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研究生:陳裕廷
研究生(外文):Yu-Ting Chen
論文名稱:EA-2相關的突變種P/Q型鈣離子通道之顯性抑制作用
論文名稱(外文):Dominant negative effect of mutant P/Q type calcium channel associated with EA-2
指導教授:湯志永
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:71
中文關鍵詞:顯性抑制作用
外文關鍵詞:dominant negative effect
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中文摘要
EA-2相關的突變種P/Q型鈣離子通道之顯性抑制作用
P/Q型鈣離子通道是由形成離子孔道 (pore-forming) 的?A subunit與其他?δ、β 等auxiliary subunits所組成,其神經生理弁鄍D要是在調控突觸傳遞作用和神經細胞的興奮性。陣發性不協調第二型(episodic ataxia type 2,EA-2)是一種與小腦運動弁鄍2`有關的遺傳性自體顯性疾病。根據分子遺傳學的研究結果顯示,EA-2是由於P/Q型鈣離子通道之?A subunit突變是所導致。生物物理研究顯示,EA-2相關的突變種鈣離子通道,與正常型鈣離子通道相比,幾乎完全失去離子通道弁遄C但是,如何由?A subunit突變進而導致EA-2諸多症狀的機制至今仍不完全清楚。
因為EA-2是一種自體顯性的遺傳疾病,病人體內通常具有正常型與突變種鈣離子通道。因此,過去釵h研究試圖瞭解突變種鈣離子通道與正常鈣離子通道混合後所產生的影響。實驗結果大多支持正常鈣離子通道與無弁鄋漪蟔傴媔t離子通道只是單純的各自表現,而產生單倍不足現象(haploinsufficiency)。至於與EA-2相關的突變種鈣離子通道是否會對正常型鈣離子通道產生如顯性抑制作用(dominant negative effect)之類的影響,則沒有明確的定論。因此,我們研究的最主要目的是在探討與EA-2相關的突變種鈣離子通道是否會對正常型鈣離子通道產生顯性抑制作用,而造成正常型鈣離子通道的弁鉦ㄔ竻鬌蒫菄滬飢C現象。
我們使用的方法是將正常P/Q型鈣離子通道之?A subunit (?A WT),以及5個EA-2相關的突變種P/Q型鈣離子通道?A subunits (?A mutant)(包括3種nonsense mutations:R1281x、R1549x、R1669x;2種missense mutations:F1406C、E1761K) 的cRNA,以不同的組合混合?δ、β auxiliary subunit cRNA共同注射入蛙卵內,再使用two-electrode voltage clamp的方法記錄通過P/Q型鈣離子通道的鋇離子電流。
首先,我們分別將?A WT的cRNA與5個?A mutant的cRNA單獨表現在蛙卵內,發現通過5個突變種鈣離子通道的鋇離子電流比正常型鈣離子通道明顯地減少(F1406C有很小的鋇離子電流通過,而R1281x、R1549x、R1669x、E1761K則沒有鋇離子電流通過)。這個結果與過去研究的發現類似,顯示EA-2相關的突變種鈣離子通道,幾乎完全失去弁遄C接著,我們將5個?A mutant的cRNA分別與?A WT的cRNA以多種不同的莫耳濃度比例混合後再去表達於蛙卵細胞,以比較混合正常型與突變種鈣離子通道與單純只有正常型的蛙卵之鋇離子電流大小。結果發現隨著混合的?A mutant濃度比例增加,所記錄到的鋇離子電流有逐漸減小的趨勢。根據這個結果可以推測,突變種鈣離子通道可能會對正常型鈣離子通道的表達,產生顯著的降低效果。
為了更進一步確定混合正常型與突變種的鈣離子通道所產生的顯著降低效果,是由突變種鈣離子通道產生。我們以非離子通道的細胞膜蛋白Densin-180代替?A mutant,以類似比例與?A WT混合,發現所記錄到的鋇離子電流並沒有因為增加Densin-180 cRNA而造成明顯的減少。此外,我們以?A WT代替?A mutant,以類似比例與?A WT混合(使用原來WT標準單位數量的1/6之濃度以避免細胞死亡)。結果發現當混合的?A WT之cRNA濃度增加時,電流反而有逐漸增大的趨勢。這個結果顯示,突變種鈣離子通道所造成對正常型鈣離子通道表達降低的現象,不是因為細胞中的cRNA含量過多所致,而是EA-2相關突變種鈣離子通道的確會對正常型鈣離子通道產生顯性抑制作用。
突變種對正常型鈣離子通道所產生的顯著抑制作用之可能原因很多,其中之一是突變種?A subunit可能對?δ、βauxiliary subunits產生競爭的作用,繼而導致正常型?A subunit缺乏足夠的auxiliary subunits以組成有效的P/Q型鈣離子通道。因此,我們進一步探討增加?δ與β subunit cRNA的比例對?A mutant產生的顯性抑制作用之效果如何。實驗結果發現,增加auxiliary subunits的比例,只能局部降低nonsense mutation鈣離子通道的顯性抑制作用,而對missense mutation鈣離子通道的顯性抑制作用則無明顯的效果。這個結果顯示,對auxiliary subunits 之競爭作用,並不是EA-2相關突變種鈣離子通道對正常型鈣離子通道產生顯性抑制作用的主要機制。
Abstract
Dominant negative effect of mutant P/Q type calcium channel associated with EA-2
P/Q-type calcium channel are composed of pore-forming ?A subunit and auxiliary ?δ and β subunits. The neurophysiological role of P/Q-type calcium channels is to modulate synaptic transmission and neuronal exitability. Episodic ataxia type-2 (EA-2) is an inherited autosomal dominant disorder related to cerebellar dysfunction. Molecular genetic studies have demonstrated that EA-2 is associated with mutations in human ?A subunits. Previous studies showed that most EA-2 related mutations result in significant loss of function of P/Q-type calcium channels. The mechanism of how mutant P/Q type calcium channel resulted in EA-2 phenotypes were, however, not fully understood.
Since EA-2 is an autosomal dominant disorder, most EA-2 patients are expected to carry both wild-type (WT) and mutant P/Q-type calcium channel alleles. Therefore, haploinsufficiency has long been suggested to be the mechanism underlying EA-2 phenotype. Whether dominant negative effect is also involved in EA-2 remains controversial. The goal of this thesis is to examine the functional consequence of coexpressing of WT and EA-2-related mutant P/Q type calcium channels, thereby determining the relevance of dominant negative effects to EA-2.
We coexpressed the cRNA of WT ?A subunit (?A WT) with five mutant ?A subunits (?A mutants) associated with EA-2, including three nonsense mutations (R1281x、R1549x、R1669x) and two missense mutations (F1406C、E1761K). Two-electrode voltage clamp method was used to record barium currents through calcium channels.
When we expressed ?A WT and the five ?A mutants individually in oocyte, the barium currents through either of the five?A mutants were significantly lower than those for ?A WT. We then coexpressed of ?A WT and ?A mutants in variable molar ratios. The amplitude of barium currents decreased as the relative molar ratio of ?A mutants increased, suggesting the existence of a ?A mutant-specific suppression effect. When we repeated the same coinjection experiment with ?A WT and Densin-180, a protein not known to interact with calcium channels, no significant suppressions effect were observed. These results show that EA-2 related ?A mutant indeed display dominant negative effect on human P/Q-type calcium channels.
To further pursue the possible mechanism of dominant negative effects of EA-2 mutants, we tested this hypothesis that competition between ?A WT and ?A mutant for the auxiliary subunits could underlie the dominant negative effects by increasing the molar ratio of cRNAs for ?δand β4 subunits. When we increased the amount of auxiliary subunits, dominant negative effects of nonsense mutants were partially reversed, but not with those the missense mutants. The result indicates that competitions between ?A WT and ?A mutant for auxiliary subunits can only partially explain for the dominant negative effects of EA-2 mutants.
目錄

中文摘要…………………………………..………….1
英文摘要…………………………………..………….3
第一章、導論………………………………..……….5
第二章、材料與方法……………………………….16
第三章、結果……………………………………….20
第四章、討論……………………………………….31
圖表………………………………………………….40
參考文獻……………………………………..……...60
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