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Sci Transl Med. 2019 Nov 20;11(519). pii: eaaw8434. doi: 10.1126/scitranslmed.aaw8434.

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

Author information

1
Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China.
2
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3
University of Chinese Academy of Sciences, Beijing 100049, China.
4
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
5
Department of Physiology, Anhui Medical University, Hefei, Anhui 230032, China.
6
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
7
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
8
Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
9
Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China. hyyang@bio.ecnu.edu.cn ruotianjiang@scu.edu.cn.
10
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China. hyyang@bio.ecnu.edu.cn ruotianjiang@scu.edu.cn.

Abstract

The paucity of selective agonists for TWIK-related acid-sensitive K+ 3 (TASK-3) channel, a member of two-pore domain K+ (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.

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