The distal C-tail of THIK channel regulates the channel gating

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06793
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: Tateyama Michihiro 生理学研究所, 分子細胞生理研究領域, 准教授 (30276472)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: THIK channel / Unnatural amino acid / mechanism

Outline of Final Research Achievements

A two-pore domain K+ (K2P) channel, THIK-1, has been reported to play important roles in microglia and macrophage and the channel conductance is regulated by C-terminal tail. We investigated the effects of distal C-tail on the channel activity, by introducing an unnatural cross-linking amino acid, 4 amido-phenylalanine (AzF), into residues at the distal C-tail and found that L398AzF mutant was significantly potentiated upon the UV-exposure. As the inner helices of K2P are thought to serve as a regulatory domain, we further investigated the effect of the C-tail on the conformation of the inner helices. The incorporation of AzF into the residues located at the inner helices made the mutants to respond to the UV-exposure, while the additional L398A mutation changed the extent and/or direction of the responses. These results show that Leu398 at the distal C-tail of THIK-1 is involved in the regulatory mechanism of the channel activity.

Free Research Field

分子細胞生理学

Academic Significance and Societal Importance of the Research Achievements

本研究により、THIK-1チャネルの遠位末端領域がゲーティングを担う膜貫通部位の構造に影響を与えることが明らかとなり、この成果はイオンチャネル制御機構の解明に寄与するものと思われる。THIK-1チャネルは、免疫細胞の機能に重要な役割を持つこと、アルツハイマー病において発現量が増加することが報告されている。Gタンパク質共役型受容体による機能制御に加え、C末端領域がゲーティングに影響を与えるという知見は、免疫細胞におけるTHIK-1の役割を理解するのに貢献するものと考えられる。