發(fā)布時(shí)間：2018-02-20 22:01

  本文關(guān)鍵詞： volume - sensitive chloride current Src EGFR ATI PI-3k NADPH PTP PTK　出處：《中國(guó)醫(yī)科大學(xué)》2005年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：前言 腫脹激活性氯電流(I_(Cl,swell))廣泛存在于心臟和其它許多組織中。當(dāng)細(xì)胞腫脹和/或膜變形時(shí)氯通道被激活,I_(Cl,swell)具有以下特性①外向整流特性;②在膜電位為正時(shí)部分失活;③翻轉(zhuǎn)電位處于坪電位和靜息電位(Em)之間;④在生理電壓范圍該通道是時(shí)間非依賴(lài)性的;⑤可以被特異性阻斷劑三苯氧胺(Tamoxifen)阻斷;以上這些生理學(xué)和藥理學(xué)特性可以將I_(Cl,swell)和其它Cl~-通道區(qū)別開(kāi)來(lái)。在等滲條件下,I_(Cl,swell)主要作為背景Cl~-電流,當(dāng)患有心臟疾病時(shí)該通道被激活,在功能方面I_(Cl,swell)的激活能夠影響心臟電生理活性和細(xì)胞容積。 I_(Cl,swell)激活的信號(hào)機(jī)制很復(fù)雜。研究表明,蛋白激酶C,蛋白激酶A和蛋白酪氨酸激酶(PTK)在心臟和其它組織對(duì)其的調(diào)控發(fā)揮作用。PTK在心肌細(xì)胞滲透性腫脹5秒內(nèi)即被激活,因此可以作為信號(hào)調(diào)節(jié)過(guò)程的早期事件。雖然大量證據(jù)表明酪氨酸殘基的磷酸化和去磷酸化參與I_(Cl,swell)的調(diào)控,但其具體機(jī)制尚不清楚。 蛋白酪氨酸磷酸酶(PTP)抑制劑原釩酸鹽(Orthovanadate)能夠降低I_(Cl,swell),而且阻止了由于Src的抑制作用而引起的氯通道開(kāi)放,由此可見(jiàn)Src活性并非是心室肌細(xì)胞I_(Cl,swell)對(duì)滲透壓反應(yīng)調(diào)控的起始因素。已有研究表明表皮生長(zhǎng)因子受體(EGFR)激酶的特異性抑制劑在人心房肌細(xì)胞中能夠抑制I_(Cl,swell),Src對(duì)I_(Cl,swell)的調(diào)控可能就是通過(guò)一種受體介導(dǎo)的PTK而發(fā)揮作用。實(shí)驗(yàn)表明EGFR參與了心肌肥厚的發(fā)生和負(fù)荷依賴(lài)性心肌肥厚在體內(nèi)的發(fā)展過(guò)程,然而EGFR和Src在心肌細(xì)胞I_(Cl,swell)的激活中確切的作用尚待進(jìn)一步探討。 腎素-血管緊張素Ⅱ(RAS)在心血管功能調(diào)控中發(fā)揮著重要的作用,許多心血管疾病如高血壓,糖尿病,冠狀動(dòng)脈供血不足,充血性心力衰竭都伴有RAS活性的提高。血管緊張素Ⅱ(Ang Ⅱ)的效應(yīng)主要是通過(guò)血管緊張
[Abstract]:Foreword. The swelling activated chloride current is widely found in the heart and many other tissues. When the cells are swollen and / or the membrane is deformed, the chloride channel is activated. (1) the outward rectifier characteristic is inactivated when the membrane potential is positive. In the physiological voltage range, the channel is time-independent and can be blocked by tamoxifen, a specific blocker. These physiological and pharmacological properties can distinguish Istip Clsswell from other Cl-channels. Under isosmotic conditions, Istin Clsswell) is primarily used as a background Cl-current, which is activated in the event of heart disease. In the functional aspect, the activation of I / C Clswell can affect cardiac electrophysiological activity and cell volume. The signaling mechanism for the activation of iatroclswell is complex. Studies have shown that protein kinase C, protein kinase A and protein tyrosine kinase PTK play a role in the regulation of heart and other tissues. PTK is activated within 5 seconds of myocardial cell permeability swelling. Although there is a lot of evidence that phosphorylation and dephosphorylation of tyrosine residues are involved in the regulation of ISCW), the mechanism is not clear. Protein tyrosine phosphatase inhibitor orthovanadate (Orthovanadate) can reduce the number of Src and prevent the opening of chloride channels due to the inhibition of Src. It can be seen that Src activity is not the initial factor in regulating the osmotic response of ventricular myocytes. It has been shown that the specific inhibitor of epidermal growth factor receptor (EGFR) kinase can inhibit the effect of I / C / C / S / S / S / c / S / S / S / S / L / S / L / S / T / S / T / S / T / S / T / T / T / T / T / T / T / T cells on the effects of I / C / S. Regulation may be mediated by a receptor-mediated PTK. Experiments have shown that EGFR is involved in the occurrence of myocardial hypertrophy and the development of load-dependent myocardial hypertrophy in vivo. However, the role of EGFR and Src in the activation of cardiac myocytes is still to be further explored. Renin-angiotensin 鈪，

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