Reduced connexin43 expression correlates with c-Src activation, proliferation, and glucose uptake in reactive astrocytes after an excitotoxic insult
Reduced connexin43 expression correlates with c-Src activation, proliferation, and glucose uptake in reactive astrocytes after an excitotoxic insult
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DOI：
10.1002/glia.22418
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发表时间：
2012-12-01
期刊：
影响因子：
6.2
通讯作者：
Tabernero, Arantxa
中科院分区：
文献类型：
--
作者：
Gangoso, Ester;Ezan, Pascal;Tabernero, Arantxa
在不同的脑病理中，星形胶质细胞变得反应性并经历深刻的表型变化。缝隙连接蛋白43（Cx43）是星形胶质细胞中主要的缝隙连接通道形成蛋白，是反应性星形胶质细胞中修饰的蛋白之一。在培养的星形胶质细胞中下调Cx43激活c-Src，促进增殖，并增加葡萄糖摄取的速率;然而，到目前为止，还没有研究检查这种级联事件是否发生在反应性星形胶质细胞中。在这项工作中，我们分析了这一途径后，皮质病变引起的红藻氨酸注射。如前所述，星形胶质细胞对病变的反应是胶质细胞酸性蛋白的增加和Cx43表达的减少。这些反应性星形胶质细胞增殖，估计溴脱氧尿苷掺入和细胞周期蛋白D1和D3上调。此外，在反应性星形胶质细胞中诱导了葡萄糖转运蛋白GLUT-3和负责葡萄糖磷酸化的酶II型己糖激酶（Hx-2）的表达，表明葡萄糖摄取增加。先前的体外研究报道，c-Src是星形胶质细胞中Cx43与葡萄糖摄取和增殖之间的联系。在这里，我们发现，c-Src活性增加，在病变区。c-Src的激活和Cx43的下调先于Hx-2和cyclin D3表达的峰值，表明c-Src可以介导Cx43对兴奋性毒性损伤后反应性星形胶质细胞葡萄糖摄取和增殖的影响。有趣的是，我们确定了c-Src，GLUT-3和Hx-2参与星形胶质细胞损伤反应的信号传导机制。总之，这些数据有助于确定新的治疗靶点，以增强星形胶质细胞的神经保护活性。(c)2012 Wiley Periodicals，Inc.
In diverse brain pathologies, astrocytes become reactive and undergo profound phenotypic changes. Connexin43 (Cx43), the main gap junction channel-forming protein in astrocytes, is one of the proteins modified in reactive astrocytes. Downregulation of Cx43 in cultured astrocytes activates c-Src, promotes proliferation, and increases the rate of glucose uptake; however, so far there have been no studies examining whether this cascade of events takes place in reactive astrocytes. In this work, we analyzed this pathway after a cortical lesion induced by a kainic acid injection. As previously described, astrocytes reacted to the lesion with an increase in glial fibrillary acidic protein and a decrease in Cx43 expression. Some of these reactive astrocytes proliferated, as estimated by bromodeoxyuridine incorporation and cyclins D1 and D3 upregulation. In addition, the expression of the glucose transporter GLUT-3 and the enzyme responsible for glucose phosphorylation, Type II hexokinase (Hx-2), were induced in reactive astrocytes, suggesting an increased glucose uptake. Previous in vitro studies reported that c-Src is the link between Cx43 and glucose uptake and proliferation in astrocytes. Here, we found that c-Src activity increased in the lesioned area. c-Src activation and Cx43 downregulation preceded the peak of Hx-2 and cyclin D3 expression, suggesting that c-Src could mediate the effect of Cx43 on glucose uptake and proliferation in reactive astrocytes after an excitotoxic insult. Interestingly, we identify c-Src, GLUT-3, and Hx-2 in the signaling mechanisms involved in the reaction of astroglia to injury. Altogether these data contribute to identify new therapeutical targets to enhance astrocyte neuroprotective activities. (c) 2012 Wiley Periodicals, Inc.