2. Academic Validation
  3. Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses

Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses

  • Nat Chem Biol. 2024 Feb 14. doi: 10.1038/s41589-024-01555-y.
Xiaoyu Zhou # 1 2,  Cheng Zhao # 3,  Haiyan Xu # 1 4,  Yixiang Xu 5,  Li Zhan 1,  Pei Wang 1,  Jingyi He 1 6,  Taotao Lu 5,  Yueling Gu 1,  Yan Yang 7,  Chanjuan Xu 8,  Yiyang Chen 8,  Yuxuan Liu 8,  Yue Zeng 1,  Fuyun Tian 9,  Qian Chen 3,  Xin Xie 1,  Jianfeng Liu 8,  Hailan Hu 7,  Jian Li 5,  Yueming Zheng 10,  Jiangtao Guo 11,  Zhaobing Gao 12 13 14 15 16
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 College of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.
  • 3 Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 5 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 6 School of Pharmacy, Henan University, Kaifeng, China.
  • 7 Liangzhu Laboratory, Zhejiang University School of Medicine, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou, China.
  • 8 Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhengyueming@simm.ac.cn.
  • 11 Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. jiangtaoguo@zju.edu.cn.
  • 12 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zbgao@simm.ac.cn.
  • 13 College of Pharmacy, University of Chinese Academy of Sciences, Beijing, China. zbgao@simm.ac.cn.
  • 14 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. zbgao@simm.ac.cn.
  • 15 School of Pharmacy, Henan University, Kaifeng, China. zbgao@simm.ac.cn.
  • 16 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. zbgao@simm.ac.cn.
  • # Contributed equally.
PMID: 38355723 DOI: 10.1038/s41589-024-01555-y
Abstract

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.

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