2020 Fiscal Year Final Research Report
Study of regulatory system for anesthetic efficacy using GABA-A receptor plasticity
| Project/Area Number |
18K08846
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 55050:Anesthesiology-related
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| Research Institution | Hirosaki University |
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Principal Investigator |
UENO Shinya 弘前大学, 医学研究科, 教授 (00312158)
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| Co-Investigator(Kenkyū-buntansha) |
古川 智範 弘前大学, 医学研究科, 助教 (60402369)
櫛方 哲也 弘前大学, 医学研究科, 准教授 (80250603)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | GABA-A受容体 / 麻酔薬 / 受容体トラフィッキング / 受容体リン酸化変異 |
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| Outline of Final Research Achievements |
We investigated the mechanism of GABA-A receptor trafficking through subunit phosphorylation. Control and mutation-induced cell lines were established using Neuro2A strain. These cell lines stably co-express three kinds of subunits, alpha-, beta3-, and gamma. HA-tag inserted in beta3 subunit introduced the visualization of GABA-A distribution. Confocal microscopy analysis revealed that mutation of phyosphorylation sites of beta3 subunit caused to disturb the trafficking of GABA-A receptors from intracellular region to plasma membrane. Consequently, GABA-induced current in cell lines with mutated beta3 subunit decreased under patch-clamp recordings. These results suggest that phyosphorylation of GABA-A receptor regulate the efficacy of anesthetics with the enhancing effect on GABA.
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| Free Research Field |
神経生理学
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| Academic Significance and Societal Importance of the Research Achievements |
吸入麻酔薬や静脈麻酔薬において全身麻酔効果発現にGABA応答の増強効果が認められている。GABA応答はGABA-A受容体を介しており、本研究結果からGABA-A受容体の応答がリン酸化調節によって可逆的に制御可能であることが示唆された。既に存在するGABA-A受容体増強作用をもつ麻酔薬の効果に対して、新たな調節機構を明らかとした。また、薬物代謝障害による麻酔薬の遷延などを、薬物投与後であっても反応進展を止める、いわゆる"麻酔状態からのリバース"を薬物種に依存せず可能とし、副作用発現の予防にも有効な手段となりうる。
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