Article
作者: Gao, Zhaobing ; Hu, Hailan ; Tian, Fuyun ; Zhao, Cheng ; Xu, Haiyan ; Lu, Taotao ; Wang, Pei ; Liu, Yuxuan ; Xu, Yixiang ; Zheng, Yueming ; Yang, Yan ; Liu, Jianfeng ; Zhou, Xiaoyu ; Chen, Yiyang ; Zhan, Li ; Chen, Qian ; He, Jingyi ; Zeng, Yue ; Xu, Chanjuan ; Gu, Yueling ; Li, Jian ; Xie, Xin ; Guo, Jiangtao
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.