RT Journal Article
SR Electronic
T1 Selective Activation of TASK-3-containing K<sup>+</sup> Channels Reveals Their Therapeutic Potentials in Analgesia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 657387
DO 10.1101/657387
A1 Ping Liao
A1 Yunguang Qiu
A1 Yiqing Mo
A1 Jie Fu
A1 Zhenpeng Song
A1 Lu Huang
A1 Suwen Bai
A1 Yang Wang
A1 Jia-Jie Zhu
A1 Fuyun Tian
A1 Zhuo Chen
A1 Nanfang Pan
A1 Er-Yi Sun
A1 Linghui Yang
A1 Xi Lan
A1 Yinbin Chen
A1 Dongping Huang
A1 Peihua Sun
A1 Lifen Zhao
A1 Dehua Yang
A1 Weiqiang Lu
A1 Tingting Yang
A1 Junjie Xiao
A1 Wei-Guang Li
A1 Zhaobing Gao
A1 Bing Shen
A1 Qiansen Zhang
A1 Jin Liu
A1 Hualiang Jiang
A1 Ruotian Jiang
A1 Huaiyu Yang
YR 2019
UL http://biorxiv.org/content/early/2019/06/05/657387.abstract
AB The paucity of selective agonists for TASK-3, a member of two-pore domain K+ (K2P) channels, limited our understanding of its biological functions. Targeting a novel druggable transmembrane cavity using 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 homomer and TASK-3/TASK-1 heteromer. CHET3 displayed unexpectedly potent analgesia in vivo in a variety of acute and chronic pain models in rodents that could be abolished by pharmacology or genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique subset population of small-sized, TRPM8, TRPV1 or Tyrosine Hydroxylase positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting the CHET3 analgesia in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a novel druggable target for treating pain.One Sentence Summary Identification of a novel drug target and its new hit compounds for developing new-generation non-opioid analgesics.