool and that 0.5 mM glutamine exogenously supplied is inadequate to sustain this pool.
机译：谷氨酸存在于囊泡以及细胞质池中，并且在代谢上与三羧酸（TCA）循环密切相关。在神经元活动期间释放的谷氨酸盐很可能在突触周围的星形胶质细胞中大量积累。从星形胶质细胞到合适的前体神经元的补偿性流量是强制性的，因为神经元无法从葡萄糖进行谷氨酸的净合成。在这种情况下，谷氨酰胺似乎起主要作用。利用培养的小脑颗粒细胞作为谷氨酸能神经元的模型系统，已在去极化条件下诱导囊泡释放的过程中研究了生物合成机制的细节。 [U-13C]葡萄糖和[U-13C]谷氨酰胺被用作标记的前体，用于通过核磁共振（NMR）光谱和液相色谱-质谱（LC-MS）技术监测代谢途径。为了表征谷氨酸能突触中谷氨酸转运蛋白的释放机理和对维持体内稳态的影响，在缺少和存在DL的条件下，通过高效液相色谱法对因去极化作用而释放的谷氨酸和天冬氨酸的量进行了定量分析（55 mM） -苏-β-苄氧基天冬氨酸（TBOA），并响应于L-反式-吡咯烷-2,4-二羧酸盐（t-2,4-PDC），是谷氨酸转运蛋白的底物。基于谷氨酸的标记模式，发现谷氨酰胺的细胞内谷氨酸池的生物合成在相当程度上（约50％）涉及TCA循环。由于PAG的线粒体定位，这不太可能仅反映通过胞质天冬氨酸氨基转移酶反应进行的氨基酸交换。在释放的谷氨酸囊泡池的合成中，TCA循环的参与显着降低。然而，在存在TBOA的情况下，抑制了谷氨酸的摄取，就TCA循环参与谷氨酰胺合成谷氨酸的程度而言，消除了细胞内和囊泡池之间的差异。出乎意料的是，在存在TBOA的情况下从囊泡池中反复释放后，谷氨酸的细胞内池减少了，这表明释放的谷氨酸的神经元再摄取与神经递质池的维持有关，并且外源提供的0.5 mM谷氨酰胺不足以维持该池。 。

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