Regulations of ion channels by fluctuation of phospholipids' distribution

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K19398
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Kyoto University
• Principal Investigator: Hara Yuji 京都大学, 工学研究科, 准教授 (60362456)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Keywords: リン脂質 / リン脂質フリッパーゼ / イオンチャネル

Outline of Final Research Achievements

Phospholipids, the main components of the plasma membrane, are asymmetrically distributed between the inner and the outer leaflets. Previous literatures including our recent finding have shown that the asymmetric distribution of phospholipids governs a variety of cellular processes including membrane biophysics, intracellular signaling, and cell migration. But it is still obscure about the molecular mechanism as to how the changes in phospholipids' distribution contributes to a variety of cellular events. In this project, we have examined the importance of phospholipids' distribution in regulation of membrane proteins. Our results identified one of Ca2+-permeable cation channels regulated by bidirectional transport of phospholipids across the plasma membrane. These results strongly support the importance of the "flip-flop switch" mechanism that changes in the trans-bilayer distribution of lipids regulates the function of membrane proteins including ion channels.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

これまでに多くの研究者が脂質と膜タンパク質の相互作用について従事してきた。しかし脂質は水に溶けない物性、またゲノムに直接コードされない理由から、科学技術が進歩した現在でも解析し難い対象である。そのため脂質環境の微細なゆらぎとイオンチャネル活性調節について深く追求した研究は未だ少ない。本研究にて膜リン脂質によるチャネル制御機構を解明することは、膜脂質とタンパク質の織りなす多様な相互作用を理解し、生体膜に機能的な多様性を賦与する分子機構を解明することにつながる。本申請によりイオンチャネルが関わる細胞応答、さらに個体レベルの恒常性維持機構、病態発症機構等についてさらなる理解深化が期待される。