| Budget Amount *help |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2004: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2003: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Research Abstract |
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.
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