Molecular mechanisms underlying the regulation of voltage-gated ion channels by volatile anesthetics

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K16445
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Fukushima Yutaka 滋賀医科大学, 医学部, 助教 (10422891)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: Kv1.5チャネル / 吸入麻酔薬 / デスフルラン / セボフルラン / 膜電位依存性イオンチャネル / 作用機構 / 標的分子

Outline of Final Research Achievements

Previous studies have detected the putative binding sites for volatile anesthetics on ligand-gated ion channels, such as GABAA receptor. However, there is only a limited information concerning the molecular basis underlying the functional effect of volatile anesthetics on voltage-gated potassium channels, which play key roles in regulating membrane potential, excitability and cellular functions in various cell types.
We investigated molecular and cellular mechanisms underlying modulatory effect of desflurane and sevoflurane on the human voltage-gated Kv1.5 (hKv1.5) channel, using multiple experimental approaches, including patch-clamp technique, site-direct mutagenesis and computer docking simulation. We found that desflurane and sevoflurane at clinically relevant concentrations produce an open-channel blocking action on hKv1.5 channel, probably through direct interaction with specific amino acids located within the pore region of hKv1.5 channel.

Free Research Field

麻酔学

Academic Significance and Societal Importance of the Research Achievements

hKv1.5チャネルは、6回膜貫通型の構造をとり、５番目（S5）と６番目（S6）の膜貫通領域の間にイオンが通るポアが形成される。これらの基本構造は他の膜電位依存性イオンチャネルと同様であるため、得られた知見は吸入麻酔薬の膜電位依存性イオンチャネルへの作用機構を理解する上で貴重な情報を提供すると期待される。さらに、全身麻酔薬の麻酔作用や全身作用の発現に関わるイオンチャネルは、GABAA受容体チャネルをはじめとするリガンド依存性イオンチャネルのみならず、膜電位依存性イオンチャネルも重要な標的分子であるという知見は、新たな全身麻酔薬の開発においても重要な情報となり、麻酔科学の発展にも寄与できる。