Molecular Mechanisms of Potassium Channel Facilitation by Blockers and its Impact on Arrhythmias

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06812
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Tokushima Bunri University
• Principal Investigator: Furutani Kazuharu 徳島文理大学, 薬学部, 准教授 (40452437)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: イオンチャネル / 薬物 / 不整脈 / 薬理学 / 心臓電気生理学 / 構造生物学 / コンピューターシミュレーション / 創薬

Outline of Final Research Achievements

A major cause of drug-induced arrhythmias is drug-induced blockade of voltage-gated potassium channels (hERG channels) in cardiomyocytes. In recent years, it has become known that many drugs known as hERG blockers not only block the channels but also facilitate their voltage-dependent activation. In the present study, we have advanced our understanding of the molecular mechanisms blocking agents that facilitate hERG channel activation. We also developed a pipeline to quantitatively predict the effects of drugs on hERG channels based on their structures and to assess how they affect ventricular myocyte and cardiac tissue function and risk of arrhythmogenesis. The results of this study may lead to the development of methods to predict and avoid drug-induced arrhythmias.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

電位依存性カリウムチャネルの一種であるhERGチャネルは、様々な薬物によって遮断され、QT延長症候群の原因となる。この機構は、長年、世界的な研究テーマである。本研究は、活性化を促進する作用を併せ持つ遮断薬に着目し、薬物によるhERGチャネル機能制御の分子機構を明らかにした。この成果は、分子薬理学領域の未解明な問題を解決し、学術的な意義があった。さらに、本研究の成果は、疾患の治療薬の開発段階で必要な心毒性の予測・評価・回避に関して示唆を与え社会的な意義もあった。