臺灣博碩士論文加值系統

ATP在腦中是重要的訊息傳遞分子，並在神經元與神經膠細胞之間扮演訊息媒介的角色。ATP主要的作用主要是透過兩大家族的受器，P2X與P2Y。在P2X家族中很有趣的是P2X7R。這個受器具有長的C端，而報導指出有11種蛋白質（其中一個蛋白質是β-actin）會和其有交互作用。最近一篇研究顯示actin可能會去調節P2X7R的功能。BzATP是P2X7受器的選擇性的激活劑，oATP多年來作為P2X7R專一性的拮抗劑，然而新的資料顯示oATP可能也具有非經由P2X7R的作用。本實驗室之前的結果顯示RBA-2第二型星狀膠細胞表現P2X7R，而活化P2X7R會刺激HSP60的表現，而且可以被抗氧化劑resveratrol及catalase抑制，而且有趣的是，oATP本身似乎也會影響HSP60的表現，本論文的主要目的是要探討是否ATP，BzATP及oATP影響HSP60的表現的機制是經由刺激過氧化物質 (Reactive oxygen species) 並影響粒線體的活性。我的實驗結果顯示，利用鈣離子影像方法發現oATP可以抑制ATP，BzATP所造成的Ca2+離子濃度上升，確認了oATP在RBA-2細胞中作為拮抗P2X7R。為了進一步探討ROS的產生，我利用流式細胞儀的實驗方法，以DCFHDA與DHE分別測量細胞內的H2O2與superoxide anion。ATP與BzATP都造成了50%的superoxide anion anion增加，但是卻不影響H2O2的產生。在實驗室中先前的結果顯示，RBA-2表現大量的Peroxiredoxin II (Prx II)，是水解H2O2的酵素，而ATP會引起Prx II的pI shift。因此我將H2O2直接外加入培養液中，利用2D-gel分析蛋白質的結果顯示H2O2也會引起Prx II的pI shift。這個結果間接證明ATP與BzATP刺激H2O2產生，卻很快被Prx II代謝成H2O。因此無法量到H2O2的增加。
因為之前的實驗觀察到oATP本身可能影響HSP60的表現，為了進一步確定這個結果，我以oATP處理RBA-2細胞，並同時分析actin，GFAP及HSP60的表現，我的結果顯示，oATP有依靠時間性地抑制actin的表現，但不影響GFAP及HSP60的表現，而利用細胞免疫染色法，以rhodamine-phalloidin染actin也發現oATP會使得actin的表現減少，而我們實驗室之前的結果顯示以ATP處理細胞0-12小時，ATP處理並不影響Prx II及actin的表現。另外長時間處理oATP以MTT方法證明並不影響細胞的存活率。而且其他的P2X antagonist，PPADS, suramine 與 brilliant blue G (BBG)並不影響actin的表現。為了要研究actin減少是否是透過細胞凋亡的機制，我就利用DNA fragmentation的實驗。結果顯示ATP能造成RBA-2細胞DNA fragmentation，但oATP處理並不會。儘管如此ATP，BzATP，oATP都會造成細胞的Mitochondria membrane potential下降，其為細胞凋亡的一個指標。縱使有報導指出actin可為ICE-like protease的受質，前處理ICE-like protease抑制劑z-vad並不能抑制oATP所造成的actin減少。為了要研究oATP是否會透過P2X7R不相關的路徑影響，我們使用不表現P2X7R的細胞株IA-1g1。發現oATP會使IA-1g1外形顯著改變而且也會使細胞內的superoxide anion下降。接下來我們以免疫沉澱法嘗試oATP對於P2X7R complex的影響。以P2X7R抗體進行免疫沉澱法得到的產物，經過SDS-PAGE以西方點墨法發現P2X7R complex可能含有P2X7R與actin，所以將來我們會針對oATP對於P2X7R 複合體的影響作更進一步的探討。總之，oATP造成的actin表現減少的原因仍然不明瞭，儘管如此，我們的結果提供了新的證據顯示，oATP可能透過與P2X7R有關和無關的機制去影響細胞的功能。除此之外，我們結果顯示活化P2X7R造成ROS產生，Prx II可能在RBA-2細胞中能夠調控H2O2訊息的flood-gate控制。

ATP is an important signaling molecule in the brain and act as a mediator between neuron and glia. The effects of ATP are mediated through two families, P2X and P2Y, of receptors. An intriguing member of P2XR family is the P2X7R. The receptor has the longest -COOH terminus, and 11 proteins （including β-actin）have been reported interacted with it. A recent finding indicated that actin may modulate the function of P2X7R. BzATP is the selective agonist and oxidized ATP (oATP) is a selective antagonist for P2X7R. However novel data showed that oATP also exhibit other effects independent to P2X7R. Our previous results indicated that RBA-2 type-2 astrocyte possess P2X7R. Activation of P2X7R stimulated HSP60 expression and oATP per se may also affect the expression HSP60. In addition, antioxidants （resveratrol and catalase）inhibited the ATP- and BzATP-stimulated HSP60 expression. In the study, we elucidated whether alteration in reaction oxygen species (ROS) production and mitochondrial activity were associated with the stimulated HSP60 expression. My results showed that oATP inhibited the ATP- and BzATP-stimulated Ca2+ influx examined by Ca2+ image analysis, confirming that oATP antagonized P2X7R in RBA-2 cells. To further elucidate the involvement of ROS, we established flow cytometry assay using DCHDA and DHE to measure the H2O2 and superoxide anion production, respectively. ATP and BzATP both stimulated a 50% increase of superoxide anion production whereas oATP decreased the levels of the intracellular superoxide anion. In addition, pretreatment of cells with oATP decreased the ATP- and BzATP-stimulated superoxide anion production to a level below the basal level. Nevertheless, ATP and BzATP did not affect the H2O2 production. Using proteomic analysis, we’ve previously identified that RBA-2 astrocyte expressed abundant peroxiredoxin II (Prx II), a thioreductase to hydrolyze H2O2 to H2O. ATP induced a pI shift of Prx II, but not its protein expression level. I report here in that addition of exogenous H2O2 also induced a pI shift of Prx II. The results indicated that ATP and BzATP might stimulate H2O2 production, but Prx II quickly hydrolyzed H2O2 to H2O. Therefore, we could not detect an increase in H2O2 in RBA-2 cells. We then treated the cells with oATP for 0-12h and elucidated the expression of actin, GFAP and HSP60. We found that oATP time-depently decreased the expression of actin. Moreover, oATP also decreased the expression of actin using rhodamine-phalloidin to stain actin and observed by immunohistochemical analysis. As a comparison, we also found that ATP treatment did not affect the expression of actin and Prx II. In addition, oATP did not affect the viability of RBA-2 cells as examined by MTT assay, and other P2 receptor antagonists PPADS, suramin and Brilliant blue G (BBG) also did not affect actin expression. To elucidate whether the oATP-decreased actin is due to apoptosis, we examined DNA fragmentation of these cells. Our results revealed that ATP treatment induced DNA fragmentation whereas oATP has no effect on DNA fragmentation. However, ATP, BzATP and oATP all decreased mitochondrial membrane potential, an early sign for apoptosis. Others have reported that actin is a substrate of ICE-like protease. Nevertheless, pretreatment of z-vad, an ICE-like protease inhibitor did not inhibit the oATP-decreased actin expression. We then examined the effect of oATP on IA-1g1, type-1 astrocytes that do not possess P2X7R. Our results showed that oATP also decreased superoxide anion of these cells, suggesting that if not all, at least in part, the effect of oATP on superoxide anion production is independent of P2X7R. To further elucidate the action of oATP, we then use immunoprecipitation to examine the interaction between actin and P2X7R. We found that P2X7R interacted with actin in RBA-2 cells. Taken together, the exact mechanism involved in oATP-decreased actin expression is remain unclear at this moment. Nevertheless, our results provide new evidence indicating that oATP affected cellular functions were both P2X7R-dependent and independent. In addition, we demonstrated that activation of P2X7R induced ROS production and Prx II may act as flood-gate control for H2O2 signaling of RBA-2 type-2 astrocytes.

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