請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56097完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王致恬(Chih-Tien Wang) | |
| dc.contributor.author | Hui-Ju Yang | en |
| dc.contributor.author | 楊蕙如 | zh_TW |
| dc.date.accessioned | 2021-06-16T05:15:22Z | - |
| dc.date.available | 2024-12-31 | |
| dc.date.copyright | 2014-09-15 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-18 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56097 | - |
| dc.description.abstract | 神經系統內衝動的傳導，主要決定於神經傳導物質的釋放與接收。神經傳遞物質主要被包覆在兩種不同的囊泡中－突觸囊泡(synaptic vesicle)和緻密核心囊泡(dense-core vesicle)，並藉由鈣離子調控的胞吐作用(Ca2+-regulated exocytosis) 調節釋放。雖然此兩種囊泡的釋放機制都是藉由鈣離子調控的胞吐作用，但只有Synapsin (Syn)這類的磷酸化蛋白會特別存在於突觸囊泡。Syn為十種同源蛋白的家族，其中Syn Ia是最廣為研究的。Syn Ia主要藉由不同蛋白激酶的磷酸化將突觸囊泡帶到靠近細胞膜的位置，因此促進突觸囊泡的胞吐作用﹔然而，目前尚未釐清此種調節突觸囊泡胞吐作用的蛋白－Syn Ia，是否也會去影響緻密核心囊泡的胞吐作用。實驗室先前的研究發現關於Syn Ia在下視丘腦下垂體系統中，可調控緻密核心囊泡中神經胜肽的釋放，特別的是，Syn Ia會藉由第62個胺基酸位置磷酸化來調控催產素和血管加壓素的釋放，但其中詳細調控機制尚未研究清楚。因此，為了進一步釐清Syn Ia如何調控緻密核心囊泡釋放的分子機制，我們利用單一囊泡安培測定法(Amperometry)直接偵測在神經內分泌細胞(neuroendocrine cell)中緻密核心囊泡的釋放，藉此可對Syn Ia如何調控緻密核心囊泡的胞吐作用有更深入的認識。
本研究結果顯示，與Syn Ia組別相比，Syn Ia-S62A(仿效無法被MAPK磷酸化的Syn Ia)可縮短融合孔(fusion pore)開啟的時間﹔除此之外，Syn Ia-S62A還增加了kc以及kd，分別為控制fusion pore關閉及擴張步驟之速率反應常數，表示Syn Ia-S62A可促進融合孔離開打開的狀態(open state)進入關閉(close state)或是擴散(dilation state)的狀態。相反地，Syn Ia-S9,566,603A(仿效無法被CaMK磷酸化的Syn Ia)除了會降低secretion rate，還增加了融合孔開啟的時間，並降低full fusion frequency。Syn Ia-S9,566,603A可同時降低kc以及kd，表示Syn Ia-S9,566,603A能夠穩定融合孔的開啟狀態。 綜合上述，可以得知Syn Ia可能藉由MAPK或是CaMK位置的磷酸化來影響緻密核心囊泡的釋放以及融合孔的動態，因此，突觸囊泡的磷酸化蛋白－Syn Ia，在緻密核心囊泡的胞吐作用動態變化上可能扮演著重要的角色。 | zh_TW |
| dc.description.abstract | In the nervous system, chemical synaptic transmission starts with neurotransmitter release. Neurotransmitters are packaged into two distinct classes of vesicles, synaptic vesicles (SVs) and dense-core vesicles (DCVs). Although the release from both vesicle classes shares a common mechanism of Ca2+-dependent exocytosis, a particular phosphoprotein, synapsin (Syn), localizes to SVs exclusively. The Syn protein family consists of ten homologous proteins, of which Syn Ia is the best studied. Upon phosphorylation by various protein kinases, Syn Ia can recruit SVs to plasma membrane, thereby increasing the dynamics of SV exocytosis. However, it remains completely unknown whether SV recruitment to plasma membrane may also facilitate trafficking or fusion of DCVs. Our preliminary results showed that Syn Ia may help neuropeptide release, such as oxytocin and vasopressin, by phosphorylation at the serine 62 site (Ser-62) in the rat hypothalamic-neurohypophysial system (HNS). To further determine the Syn Ia’s regulation of DCV exocytosis at the single-vesicle level, we directly measured neurotransmitter release from DCVs by performing single-vesicle amperometry in neuroendocrine cells. We found that Syn Ia-S62A (MAPK site-phosphodeficient mutation) shortened the opening of the initial fusion pore and increased both kc and kd compared to Syn Ia, suggesting that this phosphomutant promotes fusion pore to leave the open state and enter the close or dilation state. In contrast, Syn Ia-S9,566,603A (CaMK site-phosphodeficient mutation) decreased the secretion rate, prolongs the opening of the initial fusion pore, and decreased the frequency of full fusion compared to Syn Ia. In addition, Syn Ia-S9,566,603A decreased both kc and kd compared to Syn Ia, suggesting that this phosphomutant stabilizes an open fusion pore. Given that the Syn Ia may affect the DCV release or fusion pore dynamics by phosphorylation. Thus, this SV-phosphoprotein, Syn Ia, may play an important role in regulating the dynamics of DCV exocytosis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T05:15:22Z (GMT). No. of bitstreams: 1 ntu-103-R01b43012-1.pdf: 5478621 bytes, checksum: 50e49b6a38c4c06532145ff21fbd9199 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員審定書 i
致謝 ii 中文摘要 iv Abstract vi Abbreviations viii Chapter I Introduction 1.1 Neurotransmitter release 1 1.2 Ca2+-dependent exocytosis 1 1.3 Dense-core vesicles and synaptic vesicles 2 1.4 Synaptotagmin 3 1.5 Synapsin 3 1.5.1 Isoforms and structure of Synapsin Ia 4 1.5.2 Functions of Synapsin Ia 6 1.6 Objectives of the study 7 Chapter II Materials and Methods 2.1 Plasmid construction and subcloning 11 2.2 Cell culture 12 2.3 Transfection 12 2.4 Amperometry 13 2.5 Immunofluorescence staining 15 Chapter III Results 3.1 Syn Ia was mainly colocalized with SVs, but only little colocalized with DCVs in PC12 cells 17 3.2 Syn Ia regulated the secretion rate of DCVs by phosphorylation at multiple serine sites (Ser-9, Ser-566, and Ser-603) 18 3.3 Syn Ia did not change the post-dilation process of DCV exocytosis in PC12 cells 22 3.4 Syn Ia phosphomutants modulated the opening of the initial fusion pore 23 3.5 Syn Ia decreased he frequency of full-fusion events by phosphorylation at the Ser-9, Ser-566, and Ser-603 sites 24 3.6 Syn Ia phosphomutants regulated the fraction of kiss-and-run events 27 3.7 Syn Ia phosphomutants modulated fusion pore dynamics 28 Chapter IV Discussion 4.1 The localization of Syn Ia and the regulation of DCV exocytosis 32 4.2 Syn Ia differentially regulates DCV exocytosis by different kinases- CaMK and MAPK 34 4.3 Different kinase activities may lead to the diverse effects of Syn Ia phosphorylation in the rat HNS and PC12 cells 37 4.4 Significance 38 Chapter V Conclusion 40 References 41 List of Figures Figure 1. Neurotransmitters are packaged into vesicles and released at the synapse 51 Figure 2. The process of Ca2+-regulated exocytosis 52 Figure 3. Full fusion v.s. kiss and run in Ca2+-regulated exocytosis 53 Figure 4. The Ca2+ binding sites in Synaptotagmin 54 Figure 5. The domain structure of Synapsin Ia and distinct phosphorylation sites 55 Figure 6. The action of synapsin in SV exocytosis 56 Figure 7. The hypothesis for the role of Syn Ia in regulating DCV exocytosis 57 Figure 8. Subcellular localization of Syn I and ChB/Syp in transfected PC12 cells 58 Figure 9. The colocalization ratio of Syn I versus ChB or Syn I versus Syp in transfected PC12 cells 60 Figure 10. Secretion rate in PC12 cells that overexpress Syn Ia and its phosphomutants 62 Figure 11. Spike characteristics in PC12 cells that overexpress Syn Ia and its phosphomutants 64 Figure 12. Prespike foot (PSF) characteristics in PC12 cells that overexpress Syn Ia and its phosphomutants 66 Figure 13. Two modes of exocytosis - “kiss and run” v.s. “full fusion” in PC12 cells that overexpress Syn Ia and its phosphomutants 68 Figure 14. KR events v.s. full-fusion events in cells overexpressing Syn Ia and its phosphomutants 70 Figure 15. Fraction of KR events and spike frequency in cells overexpressing Syn Ia and its phosphomutants 72 Figure 16. Kinetics of the fusion pores in cells overexpressing Syn Ia and its phosphomutants 71 Figure 17. The kinetic models in Syn Ia phosphorylation 76 List of Tables Table 1. Primers for construction of pCMV-IRES2-Syn Ia-S9,566,603A 78 Table 2. Characteristics of spikes in cells overexpressing Syn Ia and its phosphomutants 79 Table 3. The list of primary and secondary antibodies 80 Table 4. Comparison of the effects caused by Syn Ia and its phosphomutants 81 Appendix Appendix 1. The CSP localization in cells overexpressing CSP and its phosphomutants II Appendix 2. The 9th International Symposium on the Kanagawa University-National Taiwan University Exchange Program 2014: Abstract and Poster (Japan, Mar 2014) III Appendix 3. The 2014 Poster Competition in the Institute of Molecular and Cellular Biology at National Taiwan University, Taipei, Taiwan (5/30 2014): Abstract and Poster V Appendix 4. Subcellular localization of CSP and ChB after KCl treatment in transfected PC12 cells VII Appendix 5. Subcellular localization of CSP and ChB without KCl treatment in transfected PC12 cells IX Appendix 6. Subcellular localization of CSP and Syt I after KCl treatment in transfected PC12 cells XI Appendix 7. Subcellular localization of CSP and Syt I without KCl treatment in transfected PC12 cells XIII Appendix 8. Subcellular localization of CSP and Syx after KCl treatment in transfected PC12 cells XV Appendix 9. The constructs of pCMV-IRES2-mCherry- Syn Ia and pCMV-IRES2-mCherry -Syn Ia-S62A) XVII | |
| dc.language.iso | en | |
| dc.subject | synapsin Ia 磷酸化 | zh_TW |
| dc.subject | 緻密核心囊泡 | zh_TW |
| dc.subject | 突觸囊泡 | zh_TW |
| dc.subject | 鈣離子調控的胞吐作用 | zh_TW |
| dc.subject | secretion rate | zh_TW |
| dc.subject | 融合孔的動態 | zh_TW |
| dc.subject | 單一囊泡安培測定法 | zh_TW |
| dc.subject | fusion pore dynamics | en |
| dc.subject | Ca2+-regulated exocytosis | en |
| dc.subject | synaptic vesicle | en |
| dc.subject | single-vesicle amperometry | en |
| dc.subject | dense-core vesicle | en |
| dc.subject | synapsin Ia phosphorylation | en |
| dc.subject | secretion rate | en |
| dc.title | 突觸囊泡蛋白Synapsin Ia調控緻密核心囊泡胞吐作用動態的分子機制 | zh_TW |
| dc.title | Synapsin Ia, a Synaptic Vesicle Protein, Regulates the Dynamics of Dense-Core Vesicle Exocytosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 盧主欽(Juu-Chin Lu),徐立中(Li-Chung Hsu),周申如(Shen-Ju Chou),陳示國(ShihKuo Chen) | |
| dc.subject.keyword | synapsin Ia 磷酸化,緻密核心囊泡,突觸囊泡,鈣離子調控的胞吐作用,secretion rate,融合孔的動態,單一囊泡安培測定法, | zh_TW |
| dc.subject.keyword | synapsin Ia phosphorylation,dense-core vesicle,synaptic vesicle,Ca2+-regulated exocytosis,secretion rate,fusion pore dynamics,single-vesicle amperometry, | en |
| dc.relation.page | 99 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-18 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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