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研究生(外文):Ming-wei Lin
論文名稱(外文):Regulation by CAPE, an NF-kB inhibitor, and MBCD, a Cholesterol Scavenger of Large-Conductance Ca2+-Activated K+ Channels in Pituitary Tumor (GH3) Cells
指導教授(外文):Sheng-Nan Wu
中文關鍵詞:MβCD (膽固醇清除劑)興奮性細胞CAPE (NF-kB抑制劑)巨型電導鈣離子活化鉀離子通道
外文關鍵詞:Large-conductance Ca2+-Activated K+ channelsExcitable cellMβCD (Cholesterol scavenger)CAPE (NF-kB inhibitor)
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Caffeic acid phenethyl ester (CAPE)是一種從蜂膠中分離出的苯環狀抗氧化物。CAPE過去被當為轉錄因子NFkB的抑制劑,然而它具有兩個對稱的環狀結構,與一些BKCa離子通道的活化劑類似,如nordihydroguaiaretic acid 和 resveratrol等。由於神經內分泌GH3細胞表現著功能性的BKCa離子通道,因此我們在這種細胞中來研究它對離子通道的影響。在我們的實驗中,CAPE會隨濃度活化鈣離子活化鉀離子電流(IK(Ca)),其EC50 值為14 ± 2 uM。然而先以氧化劑2,2’-azo-bis-(2-amidinopropane) hydrochloride (100 uM) 或 t-butyl hydroperoxide (1 mM)處理GH3細胞的話,會減弱CAPE活化的IK(Ca)。CAPE(50 uM)會些微抑制L型電壓依賴鈣離子電流。在inside-out的模式中,CAPE(20 uM)投予細胞膜內面會增強BKCa離子通道的活性,但並不改變單一離子通道的電導。在以CAPE(20 uM)活化BKCa離子通道後再給予nordihydroguaiaretic acid (20 uM)並不會更進一步增加離子通道的活性。CAPE所刺激的BKCa離子通道活性會依賴細胞膜電位,並且會在GH3細胞中增加這些離子通道對鈣離子的靈敏度。CAPE所增加的BKCa離子通道打開機率,主要是減少離子通道的平均關閉時間。在電流鉗制的條件下,CAPE會過極化細胞膜電位並減少動作電位的產生。再者,CAPE也減少GH3細胞內自發性的鈣離子濃度波動。因此當以CAPE當作NFkB的抑制劑時,需注意它對BKCa離子通道活性的刺激作用。
脂筏為細胞膜上特殊富含膽固醇的微域。它參與著訊息傳遞與細胞對環境改變的適應作用。許多研究報告提出證據指出一些離子通道與脂筏有所連結。因此改變細胞膜上的膽固醇應該會直接影響離子通道的活性。以一種多醣類methyl-β-cyclodextrin (MβCD)去除GH3細胞膜上的膽固醇後,會導致脂筏的破壞,並且增加IK(Ca)的電流密度。然而同時給予MβCD與膽固醇則不改變IK(Ca)的電流密度。MβCD(1.5 mg/ml)些微抑制L型電壓依賴鈣離子電流。在inside-out紀錄中,BKCa離子通道的活性因MβCD處理後增加,但並不增加單一離子通道的電導。在經MβCD處理過的細胞中,BKCa離子通道對電壓的靈敏度會增加,但並不改變對鈣離子的靈敏度,並且在inside-out模式中,對細胞內面給予dexamethasone並不能增加BKCa離子通道的活性,但CAPE與cilostazol則依舊能有效率的增加其打開機率。然而經MβCD處理過的細胞,BKCa離子通道的蛋白表現量並沒有改變。在電流鉗制的紀錄中顯示以MβCD去除細胞膜膽固醇會減少動作電位的產生。因此去除細胞膜上的脂筏來增加BKCa離子通道的活性也許會此影響神經或神經內分泌細胞的功能活性。
Large-conductance Ca2+-activated K+ (BKCa) channels differ from most of other K+ channels in that their activation is under dual control, i.e., activated by either an increase in intracellular Ca2+ or by membrane depolarization. These channels, which are widely distributed in a variety of cells, can control Ca2+ influx as well as a number of Ca2+-dependent physiological processes. In neurons or neuroendocrine cells, BKCa channels are believed to play an important role in controlling hormonal secretion by altering the duration and frequency of action potentials. Experimental observations have revealed that a variety of components can directly modulate BKCa channel activity.
Caffeic acid phenethyl ester (CAPE), a phenolic antioxidant derived from the propolis of honeybee hives, is known to be an inhibitor of the activation of nuclear transcript factor NF-κB. The molecule of this compound has the juxtaposition of two aromatic rings, the unique structure of which is similar to those of some BKCa channel openers, such as nordihydroguaiaretic acid and resveratrol. Since functional expression of BKCa channel has been demonstrated in pituitary GH3 cells, the effects of CAPE on ion currents have been investigated in these cells. In our study, this compound increased Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an EC50 value of 14 ± 2 uM. However, the magnitude of CAPE-induced stimulation of IK(Ca) was attenuated in GH3 cells preincubated with the oxidants, 2,2’-azo-bis-(2-amidinopropane) hydrochloride (100 uM) or t-butyl hydroperoxide (1 mM). CAPE (50 uM) slightly suppressed voltage-dependent L-type Ca2+ current. In inside-out configuration, CAPE (20 uM) applied to the intracellular face of the detached patch enhanced the activity of BKCa channels with no modification in single-channel conductance. After BKCa channel activity was increased by CAPE (20 uM), subsequent application of nordihydroguaiaretic acid (20 uM) did not increase the channel activity further. CAPE-stimulated BKCa channel activity was dependent on membrane potential. Results suggested that CAPE could also increase Ca2+ sensitivity of BKCa channels in these cells. Additionally, its increase in the open probability could primarily involve a decrease in the mean closed time. In current-clamp conditions, CAPE hyperpolarized the membrane potential and reduced the firing of action potentials. Moreover, CAPE also attenuated the spontaneous [Ca2+]i oscillations in GH3 cells. Therefore, the stimulatory action of CAPE on BKCa-channel activity should be noted with caution in relation to its increasing use as an inhibitor of activation of the NF-kB.
Lipid rafts are specialized cholesterol-enriched microdomains of the cellular membrane. They participate actively in signal transduction and cellular adaptation to changing environments. Several reports have provided evidence that certain ion channels physically associate with the lipid rafts. Therefore, changes in the amount of membrane cholesterol may directly modify the activity of ion channels. In this study, depletion of membrane cholesterol by pituitary GH3 cells to methyl-β-cyclodextrin (MβCD), an oligosaccharide, resulted in disruption of lipid raft and an increase in the density of IK(Ca). However, no significant change in IK(Ca) density was demonstrated in GH3 cells treated with a mixture of MβCD and cholesterol. Cholesterol depletion with MβCD (1.5 mg/ml) slightly suppressed the density of voltage-dependent L-type Ca2+ current. In inside-out patches recorded from MβCD-treated cells, the activity of BKCa channels was enhanced with no change in single-channel conductance. In MβCD-treated cells, voltage-sensitivity of BKCa channels was increased; however, no change in Ca2+-sensitivity could be demonstrated. In inside-out patches from MβCD-treated cells, dexamethasone applied to the intracellular surface did not increase BKCa-channel activity, although CAPE and cilostazol still opened its probability effectively. However, in MβCD-treated cells, the protein expression of BKCa channels remained unchanged. Current-clamp recordings demonstrated that the cholesterol depletion maneuver with MβCD reduced the firing of action potentials. Therefore, it can be concluded that the increase in BKCa-channel activity induced by membrane lipid raft disruption may, to some extent, influence the functional activities of neurons or neuroendocrine cells.
The increased activity of BKCa channels may contribute to the underlying mechanisms by which it alters neuronal or neuroendocrine excitability. Therefore, with the increased understanding of the regulation of BKCa channel will open new therapeutic perspectives in various states of abnormal neuron activity.
Chinese abstract…………………………………………….IV
Figure contents……………………..…….…….XIII
Abbreviations ……………………………………XV
Chapter 1 Introduction…………….….…………1
1-1 Ion channels……………….…………1
1-2 Calcium-activated potassium (KCa) channels…1
1-3 The structural basis of BKCa channel…2
1-4 Regulation of BKCa channels………3
1-5 Ion channels and lipid rafts……….4
1-6 Pathophysiological BKCa channel………5
1-7 BKCa channel modulator…………7
1-8 Pituitary GH3 cells…………10
1-9 Rationale and specific aims of the present study10
Chapter 2 Materials and methods……………13
2-1 Cell culture……….….………….….13
2-2 Reverse transcriptase-PCR….……...13
2-3 Immunoblotting…...…….14
2-4 Membrane, cytosolic protein isolation and Western blot analysis………………….….15
2-5 Electron microscopy……………15
2-6 Electrophysiological measurements……15
2-7 Cytosolic Ca2+ measurements………16
2-8 Data recordings and analyze……17
2-9 Solutions…………………18
Chapter 3 Stimulatory actions of CAPE on IK(Ca) in pituitary GH3 cells……….……………..20
3-1 The expression of the BKCa channels was detected in GH3 cells……………………….25
3-2 CAPE increased IK(Ca) in a concentration-dependent manner……………….…25
3-3 CAPE slightly suppressed the voltage-dependent L-type Ca2+ current…………….26
3-4 The magnitude of CAPE-induced stimulation of IK(Ca) was attenuated in GH3 cell pre-incubated with AAPH or t-buty hydroperoxide……………26
3-5 CAPE enhanced the activity of the BKCa channels27
3-6 Nordihydroguaiaretic acid did not further increase the channel activity when BKCa channel activity was increased by CAPE………….28
3-7 Effect of CAPE on the activation curve of BKCa channels…………….29
3-8 CAPE did not modify BKCa channel single-channel conductance, but increased the channels open probability by decreasing mean closed time…30
3-9 CAPE hyperpolarized the membrane potential and reduced the firing of action potentials………31
3-10 Effect of CAPE on spontaneous [Ca2+]i oscillations in pituitary GH3 cells……………32
Chapter 4 Evidence for regulation by lipid rafts of the activity of BKCa channels in pituitary GH3 Cells……38
Introduction …………………39
Results …………………42
4-1 Loss of lipid rafts in MBCD treated GH3 cells…42
4-2 Effect of MBCD treatment on the density of IK(Ca) in GH3 Cells………….….42
4-3 Effect of MBCD treatment on voltage-dependent L-Type Ca2+ current in pituitary GH3 Cells……43
4-4 Comparison of BKCa channel activity in untreated and MBCD-treated cells…………………44
4-5 Lack of effect of MBCD treatment on single-channel conductance of BKCa channels……45
4-6 Effect of MBCD treatment on the activation curve of BKCa channels………………46
4-7 Effect of internal Ca2+ concentration ([Ca2+]i) on BKCa channel activity in untreated and MBCD-treated cells…………….......46
4-8 Kinetic behavior of BKCa channels in untreated and MBCD-treated cells………………..47
4-9 Effect of CAPE, cilostazol or dexamethasone on BKCa channels in GH3 cells treated with MBCD…………….47
4-10 Discharge pattern of spontaneous action potentials in untreated and MBCD-treated GH3 cells………48
4-11 Effect of MBCD treatment on the BKCa channel protein expression……………49 Discussion……………….…..51
Chapter 5 Conclusion………….………57
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