Selective Activation of TASK-3-containing K + Channels Reveals Their Therapeutic Potentials in Analgesia
Selective Activation of TASK-3-containing K + Channels Reveals Their Therapeutic Potentials in Analgesia
ABSTRACT 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 SummaryIdentification of a novel drug target and its new hit compounds for developing new-generation non-opioid analgesics.
Chen Yinbin、Bai Suwen、Liao Ping、Fu Jie、Huang Lu、Wang Yang、Zhu Jia-Jie、Chen Zhuo、Yang Linghui、Lan Xi、Huang Dongping、Sun Peihua、Li Wei-Guang、Gao Zhaobing、Shen Bing、Liu Jin、Yang Huaiyu、Jiang Hualiang、Lu Weiqiang、Tian Fuyun、Song Zhenpeng、Zhang Qiansen、Xiao Junjie、Zhao Lifen、Jiang Ruotian、Mo Yiqing、Yang Dehua、Pan Nanfang、Yang Tingting、Sun Er-Yi、Qiu Yunguang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityDepartment of Physiology, Anhui Medical UniversityLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityDepartment of Physiology, Anhui Medical UniversityCollaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of MedicineLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow UniversityCollaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of MedicineState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Physiology, Anhui Medical UniversityLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityCardiac Regeneration and Ageing Lab, School of Life Science, Shanghai UniversityState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal UniversityState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityCardiac Regeneration and Ageing Lab, School of Life Science, Shanghai UniversityLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan UniversityState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of Sciences
药学基础医学神经病学、精神病学
Chen Yinbin,Bai Suwen,Liao Ping,Fu Jie,Huang Lu,Wang Yang,Zhu Jia-Jie,Chen Zhuo,Yang Linghui,Lan Xi,Huang Dongping,Sun Peihua,Li Wei-Guang,Gao Zhaobing,Shen Bing,Liu Jin,Yang Huaiyu,Jiang Hualiang,Lu Weiqiang,Tian Fuyun,Song Zhenpeng,Zhang Qiansen,Xiao Junjie,Zhao Lifen,Jiang Ruotian,Mo Yiqing,Yang Dehua,Pan Nanfang,Yang Tingting,Sun Er-Yi,Qiu Yunguang.Selective Activation of TASK-3-containing K + Channels Reveals Their Therapeutic Potentials in Analgesia[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/657387.点此复制
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