中樞神經受損時，細胞外麩胺酸的累積會引發神經細胞的興奮性毒性進而造成神經組織的二次傷害。星狀膠細胞可透過其專一表現的膠細胞麩胺酸轉送蛋白(GLT-1)與鈉離子依賴麩胺酸/天門冬胺酸轉送蛋白(GLAST)移除細胞外過多的麩胺酸。本論文第一部份的研究中，我們發現利用鎘所誘導的細胞壓力會透過抑制GLAST的表現而降低星狀膠細胞的麩胺酸吸收能力。利用鈣離子螯合劑抑制鎘所導致的細胞內鈣離子濃度上升則可以回復GLAST基因轉錄的能力，並且增加星狀膠細胞麩胺酸吸收的能力，顯示鈣離子依賴的訊息傳遞路徑可抑制GLAST的基因表現。此結果可進一步利用鈣離子通透促進劑A23187處理後同樣降低GLAST的表現加以確認。此外我們將人類GLAST促進子-冷光酶蛋白基因轉殖進細胞後進行促進子活性分析，實驗結果顯示鈣離子訊號傳遞主要是透過調控GLAST轉錄機制從而抑制GLAST基因表現，而此抑制作用可能是透過增加轉錄因子AP-1以及CREB與GLAST促進子結合的能力。
當中樞神經系統受到外傷後，會導致ATP持續性的從受損的神經細胞與活化的膠細胞大量釋放於組織中，並在與離子通道接受器(P2X receptor)或代謝型接受器(P2Y receptor)結合後所引發的一連串效應進而導致細胞的死亡。由於當P2X接受器活化後會增加膠細胞的鈣離子流入，因此我們將進一步探討細胞外ATP對於星狀膠細胞上GLAST表現的影響。在脊髓損傷老鼠的模式中，我們發現在脊髓損傷24小時後會導致GLAST mRNA表現量的下降。此外，體外培養的星狀膠細胞在處理ATP或BzATP (P2X7接受器活化劑)24小時後可顯著的抑制GLAST mRNA的表現與麩胺酸吸收的能力。而該抑制作用可藉由處理P2X7接受器抑制劑oxATP或利用反轉錄病毒攜帶之shRNA將P2X7接受器基因減弱加以回復。此外我們也發現P2X7接受器引發的鈣離子流入會誘導細胞內PI3K-IP3R-CaMKII訊息傳遞路徑而導致GLAST mRNA表現量下降。而我們利用GLAST促進子分析與mRNA衰退實驗發現P2X7接受器活化所誘導的鈣離子依賴PI3K訊息傳遞路徑主要是影響GLAST基因的後轉錄調控機制。這些實驗結果顯示中樞神經系統受損所釋放的ATP會持續性的活化P2X7接受器並且引發細胞內的鈣離子訊息傳遞而導致GLAST mRNA穩定性的下降；相反的，阻礙P2X7接受器則可以回復星狀膠細胞GLAST的功能，並且防止神經細胞受到麩胺酸所引發的興奮性神經毒性。
綜合上述實驗結果，中樞神經系統不同型式的傷害所導致的鈣離子流入可引發不同的訊息傳遞路徑，此外大量增加的細胞內鈣離子可影響GLAST的轉錄(轉錄因子結合)或後轉錄(mRNA穩定性)機制而調控其基因的表現。

During the CNS injury, the accumulation of extracellular glutamate induces neuronal excitotoxicity, leading to secondary tissue damage. Astrocytes are responsible for the clearance of extracellular glutamate primarily through glial specific glutamate transporters (GLT-1) and Na+-dependent glutamate/aspartate transporters (GLAST). In first part of study, by using an in vitro model of cadmium-induced cellular stress, we found that the activity of glutamate uptake by astrocytes was inhibited through the downregulation of GLAST expression. The blockage of cadmium-induced rise of intracellular Ca2+ levels by pre-exposure to Ca2+ chelators can restore GLAST transcription and then increase astrocytes to uptake extracellular glutamate, suggesting that Ca2+-dependent signaling exerts a negative control in GLAST expression. This suggestion was supported by the findings showing the reduction of GLAST mRNA in astrocytes after treatment with Ca2+-ionophore A23187. In addition, the promoter activity assay by transfection of astrocytes with human GLAST promoter showed that a Ca2+ signaling inhibited the expression of GLAST mRNA at the transcriptional levels, which was possibly due to an increase in the binding activity of Ca2+-sensitive activator protein-1 (AP-1) and cAMP response element binding protein (CREB) to their specific elements of the GLAST promoter.
Persistent release of high ATP from damaged neurons and activated glia also occurs after the occurrence of traumatic CNS injury, which results in progressive cell death through the effect of its ionotropic P2X and metabotropic P2Y receptors. The continuous study was performed to examine the effect of ATP on GLAST expression in astrocytes, since ATP can evoke [Ca2+]i in glia through the activation of ionotropic P2X. Our in vivo findings indicated that GLAST mRNA levels were reduced at 24 h post traumatic injury to the rat spinal cord tissue. Furthermore, exposure of cultured astrocytes to ATP and its P2X7R agonist, BzATP, for 24 h caused a significant reduction in astrocytic GLAST mRNA levels and their glutamate uptake activity. This inhibition was abolished by the blockade of the P2X7R by an irreversible P2X7R blocker, oxATP, and by P2X7R gene knockdown using the approach of lentivirus-short hairpin RNA (shRNA). In addition, the reduction in the expression levels of GLAST mRNA was mediated by PI3K-IP3R-CaMKII cascades triggered by a P2X7R-mediated Ca2+ influx. Interestingly, the GLAST promoter and RNA decay assays indicated that the P2X7R-triggered signaling induced the post-transcriptional regulation of GLAST expression through a Ca2+-dependent PI3K cascade. These findings indicate that prolonged activation of P2X7R by sustained releases of ATP in the injured CNS may reduce GLAST mRNA stability via Ca2+-dependent signaling, suggesting that the blockage of P2X7R may recover astrocytic GLAST function and prevent neurons from glutamate-induced excitotoxicity.
Together, the stress-induced Ca2+ influx may trigger different signaling pathways, depending on the source of stress. In addition, the GLAST gene expression can be regulated via transcriptional and post-transcriptional mechanisms, involving the binding of transcription factors and the mRNA stability respectively, by the robust increase of intracellular Ca2+ levels.

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