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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭鐘金教授(Chung-Chin Kuo) | |
| dc.contributor.author | Huai-Ren Chang | en |
| dc.contributor.author | 張懷仁 | zh_TW |
| dc.date.accessioned | 2021-06-13T00:39:10Z | - |
| dc.date.available | 2012-08-08 | |
| dc.date.copyright | 2007-08-08 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-25 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29086 | - |
| dc.description.abstract | 離子通道是造成興奮性細胞電生理活動的主要基石，而瞭解藥物對於離子通道作用之分子機轉，不僅可以幫助我們更有效的利用這些藥物來改正病態電生理活動，也往往能提供有關離子通道分子生理學方面的重要訊息。在細胞病態電生理活動所導致的疾病症狀中，由腦部神經元之突發、過度且同步化的不正常放電所引發的癲癇發作是一個常見的例子。目前臨床上已有數種藥物，可以用來改正這一類神經細胞的病態電生理活動，以治療癲癇病人。在這些抗癲癇藥物中，felbamate是被認為主要作用在NMDA受體通道上，但是其詳細的分子作用機轉仍未完全明瞭。在本論文中，我們試圖瞭解felbamate如何結合到NMDA通道及與通道本身的開關機制兩者之間的交互作用。我們詳細研究了felbamate結合到NMDA通道上的動力學，分別設計多種不同實驗來測量felbamate對於休息態以及活化態通道的結合速率常數與脫離速率常數。求得felbamate對於休息態與活化態通道的結合速率常數分別為187.5 和 4.6 × 104 M-1s-1；另一方面，對於休息態與活化態通道的脫離速率常數則分別為5.4-6.2 × 10-2 和 3.1-3.5 s-1。據此可以計算出felbamate對於休息態與活化態通道的解離常數(其倒數可以代表felbamate對於NMDA通道的親和力)分別為~300和~70 | zh_TW |
| dc.description.abstract | Felbamate (FBM) is a potent nonsedative anticonvulsant whose clinical effect is chiefly ascribable to gating modification (and thus use-dependent inhibition) rather than pore block of N-methyl-D-aspartate (NMDA) channels at pH 7.4. Using whole-cell recording in rat hippocampal neurons, we examine the kinetics of FBM binding to and unbinding from the NMDA channel, as well as the effect of FBM on NMDA and glycine affinity to the channel. We show that FBM modifies NMDA channel gating via a one-to-one binding stoichiometry (one FBM per channel) and has quantitatively the same enhancement effect on NMDA and glycine binding to the NMDA channel. Moreover, the binding rates of FBM to the closed and the open/desensitized NMDA channels are 187.5 and 4.6 × 104 M-1s-1, respectively. The unbinding rates of FBM from the closed and the open/desensitized NMDA channels are 5.4-6.2 × 10-2 and 3.1-3.5 s-1, respectively. From the binding and unbinding rate constants, apparent dissociation constants of ~300 and ~70 | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T00:39:10Z (GMT). No. of bitstreams: 1 ntu-96-F90441003-1.pdf: 2305185 bytes, checksum: 4988d2d9bab340d7429dc4f16082be4d (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | Table of Contents
Abstract ………………………………………i Abstract in Chinese (中文摘要) ………iv Table of Contents ……………………… vii Chapter 1 Introduction ……………… 1 1.1 The N-methyl-D-aspartate channel……………… 1 1.2 Molecular structure of the NMDA channel ……2 1.2.1 The NMDA channel subunits ……………………2 1.2.2 Topology and structure of the NMDA channel ……2 1.3 Endogenous allosteric modulators of the NMDA channel 4 1.3.1 Extracellular proton …………………………4 1.3.2 Extracellular zinc ……………………………5 1.3.3 Extracellular polyamines …………………5 1.4 Pharmacological modulation of the NMDA channel ……6 1.4.1 The anticonvulsant felbamate ………………………6 1.4.2 The interaction between felbamate and glycine …7 1.4.3 The nonsedative anticonvulsant effect of felbamate...8 1.4.4 The interaction between felbamate and proton ………9 1.4.5 Molecular determinants of the felbamate binding site in the NMDA channel …………………………………9 1.5 The activation gate and gating mechanism of the NMDA channel …10 1.5.1 Location of the activation gate …………………10 1.5.2 Gating mechanism of the NMDA channel……………13 1.6 The scope of this study ………………………………14 Chapter 2 Materials and Methods ..………………………16 2.1 Native NMDA channels …………………………………16 2.1.1 Dissociated neuron preparation ………………16 2.1.2 Whole-cell recordings …………………………16 2.1.3 Data analysis ……………………………………18 2.2 Recombinant NMDA channels ……………………18 2.2.1 Molecular biology and expression of NMDA channels..18 2.2.2 Intracellular recordings ……………………19 2.2.3 Constitutive open index ……………………21 2.2.4 MTS modification ……………………………21 2.2.5 Data analysis and homology modeling for the pore of NMDA channels ……………………………………………22 Chapter 3 Characterization of the Gating Conformational Changes in the Felbamate Binding Site in NMDA Channels ………24 3.1 Results …………………………………………………24 3.2 Discussion ……………………………………………33 3.3 Figures ………………………………………………37 Chapter 4 Extracellular Proton-Modulated Pore-Blocking Effect of the Anticonvulsant Felbamate on NMDA Channels ………… 45 4.1 Results ………………………………………………45 4.2 Discussion ………………………………………53 4.3 Figures ………………………………………………58 Chapter 5 Molecular Determinants of the Anticonvulsant Felbamate Binding Site in the NMDA Channel …………67 5.1 Results ………………………………………………67 5.2 Discussion …………………………………………76 5.3 Figures ………………………………………………81 5.4 Tables …………………………………………………92 Chapter 6 The Activation Gate and Gating Mechanism of the NMDA Channel ….…………..………………..…………94 6.1 Results ……………………………………………94 6.2 Discussion …………………………………………102 6.3 Figures ……………………………………………107 6.4 Tables ……………………………………………116 Chapter 7 Conclusions ……………………………117 Bibliography …………………………………………120 | |
| dc.language.iso | en | |
| dc.subject | felbamate | zh_TW |
| dc.subject | NMDA通道 | zh_TW |
| dc.subject | 門閥 | zh_TW |
| dc.subject | 活化開關 | zh_TW |
| dc.subject | 抗癲癇藥物 | zh_TW |
| dc.subject | 癲癇 | zh_TW |
| dc.subject | NMDA channel | en |
| dc.subject | activation gate | en |
| dc.subject | gating | en |
| dc.subject | felbamate | en |
| dc.subject | epilepsy | en |
| dc.subject | anticonvulsant | en |
| dc.title | NMDA受體通道的門閥開關與藥理調控之分子機制 | zh_TW |
| dc.title | Molecular Basis underlying Gating Mechanism and Pharmacological Modulation of the N-Methyl-D-Aspartate Receptor Channel | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 蔡明正教授,謝如姬副研究員,黃榮棋副教授,劉天申副教授,湯志永副教授 | |
| dc.subject.keyword | NMDA通道,felbamate,門閥,活化開關,抗癲癇藥物,癲癇, | zh_TW |
| dc.subject.keyword | NMDA channel,felbamate,gating,activation gate,anticonvulsant,epilepsy, | en |
| dc.relation.page | 128 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
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|---|---|---|---|
| ntu-96-1.pdf 未授權公開取用 | 2.25 MB | Adobe PDF |
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