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

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。这种效应被认为对房颤（Af）患者是有益的，其中一个病因是钾通道Kv1.5的功能障碍。Kv1.5携带超高速延迟整流钾电流（IKur），这是人体心房的主要复极电流。我们打算研究七氟醚如何影响精确结构尚未完全阐明的Kv1.5的功能。Kv 1.5的三维重建对于理解七氟烷的结合构象至关重要。利用同源性建模重建了Kv1.5的结构。我们在Molecular Operating Environment （MOE, Chemical Computing Group, Canada）中以Kv1.2的结构为模板构建了Kv1.5的同源性模型，并在MOE中使用ASEDock软件（Ryoka System, Japan）搜索七氟醚的结合位点。ASEDock是一种对接程序，基于蛋白质上的凹面和配体之间的形状相似性评估。同源性建模使我们能够根据相似通道Kv 1.2的结构推断和估计Kv 1.5的结构。成功重建Kv1.5的结构。七氟烷结合在过滤器附近结构水分子所在的位置和Kv1.5的螺旋间隙中的位置。结果表明，七氟醚将Kv1.5的结构水分子移出，这些水分子通常滞留在通道的预过滤部位，并阻断钾的电流。七氟醚的这些作用可能有助于延长不应期和预防房颤。

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.