Selective activation of TWIK-related acid-sensitive K + 3 subunit–containing channels is analgesic in rodent models

作者：Ping Liao, Yunguang Qiu, Yiqing Mo, Jie Fu, Zhenpeng Song, Lu Huang, Suwen Bai, Yang Wang, Jia‐Jie Zhu, Fuyun Tian, Zhuo Chen, Nanfang Pan, Er-Yi Sun, Linghui Yang, Xi Lan, Yinbin Chen, Dongping Huang, Peihua Sun, Lifen Zhao, Dehua Yang, Weiqiang Lü, Tingting Yang, Junjie Xiao, Wei‐Guang Li, Zhaobing Gao, Bing Shen, Qiansen Zhang, Jin Liu, Hualiang Jiang, Ruotian Jiang, Huaiyu Yang · 发表于：Science Translational Medicine · 年份：2019 · DOI：10.1126/scitranslmed.aaw8434 · 被引用次数：92 · 研究领域：Ion channel regulation and function、Neuroscience and Neuropharmacology Research、Ion Transport and Channel Regulation

(K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3-containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)-, transient receptor potential cation channel subfamily V member 1 (TRPV1)-, or tyrosine hydroxylase (TH)-positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a druggable target for treating pain.