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系統識別號 U0026-0812200914212941
論文名稱(中文) 雌激素受體調控劑對大型電導鈣離子活化鉀離子通道之刺激作用
論文名稱(英文) Stimulatory Effects of the Estrogen-Receptor Modulators on Large-Conductance Calcium-Activated Potassium Channels
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 王雅貞
研究生(英文) Ya-Jean Wang
學號 s5892127
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 召集委員-簡伯武
口試委員-謝如姬
口試委員-蘇銘嘉
口試委員-吳豐森
指導教授-吳勝男
口試委員-許桂森
中文關鍵字 雌激素受體調控劑  鉀離子通道 
英文關鍵字 potassium channel  estrogen receptor modulator 
學科別分類
中文摘要 大電導鈣離子活化鉀離子通道是由四個次單位所組成的結構,他是由SLO 基因所轉譯。這些鉀離子通道的活化受控於細胞內鈣離子的濃度增加與細胞膜電位去極化。最近的文獻發現雌激素受體調控劑也能透過非基因性的調控機制結合到這些鉀離子通道。然而,本實驗針對一系列已知的雌激素受體調控劑,進一步探討這些雌激素受體調控劑是否也能影響大電導鈣離子活化鉀離子通道的活性。首先,diosgenin是山藥的粹取成份之一,過去認為它是雌激素受體調控劑,本實驗發現diosgenin增加大電導鈣離子活化鉀離子通道的活性機制是透過增加細胞內鈣離子濃度,而不是直接結和到通道本身。第二個探討的是resveratrol,過去有數篇研究發現resveratrol對心臟具有保護作用,本實驗發現resveratrol能經由直接結合到心臟纖維細胞大電導鈣離子活化鉀離子通道使通道活性增加,可能的機制是resveratrol能透過增加大電導鈣離子活化鉀離子通道打開的機率,而不是改變離子通道的電導。第三個探討的是PPT 和 DPN,它們分別是雌激素受體調控劑與雌激素受體調控劑,本實驗首度發現這兩個雌激素受體調控劑能影響大電導鈣離子活化鉀離子通道的活性,可能的機制是透過直接結合到離子通道本身,增加大電導鈣離子活化鉀離子通道打開的機率,而不是改變離子通道的電導。最後,藉由心臟細胞模擬的預測,我們發現,在心臟纖維細胞受resveratrol或DPN活化的大電導鈣離子活化鉀離子通道,會經由gap junction的電訊傳導而改變心臟肌細胞動作電位,也就是說,大電導鈣離子活化鉀離子通道活性增加,會使動作電位延長的現象回復。總而言之,這些雌激素受體調控劑影響大電導鈣離子活化鉀離子通道的活性可能不是經由雌激素受體,而是直接調控大電導鈣離子活化鉀離子通道的活性,因此,這些能調控影響大電導鈣離子活化鉀離子通道活性的雌激素受體調控劑,可能可以提供臨床上神經性疾病與心臟血管疾病的治療新方針。
英文摘要 The large conductance Ca2+-activated K+ (BKCa) channels, which are formed by -subunit tetramers, are encoded by a nearly ubiquitous, alternatively spliced gene, SLO (KCNMA1). Activation of the channel is under dual control, i.e., allosterically switched on either by membrane depolarization or by increased [Ca2+]i. Recent studies demonstrated that in addition to their binding to estrogen receptors, the modulators of estrogen receptors (ERs) may have direct effects on the activity of these channels in a non-genomic pathway. In these studies, a series of compounds known to bind to ERs were investigated concerning their possible effects on ion currents. First, diosgenin (3-hydroxy-5-spirostene), originally extracted from the root of wild yam (Dioscorea villosa), was reported to antagonize the binding of estradiol to ERs. The results of this study provide the evidence that it can activate BKCa channels in HCN-1A neuronal cells through increased [Ca2+]i. Second, resveratrol (trans-3,4',5-trihydroxystilbene) is a common phytoalexin that was found in some edible materials, including grape skins, peanuts, and red wine. Several lines of evidence suggest that resveratrol may exert protective effects on the cardiovascular system. Our results also demonstrated that this compound can directly stimulate the activity of BKCa channel in human cardiac fibroblasts (HCFs). It is likely that the observed increase in activity of BKCa channels by resveratrol is due to its stimulation of the probability of channel openings which occurred in rapid open-close transitions. However, no modification in single-channel conductance of BKCa channels was found. Third, PPT (4,4′,4′′-(4-propyl-[1H]-pyrazole-1,3,5-triyl) tris-phenol) and DPN (2,3-bis(4-hydroxyphenyl)-propionitrile) were ER agonists selective for ER- and ER-β, respectively. PPT or DPN applied to the intracellular face of the membrane enhanced the activity of BKCa channels with no change in single-channel conductance. PPT- and DPN-stimulated increase in BKCa channels revealed novel pharmacological properties attributable to the activity of these channels, and their direct increase in BKCa-channels activity may contribute to cellular function. Finally, the theoretical simulations were used to predict effection of action potential duration by alterations in the BKCa channel conductance. The increase of BKCa channel conductance may reduce cardiac action potential duration. Resveratrol (or DPN) induced stimulation of BKCa channels may regulate cardiac action potential. Prolongation of action potential in electrically coupled cardiomyocytes can be reversed by increase of BKCa channel activity. Taken together, the regulation by ER modulators of BKCa-channel activity in a variety of cells can be due to a mechanism unlinked to their binding to ERs. These modulators of the channels may provide a therapeutic potential in neurological disorders and cardiovascular disease.
論文目次 Abbreviation ……………………………………………………………...……III
Figure contents…..……………………………………………………………...IV
Abstract.…………………………………………………………………………..1
Abstract in Chinese…..…………………………………………………………..3
Acknowledgement.................................................5
Chapter I. Introduction………………………………………………………7
1.1. Characteristics and structure of BKCa channels…………………………7
1.2. The physiological roles of BKCa channels…..………………….…...…..8
1.2.1. The roles in neuronal cells…………………………………….....8
1.2.2. The roles in vascular smooth muscle cells…………………..…..9
1.2.3. The roles in cell proliferation………………………………..…10
1.3. Effect of several structurally distinct compounds on BKCa channel
activity reveals novel pharmacological properties…………………….11
1.4. Effects of estrogen-receptor modulators on the activity of BKCa
channel………………………………………………………………...14
1.5. Rationale and specific aims of the present study…………………...….15
Chapter II. Materials and methods…………………………………............23
2.1. Cell preparations…………………………………………………….…23
2.2. Electrophysiological recordings…………………………...……….….24
2.3. RT-PCR………………………………………………………………...26
2.4. Western bloting………………………………………………………...28
2.5. Measurement of [Ca2+]i…………………………………….………….29
2.6. Cell proliferation assay………………………………………………...30
2.7. Simulation studies……………………………………………………..30
2.8. Drugs and statistics…………………………………………….............33
Chapter III. Results…………………………………………………………...35
3.1. Stimulation of diosgenin, a plant-derived sapogenin, on IK(Ca)
in human cortical neuronal cells………………………………………35
3.2. Evidence for functional expression of BKCa channel in human
cardiac fibroblasts (HCFs)..……………………………….…...……...39
3.3. Direct stimulation of estrogen-receptor modulators (ERM) on
BKCa channel in HCFs……………………...…………………………42
3.4. Contribution of BKCa channel activity in HCF to electrical
coupling of cardiomyocyte-fibroblast………………………………...50
Chapter IV. Discussion……………………………………………………….56
Chapter V. Conclusion………………………………………………………75
References……………………………………………………………………….77
Figures…………………………………………………………………………...89
Published papers……………………………………………………..……......117
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