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Novel ion channel functions utilizing protein-protein interactions

利用蛋白质-蛋白质相互作用的新型离子通道功能

基本信息

批准号：
15390060
负责人：
FURUKAWA Tetsushi
金额：
$ 9.22万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

To efficiently transmit various extra-cellular and intra-cellular signals, ion channels form macro-molecular complex with various proteins. In the previous research grant (2003-2004, project number 13670035), we have performed comprehensive screening of proteins interacting with various ion channels. And, we identified more than 10 novel protein-protein interactions involving ion channels. In the present grant, we carried out continuous effort to unveil novel ion channel functions that utilize identified protein-protein interactions.We identified novel ion channel regulatory system using nitric oxide (NO). NO is originally identified as a endothelial-derived relaxing factor (EDRF), and plays a very important role in cardiovascular system. NO is a gaseous signal molecule that is diffusible and easy to be oxidized. Thus, to achieve specific protein regulation, NO-producing system (NO synthase ; NOS) should be in the vicinity of target proteins, ion channels in this case. Thus, protein-protein interaction involving NOS and ion channels turns out to be intriguing research target.We demonstrated that L-type Ca^<2+> channel current (I_<ca,L>) and delayed rectifier K^+ current (I_<Ks>) are regulatory target of NO. I_<Ca,L> is inhibited by NO in a cGMP-dependent manner, while I_<KS> is activated in a cGMP-independent manner, most likely by s-nitrosylation of cysteine thiol residue. We demonstrated that these novel ion channel regulatory system plays a crucial role in several cellular phenomenon, including (1) fine-tuning of Ca^<2+> -entry ; (2) non-genomic regulation of ion channels by sex hormones ; (3) mechanisms of actions of herbal medicine ; and (4) innate immunity.We strongly believe that we should extend these findings to establish ion channel regulation by s-nitrosylation in cardiovascular system, and to develop new strategies for treatment of arrhythmias, life-style related diseases, and other common diseases in the elderly.

为了有效地传递各种细胞外和细胞内信号，离子通道与各种蛋白质形成大分子复合体。在之前的研究资助(2003年至2004年，项目编号13670035)中，我们对与各种离子通道相互作用的蛋白质进行了全面的筛选。并且，我们确定了10多种涉及离子通道的新的蛋白质-蛋白质相互作用。在目前的资助中，我们继续努力揭示新的离子通道功能，利用已识别的蛋白质-蛋白质相互作用。我们发现了使用一氧化氮(NO)的新的离子通道调节系统。一氧化氮最初被认为是一种内皮衍生的松弛因子，在心血管系统中起着非常重要的作用。NO是一种易扩散、易被氧化的气态信号分子。因此，为了实现特定的蛋白质调节，NO产生系统(一氧化氮合酶；NOS)应该在靶蛋白附近，在这种情况下是离子通道。因此，涉及一氧化氮合酶和离子通道的蛋白质-蛋白质相互作用成为研究的热点。我们论证了L型钙通道电流和延迟整流钾通道电流是一氧化氮的调节靶点。NO以依赖于cGMP的方式抑制钙离子，而非依赖于cGMP的方式激活钙通道阻断剂，很可能是通过S亚硝化半胱氨酸硫醇残基。我们证明了这些新的离子通道调节系统在几种细胞现象中起着关键作用，包括(1)钙离子通道的微调；(2)性激素对离子通道的非基因组调节；(3)中药的作用机制；(4)天然免疫。我们强烈认为，我们应该扩大这些发现，以建立S-硝酸酯对心血管系统离子通道的调节，并开发治疗心律失常、生活方式相关疾病和其他老年人常见病的新策略。