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研究生:蔡廷姍
研究生(外文):Ting-Shan Tsai
論文名稱:Levetiracetam對內流型整流鉀離子通道作用之探討
論文名稱(外文):Study on the effect of levetiracetam in Kir1.1 channels
指導教授:劉宏輝劉宏輝引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:93
中文關鍵詞:癲癇鉀離子通道
外文關鍵詞:anticonvulsantK channelsKir
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新一代抗癲癇藥物Levetiracetam (LEV, Keppra, (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide)目前在臨床上用於治療partial-onset epileptic seizures。LEV可作用於電位依賴型鉀離子通道並減少動作電位頻率,故可降低神經興奮性。鉀離子通道可調控神經的興奮性,並且可為抗癲癇藥物作用的標的。ROMK1離子通道屬於內流型整流鉀離子通道的成員,密集分布於海馬迴,具有穩定膜電位的功能。

在本實驗中,我們使用蛙卵作為表達ROMK1離子通道蛋白質之表現載體,並使用inside-out膜片電位鉗定技術 (patch clamp)測量ROMK1離子通道所表達之電流。我們發現新一代抗癲癇藥物LEV可增加ROMK1離子通道所表達之電流,且其作用具有濃度依賴性,EC50=362.6μM。而目前已知ROMK1離子通道受PIP2、細胞內酸鹼度、以及蛋白質激酶A(cyclic AMP-dependent protein kinase, PKA)與蛋白質激酶C(protein kinase C, PKC)等胞內物質調控,因此我們利用以上已知的分子調控機制探討LEV活化ROMK1離子通道的可能機轉。

根據之前的研究,已確認扮演PIP2結合位點(Arg188)、PKA磷酸化位點(Ser44、Ser219、Ser313)及PKC磷酸化位點(Ser183、The191、Thr193、Ser201、Thr234)及pH sensor(Lys80)角色之特定胺基酸,我們分別將wild type以及各種點突變之ROMK1離子通道蛋白質表現在蛙卵細胞上,發現LEV可活化PIP2結合位點之突變R188Q、PKC磷酸化位點之突變S183A、T191A、T193A、S201A、T234A,以及對pH不敏感之突變K80M,顯示LEV與ROMK1離子通道交互作用的過程並不牽涉PIP2以及PKC磷酸化,亦與胞內酸鹼值無關。而對ROMK1離子通道投與PKA抑制劑H89可部分抑制LEV的作用,且LEV無法活化PKA磷酸化位點之突變S219A以及S313A,顯示LEV透過PKA相關路徑活化ROMK1離子通道。我們進一步利用單點突變方式將PKA磷酸化位點置換為帶負電荷之天門冬胺酸(Aspartic acid,D)以模擬受磷酸化而帶負電的情形,探討LEV是否透過電荷改變而活化ROMK1離子通道。而我們的研究結果顯示,將PKA磷酸化位點突變為帶負電之胺基酸,S219D及S313D仍然無法與LEV作用,顯示電荷的改變並不足以模擬wild type ROMK1離子通道受PKA磷酸化後可與LEV交互作用的狀態,顯示電荷並不是LEV與ROMK1離子通道交互作用的必須條件。而由細胞內面投予LEV可使ROMK1離子通道表達的電流增大,暗示著ROMK1離子通道上可能具有LEV的結合位點,因此我們推測,ROMK1離子通道受PKA磷酸化之後,其構型產生改變,而LEV恰好可與此構型交互作用,進而增強ROMK1離子通道表達之電流。

本實驗證明LEV可增加ROMK1離子通道表達之電流,活化ROMK1離子通道而促進神經細胞的過極化可能是LEV尚未被發現的抗癲癇的機轉之一。
Levetiracetam (LEV, (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide), a novel antiepileptic drug, is effective in the treatment of partial-onset epileptic seizures. It is reported that LEV exerts its antiepileptic effect by modulating voltage-dependent potassium channels to lower action potential frequency. Potassium channels regulate neuronal excitability, and serve as target of anticonvulsant. ROMK1 channels, a member of inwardly rectifying potassium channels, are abundant in hippocampus which is highly related to the generation of seizure activities. The effect of LEV on ROMK1 was studied by inside-out patch-clamp recording in xenopus oocyte expression system. LEV dose-dependently enhanced ROMK current with EC¬50¬ of 362.6μM. LEV also enhanced ROMK1 current in mutations of PIP¬2¬ binding sites, R188Q and K218A, indicating that PIP¬2 is not involved in the interaction between LEV and ROMK1 channels. Substitution of PKC phosphorylation sites, Ser183, The191, Thr193, Ser201¬¬, Thr234 for alanine did not abolish the effect of LEV, meaning that LEV does not activate ROMK1 through PKC phosphorylation-dependent pathway. K80M is pH-insensitive, and LEV enhanced K80M currents, indicating that intracellular pH is not involved in the process of LEV enhancing ROMK1 current. Otherwise, PKA inhibitor H89 partially reduced the effect of LEV, and LEV failed to enhance the current expressed by S219A and S313A, mutations of PKA phosphorylation sites, suggesting that LEV may enhance ROMK currents through PKA-related pathway. Furthermore, we substitute PKA phosphorylation sites for asparatate to investigate whether negative charge is required for LEV to enhance ROMK1 currents. LEV had no effect on S219D and S313D, indicating that negative charges are not necessary for LEV to activate ROMK1 channels. We speculate that PKA phosphorylation may offer an appropriate conformation for LEV. LEV applied to the intracellular surface of the excised patches is able to activate ROMK1 channels, suggesting that its binding site could be on the intracellular leaflet, and it may interact with phosphorylated ROMK1 channels and therefore amplify the currents. This study suggests that enhacing ROMK1 currents is one of the underlying mechanisms of LEV in the reduction of neuronal excitability.
口試委員會審定書………………………………………………………………. i
誌謝……………………………………………………………………………….. ii
中文摘要…………………………………………………………………………. iii
英文摘要………………………………………………………………………….. v
第一章 導論……………………………………………………………………1
第二章 研究目的與動機………………………………………………………… 22
第三章 實驗材料與方法………………………………………………………24
第一節 實驗材料……………………………………………………………24
第二節 實驗方法……………………………………………………………27
第四章 實驗結果………………………………………………………………32
第一節 LEV可增加wild type ROMK1離子通道所表達之電流………32
第二節 胞內酸鹼度不參與LEV與ROMK1離子通道之交互作用……34
第三節 PIP2不參與LEV與ROMK1離子通道之交互作用………………36
第四節 PKC不參與LEV與ROMK1離子通道之交互作用………………38
第五節 PKA參與LEV與ROMK1離子通道之交互作用………………40
第五章 討論………………………………………………………………………43
圖表…………………………………………………………………………………58
參考文獻……………………………………………………………………………79
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