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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭鐘金(Chung-Chin Kuo) | |
| dc.contributor.author | Jian-Lin Chen | en |
| dc.contributor.author | 陳建霖 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:47:23Z | - |
| dc.date.available | 2026-02-07 | |
| dc.date.copyright | 2021-02-25 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-02-09 | |
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Am J Physiol Cell Physiol 284, C1247-1254. 林芸竹。「Rufinamide抑制鈉離子通道之分子機制」。碩士論文，國立臺灣大學醫學院生理學研究所，2019。 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78240 | - |
| dc.description.abstract | 電壓閘控型鈉離子通道Nav1.7的突變已被發現與遺傳性的疼痛疾病有所關聯，如肢端紅痛症(inherited erythromelalgia, IEM)以及陣發性劇痛症(paroxysmal extreme pain disorder, PEPD)，近年來，一些研究也顯示，這些突變會使Nav1.7的回返性電流(resurgent current, INaR)增強，進而影響神經興奮性。此外，一些抗癲癇藥物也被發現能與電壓依賴型鈉離子通道的幾種不活化態結合，抑制其興奮能力。然而，文獻顯示一些傳統的抗癲癇藥物例如phenytoin，對於 IEM 等疾病並無明顯效果，同時，對於抗癲癇藥物是否能作用於Nav1.7而影響 INaR，也仍然不清楚。本篇論文中，我們使用轉染了Nav1.7的中國倉鼠卵巢細胞(Chinese hamster ovary cell, CHO cell)進行實驗，發現rufinamide此種被認為會結合在電位閘控型鈉離子通道中速不活化態的抗癲癇藥物，對於INaR有約15%的抑制效果，並可以針對反覆性活化的通道加強抑制約30%的INaR，同時也會使INaR的活化曲線右移約13.9mV。藉由分析INaR的各項動力學數據以及模擬軟體的輔助，我們提出包含各種不活化態的Nav1.7模式，用以解釋INaR的產生機制以及rufinamide的作用機制，我們發現通道在快速以及慢速不活化態之間可能存在數種中速不活化態，這些中速不活化態很可能是產生INaR的主要結構，同時也可能是rufinamide傾向結合的狀態。這些結果可能提供了抑制INaR的有效方案，也可能作為緩解IEM以及PEPD症狀之潛在希望。 | zh_TW |
| dc.description.abstract | Mutations in voltage-gated sodium channel (VGSC) Nav1.7 are shown to be linked to inherited pain syndromes such as Inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Recent studies indicate that resurgent currents (INaR) could be enhanced in those mutant channels. Antiepileptic drugs (AEDs) are shown to inhibit the excitability of the channels by binding to the inactivated states of the VGSC. However, classic AEDs such as phenytoin have shown no definite effect on pain relief for IEM patients. Also, the effects of AEDs on INaR remain unclear. Using Chinese hamster ovary (CHO) cell transfected with Nav1.7, we found that rufinamide, a new AED showing specific affinity to the intermediate inactivated state of VGSC, significantly inhibits ~15% of INaR, and inhibit ~30% of the INaR generated from the repetitive firing channels. Rufinamide also causes ~13.9mV of the hyperpolarized shift in the activation curve of INaR. By analyzing the kinetic properties of INaR and the data from the simulation program, we propose a new Nav1.7 scheme composed of different types of inactivated states, to describe the mechanism of the generation of INaR more completely and to understand the states which rufinamide effect on. We suggest that some intermediated inactivated states(Iim) may be located between the slow inactivated state(Islow) and the fast inactivated state(Ifast). Nav1.7 most likely generates INaR from some of those Iim, which may also be the primary targets for the binding of rufinamide. The results may implicate an effective way to inhibit resurgent Nav1.7 currents, and thus a potential symptomatic relief of IEM and PEPD. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:47:23Z (GMT). No. of bitstreams: 1 U0001-0402202120161500.pdf: 2365742 bytes, checksum: f417b4de58f3bba965bd7c047cdc9bb5 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書……………………………………………………………… i 誌謝……………………………………………………………………………… ii 中文摘要………………………………………………………………………… iii 英文摘要………………………………………………………………………… iv 目錄……………………………………………………………………………… a 圖目錄…………………………………………………………………………… c 第一章 導論……………………………………………………………………… 1 1.1 電位閘控型鈉離子通道的結構與功能。……………………………… 1 1.2 電位閘控型鈉離子通道的不活化態。………………………………… 2 1.3 鈉離子通道的回返性電流。…………………………………………… 4 1.4 Nav1.7的不活化態、回返性電流與相關疾病的關係。……………… 5 1.5 電位閘控型鈉離子通道與幾種抗癲癇藥物的關係。………………… 7 第二章 方法與材料……………………………………………………………… 9 2.1 人類Nav1.7通道(SCN9A 基因)重組DNA的製備。………………… 9 2.2 中國倉鼠卵巢K1細胞的培養與轉染。……………………………… 9 2.3 玻璃毛細管電極以及沖藥管製備。…………………………………… 9 2.4 全細胞膜片鉗電生理紀錄。…………………………………………… 10 2.5 回返性電流以及河豚毒素敏感性鈉電流的測量。…………………… 10 2.6 Nav1.7回返性電流電腦模擬軟體以及資料分析。…………………… 11 第三章 結果……………………………………………………………………… 12 3.1 Nav1.7回返性電流與尾電流的差異。………………………………… 12 3.2 Nav1.7的回返性電流受到去極化強度和長度的影響。……………… 12 3.3 Nav1.7的回返性電流，電流衰退速率會受到去極化長度影響。…… 14 3.4 Rufinamide可以抑制回返性電流，而phenytoin及lacosamide則較無作用。…………………………………………………………………………… 15 3.5 Rufinamide能結合在Nav1.7的中速不活化態，影響回返性電流產生。…………………………………………………………………………… 15 3.6 連續高強度的去極化刺激，會對回返性電流有選擇性影響，並且rufinamide會加強抑制此狀態下的回返性電流。………………………… 16 3.7 Rufinamide能使回返性電流的活化曲線右移。……………………… 18 第四章 討論……………………………………………………………………… 20 4.1 回返性電流與中速不活化態的關係，以及rufinamide所扮演的角色。…………………………………………………………………………… 20 4.2 以全新的Scheme解釋Nav1.7回返性電流與各種不活化態的關係。 21 4.3 Rufinamide針對回返性電流的作用優勢。…………………………… 23 圖目錄 圖一、不同去極化電位持續0.5ms以及4ms的時間下，Nav1.7之回返性鈉電流與尾電流大小關係。……………………………………………………………… 25 圖二、短暫性電流及回返性電流的恢復速率，以及去極化時間對Nav1.7之回返性鈉電流的關係。………………………………………………………………… 27 圖三、持續4ms的去極化時間下，不同去極化電位與Nav1.7之回返性鈉電流的大小關係。………………………………………………………………………… 29 圖四、去極化時間對Nav1.7之回返性鈉電流衰退速率的關係。…………… 31 圖五、Rufinamide、lacosamide以及phenytoin對回返性電流的影響。……… 33 圖六、Rufinamide在中速不活化態之下，對短暫性電流及回返性電流的影響。………………………………………………………………………………… 35 圖七、Rufinamide對短暫性電流及回返性電流在中速不活化態的恢復速率影響。………………………………………………………………………………… 37 圖八、連續高強度去極化電位中，在相對不足的過極化休息間隔下，回返性電位的衰退情形以及rufinamide對衰退狀況的影響。…………………………… 39 圖九、Rufinamide比起phenytoin，在連續高強度去極化電位中，對回返性電流有更明顯的抑制效果。…………………………………………………………… 42 圖十、Rufinamide對回返性電流的活化曲線(activation curve)的影響。……… 44 圖十一、以特殊的Nav1.7的開關狀態模式，模擬繪製回返性電流的活化曲線，並推測rufinamide的作用機制。………………………………………………… 46 圖十二、以全新Nav1.7的開關狀態模式，說明回返性電流與各種不活化態的關係，並以此為基礎模擬回返性電流的各項特性。…………………………… 48 圖十三、Nav1.7模擬軟體的開關狀態模式圖以及各項參數。……………… 50 參考文獻…………………………………………………………………………… 52 | |
| dc.language.iso | zh-TW | |
| dc.subject | Nav1.7 | zh_TW |
| dc.subject | 電壓閘控型鈉離子通道 | zh_TW |
| dc.subject | 神經藥理 | zh_TW |
| dc.subject | 肢端紅痛症 | zh_TW |
| dc.subject | 回返性電流 | zh_TW |
| dc.subject | 陣發性劇痛症 | zh_TW |
| dc.subject | 中速不活化態 | zh_TW |
| dc.subject | rufinamide | zh_TW |
| dc.subject | intermediate inactivated state | en |
| dc.subject | Nav1.7 | en |
| dc.subject | Paroxysmal extreme pain disorder | en |
| dc.subject | inherited erythromelalgia | en |
| dc.subject | resurgent current | en |
| dc.subject | antiepileptic drug | en |
| dc.subject | voltage-gated sodium channel | en |
| dc.subject | neuropharmacology | en |
| dc.title | 抗癲癇藥物對於Nav1.7通道回返性鈉電流之作用 | zh_TW |
| dc.title | Effects of Antiepileptic Drugs on Resurgent Nav1.7 Sodium Currents | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 109-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.author-orcid | 0000-0003-3966-0658 | |
| dc.contributor.oralexamcommittee | 楊雅晴(Ya-Chin Yang),蔡明正(ming-cheng Tsai) | |
| dc.subject.keyword | 電壓閘控型鈉離子通道,Nav1.7,肢端紅痛症,陣發性劇痛症,回返性電流,rufinamide,中速不活化態,神經藥理, | zh_TW |
| dc.subject.keyword | voltage-gated sodium channel,Nav1.7,Paroxysmal extreme pain disorder,inherited erythromelalgia,resurgent current,antiepileptic drug,intermediate inactivated state,neuropharmacology, | en |
| dc.relation.page | 58 | |
| dc.identifier.doi | 10.6342/NTU202100537 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2021-02-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-02-07 | - |
| 顯示於系所單位： | 生理學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-0402202120161500.pdf 未授權公開取用 | 2.31 MB | Adobe PDF |
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