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首页> 外文期刊>Experimental Neurology >Thrombin decreases expression of the glutamate transporter GLAST and inhibits glutamate uptake in primary cortical astrocytes via the Rho kinase pathway
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Thrombin decreases expression of the glutamate transporter GLAST and inhibits glutamate uptake in primary cortical astrocytes via the Rho kinase pathway

机译：凝血酶通过Rho激酶途径降低谷氨酸转运蛋白GLAST的表达并抑制原代皮质星形胶质细胞摄取谷氨酸。

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Astrocyte glutamate transporters GLAST and GLT1 play a key role in regulating neuronal excitation and their levels are altered in patients with epilepsy, and after traumatic brain injury. The mechanisms which regulate their expression are not well understood. We tested the hypothesis that exposure of astrocytes to high levels of thrombin, as may occur after a compromise of the blood-brain barrier, would reduce astrocyte glutamate transporter levels. In isolated rat cortical astrocytes we examined the effects of thrombin on the expression and function of glutamate transporters, and the signaling pathways involved in these responses by using Western blotting and selective inhibitors. Thrombin induced a selective decrease in the expression of GLAST but not GLT1, with a corresponding decrease in the capacity of astrocytes to take up glutamate. Activation of the thrombin receptor PAR-1 with an activating peptide induced a similar decrease in the expression of GLAST and compromise of glutamate uptake. The downregulation of GLAST induced by thrombin was mediated by the mitogen activated protein kinases p38 MAPK, ERK and JNK, but inhibition of these kinases did not prevent the decrease in glutamate uptake induced by thrombin. In contrast, inhibition of the Rho kinase pathway using the specific inhibitor, Y27632, suppressed both the decrease in the expression of GLAST and the decrease in glutamate uptake induced by thrombin. In hippocampal astrocyte cultures, thrombin caused a decrease in both GLAST and GLT1. In tissue resected from brains of children with intractable epilepsy, we found a decrease in the integrity of the blood-brain barrier along with a reduction in immunoreactivity for both transporters which was associated with an increase in cleaved thrombin and reactive astrogliosis. The in vitro results suggest a specific mechanism by which thrombin may lead to a compromise of astrocyte function and enhanced synaptic excitability after the blood-brain barrier is compromised. The human in vivo results provide indirect support evidence linking the compromise of the blood-brain barrier to thrombin-induced reduction in glutamate transporter expression and an increase in neuronal excitation. (C) 2015 Elsevier Inc All rights reserved.
机译：星形胶质细胞谷氨酸转运蛋白GLAST和GLT1在调节神经元兴奋中起关键作用，在癫痫患者以及脑外伤后它们的水平发生改变。调节其表达的机制尚不十分清楚。我们测试了这样的假设：星形胶质细胞暴露于高水平的凝血酶（如血脑屏障受损后可能发生）会降低星形胶质细胞的谷氨酸转运蛋白水平。在分离的大鼠皮质星形胶质细胞中，我们通过使用蛋白质印迹和选择性抑制剂检查了凝血酶对谷氨酸转运蛋白表达和功能的影响，以及这些反应涉及的信号传导途径。凝血酶诱导GLAST表达选择性降低，但不诱导GLT1表达降低，星形胶质细胞吸收谷氨酸的能力相应降低。用激活肽激活凝血酶受体PAR-1会引起类似的GLAST表达下降和谷氨酸吸收的降低。凝血酶诱导的GLAST的下调是由有丝分裂原激活的蛋白激酶p38 MAPK，ERK和JNK介导的，但抑制这些激酶并不能阻止凝血酶诱导的谷氨酸摄取的减少。相反，使用特异性抑制剂Y27632抑制Rho激酶途径既抑制了GLAST表达的降低，也抑制了凝血酶诱导的谷氨酸摄取的降低。在海马星形胶质细胞培养物中，凝血酶导致GLAST和GLT1均减少。在从顽固性癫痫患儿的大脑中切除的组织中，我们发现血脑屏障的完整性降低，并且两种转运蛋白的免疫反应性降低，这与裂解的凝血酶和反应性星形胶质增生有关。体外结果表明，在血脑屏障受损后，凝血酶可导致星形胶质细胞功能受损和突触兴奋性增强的特定机制。人类体内的结果提供了间接的支持证据，将血脑屏障的损害与凝血酶诱导的谷氨酸转运蛋白表达的减少和神经元兴奋的增加联系起来。 （C）2015 Elsevier Inc保留所有权利。

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