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的信号，离子通道与各种蛋白质形成大分子复合物。在之前的研究资助（2003-2004，项目号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。而且，我们还发现了 10 多种涉及离子通道的新型蛋白质-蛋白质相互作用。在目前的资助中，我们不断努力揭示利用已确定的蛋白质-蛋白质相互作用的新型离子通道功能。我们利用一氧化氮（NO）确定了新型离子通道调节系统。 NO最初被认为是一种内皮源性舒张因子（EDRF），在心血管系统中发挥着非常重要的作用。 NO是一种气态信号分子，具有扩散性，易被氧化。因此，为了实现特定的蛋白质调节，NO产生系统（NO合酶；NOS）应该位于靶蛋白（本例中为离子通道）附近。因此，涉及 NOS 和离子通道的蛋白质-蛋白质相互作用成为令人感兴趣的研究目标。我们证明了 L 型 Ca^<2+> 通道电流 (I_<ca,L>) 和延迟整流 K^+ 电流 (I_ <Ks>) 是 NO 的监管目标。 I_<Ca,L> 以 cGMP 依赖性方式被 NO 抑制，而 I_<KS> 以不依赖 cGMP 的方式被激活，很可能是通过半胱氨酸硫醇残基的 s-亚硝基化。我们证明了这些新型离子通道调节系统在多种细胞现象中发挥着至关重要的作用，包括（1）Ca^2+进入的微调； (2)性激素对离子通道的非基因组调控； (3) 草药的作用机制； (4)先天免疫。我们坚信，我们应该扩展这些发现，建立心血管系统中通过s-亚硝基化调节离子通道的机制，并开发治疗心律失常、生活方式相关疾病和其他常见疾病的新策略。老年人。