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Molecular Mechanism of the Effect of volatile anesthetic on the Potassium Channel Kv1.5 of the Atrium.

挥发性麻醉剂对心房钾通道Kv1.5影响的分子机制。

基本信息

批准号：
21791446
负责人：
OZAKI Masayuki
金额：
$ 1万
依托单位：
Shiga University of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

项目摘要

Recent evidence suggests that sevoflurane prolongs the refractory period of the heart by modifying the function of potassium channels. This effect is considered to be beneficial in patients with atrial fibrillation (Af) in which one of the causative factors is a malfunction of the potassium channel Kv1.5. Kv1.5 carries the ultra-rapid delayed rectifier potassium current (IKur) that is a major repolarizing current in the human atrium. We intended to study how sevoflurane affects the function of Kv1.5 whose precise structure was not fully elucidated. A three dimensional re-creation of Kv 1.5 was essential to gaining an understanding of the binding conformation of sevoflurane. The structure of Kv1.5 was re-created with homology modeling. We constructed a homology model of Kv1.5 using the structure of Kv1.2 as a template in Molecular Operating Environment (MOE, Chemical Computing Group, Canada) and searched binding sites of sevoflurane with ASEDock software (Ryoka System, Japan) in MOE. ASEDock is a docking program based on a shape similarity assessment between a concavity on a protein and the ligand. Homology modeling allowed us to extrapolate and estimate the structure of Kv 1.5 based on that of a similar channel Kv 1.2. The structure of Kv1.5 was successfully re-created. Sevoflurane bound to the sites adjacent to the filter where the structured water molecules are located and sites in the inter-helical spaces of Kv1.5. The results suggest that sevoflurane dislodges the structured water molecules of Kv1.5 which are usually stuck in the prefilter site of the channel and blocks the current of potassium. These effects of sevoflurane may contribute to the prolongation of the refractory period and to the prevention of Af.

最近的证据表明，七氟醚通过改变钾通道的功能来延长心脏的不应期。这种效应被认为对心房颤动(Af)患者是有益的，其中一个原因是钾通道Kv1.5的故障。Kv1.5携带着超快延迟整流钾电流(IKUR)，这是人体心房的一种主要的复极电流。我们打算研究七氟醚对Kv1.5功能的影响，Kv1.5的确切结构尚未完全阐明。Kv 1.5的三维重建对于了解七氟醚的结合构象是必不可少的。通过同源建模重建了Kv1.5的结构。我们以Kv1.2的结构为模板，在分子操作环境(MOE，加拿大化学计算集团)中构建了Kv1.5的同源模型，并用ASEDock软件(日本Ryoka系统)在分子操作环境中搜索了七氟醚的结合位点。ASEDock是一个基于蛋白质凹陷和配体之间形状相似性评估的对接程序。同源建模使我们能够根据类似通道Kv 1.2的结构外推和估计Kv 1.5的结构。成功地重建了Kv1.5的结构。七氟醚结合到结构水分子所在的过滤器附近的位置和Kv1.5螺旋间隙中的位置。结果表明，七氟醚取代了Kv1.5的结构水分子，这些水分子通常滞留在通道的预过滤位置，并阻断钾电流。七氟醚的这些作用可能有助于延长不应期和预防房颤。