星狀膠細胞是中樞神經系統數量最多的膠細胞，於生理及病理皆扮演維持神經細胞功能的角色。在健康的中樞神經系統中，高濃度的麩胺酸(glutamate)被短暫釋放到細胞外，刺激突觸間訊息傳遞，並立即透過星狀膠細胞膜上特定表現的麩胺酸轉運蛋白-1(GLT-1)回收(uptake)，以維持突觸間麩胺酸濃度的恆定。然而，當神經細胞接受刺激或受到損傷後會釋放大量的麩胺酸而造成興奮性神經毒性。換言之，當星狀膠細胞膜上的麩胺酸轉運蛋白表現功能缺失時，會導致胞外麩胺酸分子的累積，進而增加興奮性神經毒性及神經退化的擴大。因此，基於有效清除中樞神經系統突觸間堆積的麩胺酸分子，了解星狀膠細胞GLT-1表現的調節機制是一項重要的課題。實驗室前期研究顯示，5 M氯化鎘(CdCl2)可誘導星狀膠細胞GLT-1 mRNA表現量上升，然而，作用機制未被深入探討。本研究首先確定，5 M氯化鎘作用二十四小時後，可提升GLT-1 mRNA與蛋白質。進一步，前處理胞外鈣離子螯合劑EGTA與胞內鈣離子螯合劑BAPTA-AM，可抑制氯化鎘誘導之GLT-1 mRNA表現，顯示鈣離子應參與GLT-1 mRNA的表現。相同地，給予ATP、P2X7受體致效劑BzATP、P2Y6受體致效劑UDP與鈣離子載體A23187刺激胞內鈣離子上升，也都可觀察到GLT-1 mRNA顯著增加，推測星狀膠細胞GLT-1 mRNA表現，應透過鈣離子依賴路徑所調控。此外，我們以免疫螢光染色觀察磷酸化之CaMKⅡ(鈣/調鈣蛋白依賴性蛋白激酶Ⅱ)，發現鎘離子與BzATP可刺激CaMKⅡ活化。進一步，利用CaMKⅡ抑制劑KN93探討CaMKⅡ是否參與GLT-1 mRNA表現調控。實驗結果顯示，KN93有效地抑制氯化鎘誘導之星狀膠細胞GLT-1 mRNA表現上升。另外，我們也想了解胞內鈣離子釋放與JNK訊息傳遞路徑對於GLT-1 mRNA表現的影響，於是分別處理IP3受體阻斷劑2-APB與JNK抑制劑SP600125。我們發現氯化鎘引起的GLT-1表現增加，會受到2-APB與SP600125的抑制。於是我們推測，細胞中鈣離子濃度(由胞外流入或胞內釋放) 提升，可活化CaMKⅡ，並正向調控GLT-1的轉錄表現，而JNK訊息路徑可能也參與其調控。除此之外，我們利用GLT-1 慢病毒(lentivirus)載體感染法觀察其結果發現，在處理BzATP二十四小時後，GLT-1蛋白增加在星狀膠細胞觸角的分佈。綜合以上結果，我們推測CaMKⅡ與JNK訊息傳遞路徑，應參與鈣離子誘導之GLT-1轉錄調控，且於突觸間隙中維持麩胺酸濃度的恆定，扮演重要角色。

Astrocytes, the most abundant glial cell population in the CNS, have physiological and pathological roles in the support of the neuronal function. Glutamate transporter-1 (GLT-1) responsible for the clearance of extracellular glutamate in the adult forebrain is predominantly expressed in astrocytes in order to maintain homeostasis of extracellular glutamate at synapse. However, the mechanism underlying the regulation of GLT-1 expression in astrocytes is not clear. Herein, we demonstrate that exposure to 5 M of cadmium for 24 h increased the expression of GLT-1 mRNA expression. Furthermore, pretreatment with intracellular calcium chelator BAPTA-AM or extracellular calcium chelator EGTA blocked the induction of glial GLT-1 expression, pointing to the role of calcium in glial GLT-1 expression. ATP, P2X7 receptor agonist BzATP, P2Y6 receptor agonist UDP and calcium carrier A23187 were able to upregulate the expression of glial GLT-1, suggesting that GLT-1 mRNA expression in astrocyte was calcium-dependent. We also observed that treatment with Cd2+ or BzATP can induce CaMK-II activation using immunofluorescence for the phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMk-II). Furthermore, KN-93, the inhibitor for CaMK-II were used to examine whether CaMK-II are involved in the upregulation of GLT-1 mRNA expression. The results showed that KN-93 effectively blocked Cd2+-mediated induction of astrocytic GLT-1 mRNA expression. We also examined the role of calcium released from internal stores and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) in the regulation of GLT-1 mRNA expression in astrocytes by using the blocker of IP3 receptor (2-APB) and JNK inhibitor (SP600125), respectively. Our findings indicated that astrocytic GLT-1 upregulation by Cd2+ was blockaded by 2-APB and SP600125. Accordingly, CaMK-II actiavated by an increase in intracellular calcium levels by influx or internal release involves the upregulation of GLT-1 expression at the transcriptional levels. The JNK signaling pathway also plays the regulatory role in astrocytic GLT-1 mRNA expression. Molecular approach using lentiviral vector encoding GLT-1 cDNA showed that GLT-1 protein distribution over astrocytic processes was observed after exposure of astrocytes to BzATP for 24 h. Taken togther, calcium/CaMK-II and JNK signaling positively regulate astrocytic GLT-1 transcription, and possibly play the role in maintenance of glutamate homeostasis at the synaptic site in the CNS.

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