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系統識別號 U0026-2208202014493000
論文名稱(中文) 探索血清素2C受體在胰島素分泌中的作用
論文名稱(英文) Exploring the Role of Serotonin 2C Receptor in Insulin Secretion
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 108
學期 2
出版年 109
研究生(中文) 謝可筠
研究生(英文) Ke-Yun Xie
學號 S26074138
學位類別 碩士
語文別 英文
論文頁數 84頁
口試委員 指導教授-陳韻雯
口試委員-蔡曜聲
口試委員-邱文泰
口試委員-譚賢明
中文關鍵字 第二型糖尿病  血清素2C受體  RNA編輯  鈣穩態 
英文關鍵字 Type II diabetes mellitus  5-hydroxytryptamine2C receptor  RNA editing  calcium homeostasis 
學科別分類
中文摘要 第二型糖尿病(T2DM)常常伴有過量的游離脂肪酸(FFAs),游離脂肪酸已被認為是胰島素分泌的潛在介質。血清素2C受體(5-HT2CR)是唯一已知由作用於RNA的腺苷脫氨酶( ADAR )以產生具有不同生物學活性的多種亞型的方法。在本篇研究,我們主要研究在5-HT2CR RNA編輯所涉及的胰島素分泌調節機制。我們的結果表示,棕櫚酸(PA)處理可顯著誘導在分泌胰島素的MIN6 β細胞中5-HT2CR以及ADAR2的表現量。PA誘導的ADAR2表現量是透過活化ERK / CREB信號傳導路徑所調控。我們使用慢病毒感染進入分泌胰島素的MIN6 β細胞以產生三個具有GFP表達的5-HT2CR RNA編輯的亞型,未編輯的INI(5-HT2C-INI),部分編輯的VSV(5-HT2C-VSV)和完全編輯的VGV(5-HT2C-VGV)。我們發現在分泌胰島素的MIN6β細胞中過表達的5-HT2CR亞型具有不同的增殖速率,並且與naïve細胞之間的細胞存活率沒有顯著差異。我們的結果表示,高葡萄糖會增加5-HT2CR編輯的β細胞的胰島素分泌,但是,與GFP表達的細胞相比,暴露於PA會降低5-HT2CR亞型之間的葡萄糖刺激的胰島素分泌(GSIS),原因是改變內質網(ER)鈣釋放和儲存操作性鈣進入(SOCE)激活,可能是透過抑制5-HT2CR編輯的β細胞中的基質相互作用分子1(STIM1)轉運來抑制SOCE的活性。我們的結果表示,暴露於PA導致GSIS受損與5-HT2CR編輯介導的亞型改變鈣穩態有關。
英文摘要 Type II diabetes mellitus (T2DM) is accompanied by excessive free fatty acids (FFAs), which has been recognized as a potential mediator of insulin secretion. The 5-hydroxytryptamine 2C receptor (5-HT2CR) is the only known to be edited by adenosine deaminases acting on RNA (ADAR) enzyme to generate multiple isoforms possessing different biological activities. Here, we aim to investigate the mechanisms underlie edited 5-HT2CR RNA editing involves in regulation of insulin secretion. Our results showed that palmitic acid (PA) treatment significantly induced the expression of 5-HT2CR and ADAR2 in insulin-secreting MIN6 β cells. PA-induced ADAR2 expression was through activation of the ERK/CREB signaling pathway. We generated three 5-HT2CR edited isoforms with GFP expression, the unedited INI (5-HT2C-INI), the partially edited VSV (5-HT2C-VSV), and the fully edited VGV (5-HT2C-VGV) by lentivirus infection into the insulin-secreting MIN6 β cells. We found that overexpressed 5-HT2CR isoforms in insulin-secreting MIN6 β cells had different proliferation rates and there was no significant different in cell viability between naïve cells. Our results showed that high glucose increased insulin secretion in 5-HT2CR edited β cells, however, exposure to PA decreased glucose-stimulated insulin secretion (GSIS) between edited 5-HT2CR isoforms compared with GFP expressed cells through alteration of endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through inhibition of stromal interaction molecule 1 (STIM1) trafficking in 5-HT2CR edited β cells to suppress the activity of SOCE. Our results indicated that exposure to PA resulted in impaired GSIS was correlated with 5-HT2CR RNA editing-mediated isoforms altered calcium homeostasis.
論文目次 中文摘要 Abstract in Chinese ……………………………………………………………I
英文摘要 Abstract in English …………………………………………………………..III
表格索引 List of Tables ………………………………………………………………..IX
圖表索引 List of Figures ………………………………………………………………..XI
縮寫檢索表 Abbreviations ……………………………………………………………XIV
Introduction ……………………………………………………………………………….1
1. Diabetes mellitus (DM) ……………………………………………………………….2
1.1 Epidemiology
1.2 Definition and Category
1.3 Pathophysiology
1.4 Diagnose
2. Free fatty acids (FFAs) ………………………………………………………………5
2.1 Category
2.2 FFAs metabolism
2.3 FFAs links between obesity and the development of type 2 diabetes
3. Serotonin (5-HT) ……………………………………………………………………9
3.1 Origin and distribution in the body
3.2 Serotonin synthesis and signaling
3.3 Roles of peripheral serotonin in metabolic homeostasis
3.4 Regulation of pancreatic β cell function
4. Serotonin 2C receptor (5-HT2CR) ……………………………………………………12
4.1 Gene structure and signaling
4.2 Pre-mRNA editing
4.3 Alternative splicing
4.4 Effects of 5-HT2CR RNA editing on its function
5. Adenosine to inosine (A-to-I) RNA editing …………………………………………16
5.1 ADARs family
5.2 Regulation of ADAR2 expression and its underlying mechanism
6. Calcium ……………………………………………………………………………...19
6.1 Calcium signaling in pancreatic β cells
6.2 Endoplasmic reticulum (ER) calcium regulation
6.3 Store-operated calcium entry (SOCE)
7. Specific aim of this study ……………………………………………………………22
Materials and methods …………………………………………………………………..23
1. Materials
2. Recipes
3. Methods ……………………………………………………………………………...30
3.1 Cell culture
3.2 Free fatty acids preparation
3.3 Western blots
3.4 Lentivirus infection and flow sorting
3.5 Glucose-stimulated insulin secretion assay
3.6 Single cell calcium measurement
3.7 Trypan blue assay
3.8 Immunofluorescence, confocal microscopy, and image analysis
3.9 TaqMan○R MGB assay
Results …………………………………………………………………………………….34
1. Palmitic acid (PA) treatment significantly induced the 5-HT2CR protein expression in MIN6 β cells.
2. Palmitic acid (PA) treatment significantly induced the ADAR2 protein expression in MIN6 β cells, but not ADAR1 protein.
3. Palmitic acid (PA) treatment significantly induced the ADAR2 protein expression through ERK/CREB signaling pathway in MIN6 β cells, but not c-Jun/JNK signaling pathway.
4. Overexpressed 5-HT2CR isoforms had different proliferation rates and there was no significant different in cell viability compared with naïve cells.
5. Effect of PA on 5-HT2CR RNA isoform profiles of MIN6 β cells.
6. Effect of 5-HT2CR edited isoforms on insulin secretion in MIN6 β cells.
7. PA treatment decreased glucose-stimulated insulin secretion (GSIS) between edited 5-HT2CR isoforms compared with GFP expressed cells.
8. 5-HT2CR edited isoforms displayed increase endoplasmic reticulum (ER) calcium release and decrease store-operated calcium entry (SOCE) activation.
9. 5-HT2CR edited isoforms displayed alteration of ER calcium release and SOCE activation under PA treatment.
10. 5-HT2CR edited isoforms did not affect ER calcium storage under PA treatment.
11. PA treatment inhibited STIM1 trafficking in 5-HT2CR edited β cells to suppress the activity of SOCE, rather than affecting STIM1 protein expression.
Conclusion and discussion ………………………………………………………………41
Tables ……………………………………………………………………………………..46
Figures ……………………………………………………………………………………49
Supplementary figures …………………………………………………………………..73
References ………………………………………………………………………………..76

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