2022 Fiscal Year Final Research Report
Mechanisms of spatio-temporal regulation of ion channel dynamics via PIP2 generating neuroplasticity
| Project/Area Number |
20K22631
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0701:Biology at molecular to cellular levels, and related fields
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2020-09-11 – 2023-03-31
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| Keywords | １分子イメージング / 神経可塑性 / 軸索起始部（AIS） / イオンチャネル / PIP2 / 拡散 / エンドサイトーシス / エキソサイトーシス |
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| Outline of Final Research Achievements |
The inositol phospholipid PI(4,5)P2 is well known signaling molecules, and regulate a wide variety of membrane proteins. In particular, a kind of the voltage-gated potassium channel, KCNQ2/3, has long been investigated for its regulation by PI(4,5)P2. In highly polarized neurons, KCNQ2/3 asymmetrically localized to axon initial segment (AIS), and the characteristic spatial distribution of KCNQ2/3 is directly related to the neuronal excitability. In this study, to elucidate the role of PI(4,5)P2 in the regulation of channel trafficking, the spatial dynamics of KCNQ3 were quantitatively analyzed in living neurons at multiple- and single-molecule level. As a result, it was revealed that the trafficking efficiency of mutant KCNQ3, which lacks PI(4,5)P2 binding ability, was decreased depending on its channel activity.
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| Free Research Field |
神経科学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、神経におけるKCNQ2/3の空間動態を初めて１分子レベルで検出し、定量解析することに成功した。さらに、KCNQ2/3のトラフィッキング制御におけるPIP2結合サイトの新たな役割を明らかにした。病理学的にもAISの変容は双極性障害や統合失調症を含む神経精神疾患で一貫して観察される他（Iqbal, Hum. Mol. Genet., 2013）、KCNQ2/3のPIP2結合サイトにおける遺伝子変異はてんかんの発症原因ともなり得る。そのため、本研究で得られた成果はこれら疾患の発症機序の理解を助け、新たな治療・創薬戦略の基盤となることで医学・臨床の分野へも貢献することが期待される。
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