Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses
文献类型：期刊论文
| 作者 | Zhou, Xiaoyu1,2; Zhao, Cheng3,4; Xu, Haiyan1,5; Xu, Yixiang6; Zhan, Li1; Wang, Pei1; He, Jingyi1,7; Lu, Taotao6; Gu, Yueling1; Yang, Yan8 |
| 刊名 | NATURE CHEMICAL BIOLOGY
 |
| 出版日期 | 2024-02-14 |
| 页码 | 29 |
| ISSN号 | 1552-4450 |
| DOI | 10.1038/s41589-024-01555-y |
| 通讯作者 | Zheng, Yueming(zhengyueming@simm.ac.cn) ; Guo, Jiangtao(jiangtaoguo@zju.edu.cn) ; Gao, Zhaobing(zbgao@simm.ac.cn) |
| 英文摘要 | Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects. Zhou et al. developed a specific small-molecule inhibitor of astrocytic Kir4.1 channels, Lys05, which exerts rapid-onset antidepressant effects in rodents without unwanted side effects, indicating Kir4.1 as a promising drug target. |
| WOS关键词 | HIPPOCAMPAL NEUROGENESIS ; SENSORINEURAL DEAFNESS ; MOLECULAR-DYNAMICS ; ASTROGLIAL KIR4.1 ; LATERAL HABENULA ; GLUTAMATE UPTAKE ; CHANNEL SUBUNIT ; KNOCK-OUT ; IN-VIVO ; POTASSIUM |
| 资助项目 | China National Funds for Distinguished Young Scientists[81825021] ; National Science Fund for Distinguished Young Scholars[92169202] ; National Science Fund for Distinguished Young Scholars[2021ZD0200900] ; National Natural Science Foundation of China[2018SHZDZX05] ; Shanghai Municipal Science and Technology Major Project[2020284] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[LG202103-01-06] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[LG202103-01-05] ; Lingang Laboratory ; MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| 出版者 | NATURE PORTFOLIO |
| WOS记录号 | WOS:001162200100004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309587]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zheng, Yueming; Guo, Jiangtao; Gao, Zhaobing |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Coll Pharm, Beijing, Peoples R China 3.Zhejiang Univ, Affiliated Hosp 4, Sch Med, Dept Neurol, Hangzhou, Peoples R China 4.Zhejiang Univ, Affiliated Hosp 4, Sch Med, Dept Biophys, Hangzhou, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China 6.East China Univ Sci & Technol, Sch Pharm, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Shanghai, Peoples R China 7.Henan Univ, Sch Pharm, Kaifeng, Peoples R China 8.Zhejiang Univ, Sch Med, Liangzhu Lab, New Cornerstone Sci Lab, Hangzhou, Peoples R China 9.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Cellular Signaling Lab, Key Lab Mol Biophys,Minist Educ, Wuhan, Peoples R China 10.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Xiaoyu,Zhao, Cheng,Xu, Haiyan,et al. Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses[J]. NATURE CHEMICAL BIOLOGY,2024:29. |
| APA | Zhou, Xiaoyu.,Zhao, Cheng.,Xu, Haiyan.,Xu, Yixiang.,Zhan, Li.,...&Gao, Zhaobing.(2024).Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.NATURE CHEMICAL BIOLOGY,29. |
| MLA | Zhou, Xiaoyu,et al."Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses".NATURE CHEMICAL BIOLOGY (2024):29. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。