Study on bupivacaine enantiomer binding site of KcsA channel and its open-close modification

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K10511
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Seto Tomoyoshi 滋賀医科大学, 医学部, 講師 (10335177)
• Co-Investigator(Kenkyū-buntansha): 加藤 稔 立命館大学, 生命科学部, 教授 (00241258)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: KcsA(E71A) / bupivacaine / enantiomer / molecular docking / open channel block / conductance / mean open time

Outline of Final Research Achievements

We used KcsA channels to elucidate the inhibitory mechanism of channel gating in high intoxication zone. The opening and closing of KcsA were measured from single molecule current measurement. Bupivacaine was added and amplitude analysis and open-close transition analysis were performed. (1) Bupivacaine reduced the conductance in a concentration-dependent manner, and (2) decreased the mean opening time. (3) The average closing time remained constant and was not concentration dependent. Docking calculations revealed that bupivacaine (1) bound to the ion conduction cavity. Binding to the ion conduction pathway could explain the gradual decrease in conductance, and bupivacaine could open-channel block and explain the decrease in mean open time.

Free Research Field

麻酔メカニズム

Academic Significance and Societal Importance of the Research Achievements

ブピバカインの副作用-心毒性・循環虚脱は心筋カリウムチャネルの抑制が関与する。中毒域におけるチャネル開閉動態の抑制メカニズムを開閉動態から解明した。対掌体ブピバカインの結合様式を求め、 ブピバカイン結合による開閉動態修飾を説明し、「なぜ、(S)-ブピバカインは(R)-に比べて循環虚脱を起こしにくいのか？」という問題を解明した。