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.

重度抑郁症是一种普遍且严重的精神疾病，需要开发新型速效抗抑郁药。外侧缰核星形细胞内向整流钾通道 4.1 (Kir4.1) 的基因抑制可改善小鼠抑郁样表型。然而，Kir4.1 仍然是抑郁症难以捉摸的药物靶点。在这里，我们通过高通量筛选发现了一系列Kir4.1抑制剂。 Lys05 是迄今为止最有效的一种，可有效抑制天然 Kir4.1 通道，同时对速效抗抑郁药的既定靶点表现出高选择性。低温电子显微镜结构与电生理学特征相结合显示 Lys05 直接结合在 Kir4.1 的中央腔中。值得注意的是，单剂量的 Lys05 逆转了 Kir4.1 驱动的抑郁样表型，并在多种典型抑郁症啮齿动物模型中发挥快速起效（最早 1 小时）的抗抑郁作用，其功效与 ( S )-氯胺酮相当。总体而言，我们提供了一个概念证明，即 Kir4.1 是快速起效抗抑郁作用的一个有希望的目标。