臺灣博碩士論文加值系統

P/Q-型鈣離子通道是由形成離子孔道 (pore-forming)的α1A subunit與其他α2δ、β等auxiliary subunit組成。絕大多數的P/Q-型鈣離子通道是位於神經細胞的樹突和軸突末端，因此其神經生理功能主要是神經細胞的興奮性及調控突觸神經傳導物質的作用。P/Q-型鈣離子通道之突變與多種遺傳性神經病變有關，詳細機制則尚未完全清楚。目前已知P/Q-型鈣離子通道調控蛋白質包括：SNARE proteins、G proteins、calmodulin (CaM)、RIM (Rab3-interacting molecules)及RIMBP (RIM binding protein)等，多數是經由離子通道的C-terminus產生作用。為了進一步尋找在神經細胞中其他可能和C-terminus結合的蛋白質，我們以酵母雙雜交技術篩檢在大鼠腦中與P/Q-型鈣離子通道交互作用的蛋白質。
對大鼠腦部cDNA library進行篩選後，我們共發現了156個蛋白質可能與P/Q-型鈣離子通道有交互作用。在經過進一步的序列分析和扣除胺基酸序列有frame shift的選項後，剩下67個可能P/Q-型鈣離子通道有相互作用的蛋白質。我們從中挑選10個蛋白質，以進一步的實驗以確認其與P/Q-型鈣離子通道的相互作用能力。X-gal測試分析和白胺酸需求分析實驗的結果顯示，這10個蛋白質都能在進行X-gal分析時使菌落由白變藍，並且在缺乏白胺酸的培養皿上生長。我們進一步以GST pull-down之方式驗證，發現其中的7個得到正反應。另外，在Co-IP檢驗中，目前檢驗了其中3個，而在之中的2個蛋白質有正反應。接著，我們以免疫螢光染色的實驗方法，由共軛焦顯微鏡影像觀察與P/Q-型鈣離子通道交互作用的蛋白質，在細胞中的分布情形。藉此實驗我們可得知有哪些蛋白質和P/Q-型鈣離子通道分布位置重合。
針對本篇研究所篩選到的蛋白質，我們除了以不同的生化實驗證明它們的交互作用外，我們期望藉此由後續的電生理實驗方式，證明對於P/Q-型鈣離子通道性質的影響，而能對於P/Q-型鈣離子通道之生理機制以及相關遺傳性神經退化性疾病，有更進一步的了解。

P/Q type voltage-gated Ca2+ channels are composed of pore-forming α1A subunit and auxiliary α2δ and β subunits. In neurons, P/Q type voltage-gated Ca2+ channels are primarily located at dendrite and axon terminal, the neurophysiological role of P/Q type voltage-gated Ca2+ channels may include the neuronal excitability and modulation of synaptic transmission. Mutations in P/Q type voltage-gated Ca2+ channels are associated with a variety of hereditary neuropathy, the detail mechanisms of which remain unclear. P/Q type voltage-gated Ca2+ channels were regulated by SNARE proteins, G proteins and calmodulin (CaM). In this study, we aim to apply the cytoplasma C-terminus of P/Q type voltage-gated Ca2+ channels as the bait for yeast two-hybrid screening to search for novel P/Q type voltage-gated Ca2+ channels interacting proteins.
156 prey clones were identified after screening a rat brain cDNA library. By DNA sequencing and eliminating the clones with incorrect reading frames, we have obtained 67 positive clones. 10 potential candidates from 67 positive clones were chosen for further characterization. X-gal assays and leucine requirement tests were performed to reconfirm the interaction between P/Q type voltage-gated Ca2+ channels and potential candidate proteins. All of the 10 candidate proteins showed blue patches on blue and/white tests and were able to grow on leucine-deficient plates, suggesting that these clones may indeed interact with P/Q type voltage-gated Ca2+ channels. We performed GST pull-down assay, and found the 7 of the 10 candidate proteins have positive reaction. We performed Co-IP assay, so far, we test 3 of these candidate proteins and found the 2 of the 3 candidate proteins have positive reaction. And then, we performed immunofluorescence microscopy imaging to observe subcelluar lococaliztion of these candidate proteins. We can find which candidate protein might colocolize with P/Q-type calcium channels. We expect to take electrophysiological experiments prove P/Q-type calcium channel properties, in addition to prove their interactions with different biochemical experiments. We hope to better understand about physiological mechanism of the P/Q-type calcium channels and the related hereditary neurodegenerative disease.

誌謝 1
中文摘要 3
Abstract 4
圖次 9
表次 10
緒論 (Introduction) 11
1. 鈣離子通道 11
2. 電位控制開關鈣離子通道之分類及結構 12
2.1 α1 subunit 13
2.2 β subunit 15
2.3 α2δ subunit 15
2.4 γ subunit 16
3. P/Q-型鈣離子通道 16
4. P/Q-型鈣離子通道α1A 之轉錄變異 17
5. 與P/Q-型鈣離子通道相關之疾病 18
6. 已知與P/Q-型鈣離子通道相互作用蛋白質之研究 20
7. 研究目的 23
材料與方法(Materials and Methods) 25
1. Yeast Two-Hybrid system 25
1.1 酵母雙雜交技術之原理及方法 25
1.2 誘餌載體置備（Construction of Baits） 25
1.3 將載體轉殖入酵母菌中 26
1.4 X-gal 測試及Leucine 需求分析 27
1.5 大鼠腦部cDNA library的篩選 27
1.6 萃取酵母菌中pJG4-5 plasmid 28
1.7 將pJG4-5 plasmid轉殖入細菌菌株 29
2. Molecular biology 29
2.1 Colony PCR 29
2.2 DNA電泳 29
2.3 Candidate protein製備 30
2.4 GST-Cav2.1載體置備 30
3. Protein Biochemistry 30
3.1 將plasmid DNA轉殖至HEK293T 細胞 30
3.2 GST pull-down 31
3.3 共同免疫沉降法 (Co-Immunoprecipitation, Co-IP) 32
3.4 西方墨點法 (Western blotting) 33
3.5 免疫螢光染色(Immunofluorescence microscopy) 34
結果 (Results) 36
1. 酵母菌雙雜交篩選 36
1.1 Autoactivation test 36
1.2 以西方點墨法確認P/Q-型鈣離子通道誘餌蛋白的表現 37
1.3 利用酵母菌雙雜交系統對大鼠腦部cDNA library進行篩選 38
2. 進一步驗證所篩選出之蛋白質與P/Q-型鈣離子通道之相互作用 39
2.1 酵母菌雙雜交確認篩選出的蛋白質與P/Q-型鈣離子通道相互作用關係 40
2.2 以西方點墨法確認篩選出的蛋白質在HEK 293T細胞株之表現 40
2.3 製備GST及GST-Cav2.1之binding beads 41
2.4 以GST pull-down assay檢驗和P/Q-型鈣離子通道有作用的蛋白質 41
2.5 以Co-IP檢驗和P/Q-型鈣離子通道有作用的蛋白質 42
3. 觀察具交互作用之蛋白質對Cav2.1在細胞中分佈位置的影響 42
討論 (Discussion) 44
1. 所篩選出的蛋白質在細胞中可能參與之功能 44
2. 蛋白質交互作用實驗系統的比較 49
3. 所篩選之蛋白質與P/Q-型鈣離子通道相互作用的結果探討 51
4. P/Q-型鈣離子通道C端與蛋白質的交互作用區域 53
5. 待解決之問題及未來目標 54
參考資料 (References) 60
圖表 (Figures and Tables) 77

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