| Project/Area Number |
21791446
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
OZAKI Masayuki Shiga University of Medical Science, 医学部, 特任助教 (50389459)
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| Research Collaborator |
SETO Tomoyoshi 滋賀医科大学, 医学部, 講師 (10335177)
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| Project Period (FY) |
2009 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2009: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | 麻酔薬 / セボフルラン / 心房細動 / 抗不整脈作用 / カリウムチャネル / カリウムイオンチャンネル / 麻酔薬結合部位 / ドッキングシミュレーション / Kチャンネル |
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| Research Abstract |
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.
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