谷氨酸转运体亚型谷氨酸转运体1与其调控药物的研究进展

胞外谷氨酸浓度的动态平衡是由谷氨酸转运体精确调控的,谷氨酸转运体功能或表达失调时导致胞外谷氨酸水平异常,引起一系列神经系统疾病。其中谷氨酸转运体1(GLT-1)起着"谷氨酸泵"作用,近年来还发现了仅在肽链C末端发生改变的GLT-1剪切变异体;其中GLT-1a、GLT-1b和GLT-1v发现与某些疾病具有相关性。药物调控谷氨酸转运体的表达或功能,维持胞外谷氨酸正常浓度,能有效改善病理状况。目前已有多种药物被报道对谷氨酸转运体具有激动或抑制作用,如能够上调GLT-1活性的药物有头孢曲松、苯环己哌啶、胞二磷胆碱、利鲁唑、凝血酶、蛋白激酶B等;下调GLT-1活性的药物有依托咪酯、氯氮平、天冬酰胺类衍生物、内皮素等。该文将调控谷氨酸转运体的药物做一总结,为药物开发和临床治疗提供新的思路。

Current research progress in glutamate transporter subtype GLT-1 and its regulated drugs

The homeostasis of extracellular glutamate concentration is critically regulated by glutamate transporters(GTs).Malfunction or decreased expression of GTs has been implicated in the pathogenesis of various nervous system diseases.And among the GTs,glutamate transporter 1(GLT-1)plays a critical role as "glutamate pump".Recent research also finds some GLT-1 variants which alternate C-terminal splicings.Altered expression of proteins encoded by splice variants of GLT-1 has been noted in a number of disease states.Maintaining a physiological range of extracellular glutamate through regulating GTs expression or function may improve some pathological conditions.Many drugs are reported that can regulate GTs.For example,ceftriaxone,phencyclidine,citicoline,riluzole,AKT,thrombosin can up-regulate the expression or function of glutamate transporters;etomidate,clozapine,aspartic acid analogs,endothelin can down-regulate the expression or function of glutamate transporters.In this paper,the drugs which effect GTs will be summarized in order to provide a new insight into the drug design and clinical treatment of neurological diseases.