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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 >High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamineeutral amino acid transporter ASCT2 in human fetal astrocytes.
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High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamineeutral amino acid transporter ASCT2 in human fetal astrocytes.

机译：高亲和力谷氨酸转运蛋白GLAST / EAAT1调节人胎儿星形胶质细胞中谷氨酰胺/中性氨基酸转运蛋白ASCT2的细胞表面表达。

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摘要

Neutral amino acid transporter ASCT2, together with high-affinity glutamate transporters, belongs to the SLC1 gene family of Na(+)-dependent solute carriers and is one of the major transporters of glutamine in cultured astrocytes. Besides glutamine and other high-affinity substrates--alanine, serine, cysteine or threonine, ASCT2 can also translocate protonated glutamate. The present study elucidated substrate-dependent trafficking of ASCT2 in differentiated primary cultures of human fetal astrocytes. The differentiation induced by 8-bromo-cAMP caused dramatic up-regulation of two co-localized and functionally linked astroglial proteins--glutamate transporter GLAST, that is the only high-affinity router of glutamate into cultured astrocytes, and glutamine synthetase (GS), a cytosolic enzyme that converts at least a part of the arriving glutamate into glutamine. In order to distinguish individual intracellular effects of these two substrates on ASCT2, in some cultures glutamine synthetase was effectively knocked down using siRNA silencing technique. In control conditions, regardless of GS levels, almost the entire ASCT2 immunoreactivity was restricted to the cytosol. Both glutamine and alanine, though to different extents, induced partial redistribution of ASCT2 from the cytosolic compartment to the plasma membrane. However, in cultures with high GS expression, micromolar concentrations of glutamate exhibited more pronounced effect on ASCT2 trafficking than the preferred substrates of this carrier. In contrast, glutamate had no effect on ASCT2 distribution in cultures devoid of GS. D-Aspartate, a metabolically inert substrate effectively transported by GLAST, had no effect in any cell culture utilized. It seems that intracellular glutamine produced by GS from glutamate that, in turn, is supplied by GLAST, is a more potent inducer of ASCT2 trafficking to the cell surface than the ASCT2-mediated translocation of extracellular substrates. At lower pH values (6.2-6.7), the cell surface pool of ASCT2 was significantly larger than at physiological pH. In addition, high concentrations of glutamate, independently from GLAST or glutamate receptor activation, induced further arrival of ASCT2 to the plasma membrane. The pH-dependent functional activation of ASCT2 and the ASCT2-mediated glutamate uptake may play important roles during ischemic acidosis or synaptic activity-induced local acidification.
机译：中性氨基酸转运蛋白ASCT2，与高亲和力谷氨酸转运蛋白一起，属于Na（+）依赖性溶质载体的SLC1基因家族，是培养的星形胶质细胞中谷氨酰胺的主要转运蛋白之一。除了谷氨酰胺和其他高亲和力底物-丙氨酸，丝氨酸，半胱氨酸或苏氨酸外，ASCT2还可转运质子化的谷氨酸。本研究阐明了在人类胎儿星形胶质细胞分化的原代培养物中ASCT2的底物依赖性运输。 8-溴-cAMP诱导的分化导致两种共定位且功能相关的星形胶质蛋白-谷氨酸转运蛋白GLAST（谷氨酸向培养的星形胶质细胞中的唯一高亲和力的途径）和谷氨酰胺合成酶（GS）的显着上调，一种将至少一部分到达的谷氨酸转化为谷氨酰胺的胞质酶。为了区分这两种底物对ASCT2的个别细胞内作用，在某些培养物中，使用siRNA沉默技术可有效地敲除谷氨酰胺合成酶。在对照条件下，无论GS水平如何，几乎整个ASCT2免疫反应性都限于细胞质。谷氨酰胺和丙氨酸，尽管程度不同，都诱导了ASCT2从胞浆区到质膜的部分重新分布。然而，在具有高GS表达的培养物中，微摩尔浓度的谷氨酸盐对ASCT2运输表现出比该载体的优选底物更明显的作用。相反，在没有GS的培养物中，谷氨酸对ASCT2的分布没有影响。 D-天冬氨酸（一种由GLAST有效转运的代谢惰性底物）在任何使用的细胞培养中均无作用。似乎由GS由谷氨酸生成的细胞内谷氨酰胺反过来由GLAST提供，它比ASCT2介导的细胞外底物转运更有效地诱导ASCT2转运到细胞表面。在较低的pH值（6.2-6.7）下，ASCT2的细胞表面池明显大于生理pH值。另外，独立于GLAST或谷氨酸受体活化的高浓度谷氨酸盐诱导了ASCT2进一步到达质膜。在缺血性酸中毒或突触活动诱导的局部酸化过程中，ASCT2的pH依赖性功能激活和ASCT2介导的谷氨酸摄取可能起重要作用。

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