权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cell death-inducing function and activation mechanism of Cl- channel

Cl-通道的细胞死亡诱导功能及激活机制

基本信息

批准号：
14207002
负责人：
OKADA Yasunobu
金额：
$ 31.78万
依托单位：
National Institute for Physiological Sciences (2004)Okazaki National Research Institutes (2002-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Cell acidosis may induce the necrotic cell volume increase (NVI) due to NaCl accumulation within the cells by stimulation of Na+-H+ antiporter and C1--HC03- antiporter. Acidosis with lactate accumulation due to augmented glycolysis-fermentation reactions is known to be frequently associated with cerebral ischemia or trauma and to result in necrosis of glial and neuronal cells. Under such conditions called lactacidosis, cell swelling is strengthened by entry of lactate and proton via monocarboxylate transporters. In cultured glial C6 cells, persistent swelling was in fact induced by lactacidosis. Furthermore, the succeeding regulatory volume decrease (RVD) was impaired under lactacidosis conditions due to inhibition on volume-sensitive outwardly rectifying (VSOR) Cl- channels. When lactacidosis-resistant anion channels were exogenously introduced by applying an anion channel-forming toxin protein purified from Helicobacter pylori, VacA, glial cells restored the RVD. Furthermore, lactaci … More dosis-induced necrotic cell death was significantly rescued, when lactacidosis-resistant anion channels were exogenously introduced into C6 cells by pretreatment with the VacA protein. Thus, it is concluded that inhibition of volume-regulatory VSOR Cl- channels are involved in the NVI in glial cells.Apoptotic volume decrease (AVD) is a pivotal event triggering a cell to undergo apoptosis and is induced by ionic effluxes resulting mainly from increased K+ and Cl- conductances. In human epithelia HeLa cells both mitochondrion- and death receptor-mediated apoptosis inducers (staurosporine and Fas ligand or TNFα) rapidly activate Cl- currents that show properties phenotypical of VSOR Cl- channel currents. Staurosporine rapidly increased the intracellular level of reactive oxygen species (ROS). A ROS scavenger and an NAD(P)H oxidase inhibitor blocked the current activation by staurosporine. A ROS scavenger also inhibited AVD, caspase-3 activation and apoptotic cell death induced by staurosporine. Thus, it is concluded that an apoptosis-triggering anion conductance is carried by the VSOR Cl- channel and that the channel activation upon apoptotic stimulation with staurosporine is mediated by reactive oxygen species.Cultured mouse cortical neurons express the volume-sensitive outwardly rectifying (VSOR) anion channel. Under excitotoxic conditions, neurons suffered from pathological swelling and dendritic beading, called varicosity, and thereafter necrosis. Both whole-cell and single-channel recordings confirmed that the VSOR channel was activated by excitotoxicity. When a VSOR channel blocker was applied during exctitotoxic stimulation, varicosity formation and necrotic cell death were largely inhibited. Thus, it is concluded that the VSOR channel plays a role in excitotoxicity-induced varicosity formation and necrotic cell death. Less

细胞酸中毒可诱导坏死细胞体积增加（NVI），这是由于通过刺激Na+-H+反向转运蛋白和Cl--HCO 3-反向转运蛋白在细胞内的NaCl积累。由于糖酵解-发酵反应增强而导致的乳酸盐蓄积的酸中毒通常与脑缺血或创伤相关，并导致神经胶质细胞和神经元细胞坏死。在这种被称为乳酸中毒的情况下，细胞肿胀通过乳酸和质子经由单羧酸转运蛋白的进入而加强。在培养的胶质C6细胞，持续肿胀，实际上是由乳酸中毒。此外，在乳酸中毒条件下，由于对容积敏感性外向整流（VSOR）Cl-通道的抑制，随后的调节性容积减少（RVD）受损。当乳酸中毒抗性阴离子通道通过应用从幽门螺杆菌纯化的阴离子通道形成毒素蛋白VacA外源性引入时，胶质细胞恢复RVD。此外，lactaci ...更多信息剂量诱导的坏死性细胞死亡显着获救时，乳酸中毒抗性阴离子通道外源性引入C6细胞的预处理与VacA蛋白。因此，可以认为，体积调节性VSOR Cl-通道的抑制参与了神经胶质细胞NVI的发生，凋亡性体积减少（Apoptotic volume decrease，AVD）是触发细胞凋亡的关键事件，主要由K+和Cl-电导增加引起的离子流出引起。在人上皮细胞HeLa细胞中，细胞因子和死亡受体介导的凋亡诱导剂（星形孢菌素和Fas配体或TNFα）快速激活Cl-电流，其显示VSOR Cl-通道电流的表型特性。星形孢菌素迅速增加细胞内活性氧（ROS）水平。活性氧清除剂和NAD（P）H氧化酶抑制剂阻断电流激活星形孢菌素。活性氧清除剂也抑制AVD，半胱天冬酶-3激活和星形孢菌素诱导的细胞凋亡。因此，可以得出结论，凋亡触发阴离子电导进行的VSOR Cl-通道和通道激活后，与staurosporine凋亡刺激介导的活性氧species.Cultured小鼠皮层神经元表达的体积敏感性外向整流（VSOR）阴离子通道。在兴奋性毒性条件下，神经元遭受病理性肿胀和树突状串珠，称为静脉曲张，然后坏死。全细胞和单通道记录都证实了VSOR通道被兴奋性毒性激活。当VSOR通道阻滞剂在兴奋毒性刺激期间应用时，静脉曲张形成和坏死细胞死亡在很大程度上受到抑制。因此，可以得出结论，VSOR通道在兴奋性毒性诱导的静脉曲张形成和坏死细胞死亡中起作用。少

项目成果

期刊论文数量（62）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of ATP-conductive anion channel in ATP release from neonatal rat cardiomyocytes in ischemic or hypoxic conditions.

ATP 传导阴离子通道在缺血或缺氧条件下新生大鼠心肌细胞 ATP 释放中的作用。

DOI：
发表时间：
2004
期刊：
J.Physiol.(London) 559
影响因子：
0
作者：
Lee E-J.;Iai H.;Koizumi N.;Sano H.;Kanzaki-Kato N. et al.;Harada M. et al.;Kameda T. et al.;Yan M.Y.et al.;Ise N.et al.;Nakayama K. et al.;A.K.Dutta
通讯作者：
A.K.Dutta

Dutta AK, Okada Y, Sabirov RZ: "Regulation of an ATP-conductive large-conductance anion channel and swelling-induced ATP release by arachidonic acid"J.Physiol.(London). 542. 803-816 (2002)

Dutta AK、Okada Y、Sabirov RZ：“花生四烯酸调节 ATP 传导性大电导阴离子通道和肿胀诱导的 ATP 释放”J.Physiol.（伦敦）。