文献类型：期刊文献

英文题名：Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses

作者：Zhou, Xiaoyu[1,2];Zhao, Cheng[3,4];Xu, Haiyan[1,5];Xu, Yixiang[6];Zhan, Li[1];Wang, Pei[1];He, Jingyi[1,7];Lu, Taotao[6];Gu, Yueling[1];Yang, Yan[8];Xu, Chanjuan[9];Chen, Yiyang[9];Liu, Yuxuan[9];Zeng, Yue[1];Tian, Fuyun[10];Chen, Qian[3,4];Xie, Xin[1];Liu, Jianfeng[9];Hu, Hailan[8];Li, Jian[6];Zheng, Yueming[1];Guo, Jiangtao[3,4];Gao, Zhaobing[1,2,5,7,10]

机构：[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

年份：2024

卷号：20

期号：7

外文期刊名：NATURE CHEMICAL BIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001162200100004)】；

基金：We thank Y. Li and F. Guo for assistance with in vivo electrophysiology. We thank C. Xie for advice on renal metabolism experiments. Z.G. is supported by the National Science Fund for Distinguished Young Scholars (grant no. 81825021), the National Natural Science Foundation of China (grant no. 92169202), the National Science and Technology Innovation 2030 Major Program (grant no. 2021ZD0200900) and the Shanghai Municipal Science and Technology Major Project (grant no. 2018SHZDZX05). Y. Zheng is supported by the Youth Innovation Promotion Association of the Chinese Academy of Sciences (grant no. 2020284) and the Lingang Laboratory (grant nos. LG202103-01-06, LG202103-01-05). J.G. is supported by MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University.

语种：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.