The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms
The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms
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DOI：
10.1016/s0197-0186(00)00019-x
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发表时间：
2000-08-01
影响因子：
4.2
通讯作者：
Schousboe, A
中科院分区：
文献类型：
--
作者：
Gegelashvili, G;Dehnes, Y;Schousboe, A
高亲和力谷氨酸转运体确保谷氨酸能神经传递的终止，并将这种：氨基酸：酸的突触浓度保持在兴奋性毒性水平以下。然而，神经元谷氨酸转运体EAAC1和EAAT4位于突触间隙之外，对脑内谷氨酸摄取的贡献低于两种星形胶质转运体GLAST和GLT1。谷氨酸摄取系统的异常功能似乎与一些神经退行性疾病(如肌萎缩侧索硬化症)有关。谷氨酸转运蛋白的表达通过不同的细胞机制受到不同的调控。CLT1在培养的星形胶质细胞中的表达水平非常低，在神经元存在的情况下被强烈诱导。免疫细胞化学数据进一步证明，神经元可溶性因子，而不是神经元和胶质细胞之间的物理接触，决定了星形胶质细胞GLT1的诱导。这种作用显然是由尚未确定的生长因子(S)通过酪氨酸蛋白敏感的受体酪氨酸激酶(RTK)信号介导的，而RTK信号又支持p42/44 MAP激酶以及CREM和ATF-1转录因子的下游激活。CREB转录因子非依赖于RTK的同时激活提示可能参与了互补途径(S)。神经元可溶性因子不影响GLAST的表达，但通过星形胶质细胞运动性谷氨酸受体mGluR3和mGluR5诱导GLAST的不同调节机制。因此，长期使用I组mGluR激动剂DHPG可下调GLAST的表达，而II组激动剂DCG-IV对星形胶质细胞中GLAST的表达有相反的影响。然而，在BT4C胶质瘤细胞中，谷氨酸或其他可运输底物(D-天冬氨酸和L-2，4-反式-PDC)以非受体依赖的方式诱导细胞表面EAAT4的表达。这种转运蛋白的活性依赖性转运也表现出谷氨酸门控氯离子通道的特性，不仅在神经元兴奋性中发挥作用，而且在胶质瘤细胞生物学中也发挥功能作用。(C)2000爱思唯尔科学有限公司。保留所有权利。
High-affinity glutamate transporters ensure termination of glutamatergic neurotransmission and keep the synaptic concentration of this: amino :acid below excitotoxic levels. However, neuronal glutamate transporters, EAAC1 and EAAT4, are located outside the synaptic cleft and contribute less significantly to the glutamate uptake in the brain than two astroglial transporters, GLAST and GLT1. Aberrant functioning of the glutamate uptake system seems to be linked to some neurodegenerative disorders (eg amyotrophic lateral sclerosis, ALS). Expression of glutamate transporters is differentially regulated via distinct cellular mechanisms. CLT1, which is expressed at very low levels in cultured astrocytes, is strongly induced in the presence of neurons. The presence immunocytochemical data provide further evidence that neuronal soluble factors, rather than physical contact between neurons and glia, determine the induction of GLT1 in astrocytes. This effect is apparently mediated by yet undefined growth factors(s) via the tyrphostin-sensitive receptor tyrosine kinase (RTK) signalling, that in turn, supports the downstream activation of p42/44 MAP kinases and the CREM and ATF-1 transcription factors. RTK-independent simultaneous activation of the CREB transcription factor suggests a possible involvement of complementary pathway(s). Neuronal soluble factors do not affect expression of GLAST, but induce supporting machinery for differential regulation of GLAST via the astroglial motabotropic glutamate receptors, mGluR3 and mGluR5. Thus, long-term treatment with the group I mGluR agonist, DHPG, causes down-regulation of GLAST, whereas the group II agonist, DCG-IV, has an opposite effect on the expression of GLAST in astrocytes. However, in BT4C glioma cells glutamate or other transportable substrates (D-aspartate and L-2,4-trans-PDC) induced cell-surface expression of EAAT4 in a receptor-independent manner. The activity-dependent trafficking of this transporter which also exhibits properties of a glutamate-gated chloride channel may play functional roles not only in neuronal excitability, but in glioma cell biology as well. (C) 2000 Elsevier Science Ltd. All rights reserved.