心室肌细胞肿胀激活性氯电流的功能与调控机制

发布时间：2018-02-20 22:01

  本文关键词： volume - sensitive chloride current Src EGFR ATI PI-3k NADPH PTP PTK　出处：《中国医科大学》2005年博士论文　论文类型：学位论文

【摘要】：前言 肿胀激活性氯电流(I_(Cl,swell))广泛存在于心脏和其它许多组织中。当细胞肿胀和/或膜变形时氯通道被激活,I_(Cl,swell)具有以下特性①外向整流特性;②在膜电位为正时部分失活;③翻转电位处于坪电位和静息电位(Em)之间;④在生理电压范围该通道是时间非依赖性的;⑤可以被特异性阻断剂三苯氧胺(Tamoxifen)阻断;以上这些生理学和药理学特性可以将I_(Cl,swell)和其它Cl~-通道区别开来。在等渗条件下,I_(Cl,swell)主要作为背景Cl~-电流,当患有心脏疾病时该通道被激活,在功能方面I_(Cl,swell)的激活能够影响心脏电生理活性和细胞容积。 I_(Cl,swell)激活的信号机制很复杂。研究表明,蛋白激酶C,蛋白激酶A和蛋白酪氨酸激酶(PTK)在心脏和其它组织对其的调控发挥作用。PTK在心肌细胞渗透性肿胀5秒内即被激活,因此可以作为信号调节过程的早期事件。虽然大量证据表明酪氨酸残基的磷酸化和去磷酸化参与I_(Cl,swell)的调控,但其具体机制尚不清楚。 蛋白酪氨酸磷酸酶(PTP)抑制剂原钒酸盐(Orthovanadate)能够降低I_(Cl,swell),而且阻止了由于Src的抑制作用而引起的氯通道开放,由此可见Src活性并非是心室肌细胞I_(Cl,swell)对渗透压反应调控的起始因素。已有研究表明表皮生长因子受体(EGFR)激酶的特异性抑制剂在人心房肌细胞中能够抑制I_(Cl,swell),Src对I_(Cl,swell)的调控可能就是通过一种受体介导的PTK而发挥作用。实验表明EGFR参与了心肌肥厚的发生和负荷依赖性心肌肥厚在体内的发展过程,然而EGFR和Src在心肌细胞I_(Cl,swell)的激活中确切的作用尚待进一步探讨。 肾素-血管紧张素Ⅱ(RAS)在心血管功能调控中发挥着重要的作用,许多心血管疾病如高血压,糖尿病,冠状动脉供血不足,充血性心力衰竭都伴有RAS活性的提高。血管紧张素Ⅱ(Ang Ⅱ)的效应主要是通过血管紧张
[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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