Selective Activation of TASK-3-containing K+ Channels Reveals Their Therapeutic Potentials in Analgesia

Liao, P.; Qiu, Y.; Mo, Y.; Fu, J.; Song, Z.; Huang, L.; Bai, S.; Wang, Y.; Zhu, J. J.; Tian, F.; Chen, Z.; Pan, N.; Sun, E. Y.; Yang, L.; Lan, X.; Chen, Y.; Huang, D.; Sun, P.; Zhao, L.; Yang, D.; Lu, W.; Yang, T.; Xiao, J.; Li, W. G.; Gao, Z.; Shen, B.; Zhang, Q.; Liu, J.; Jiang, H.; Jiang, R.; Yang, H.

doi:10.1101/657387

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bioRxiv · 10.1101/657387

Selective Activation of TASK-3-containing K+ Channels Reveals Their Therapeutic Potentials in Analgesia

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Abstract

The paucity of selective agonists for TASK-3, a member of two-pore domain K+ (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a novel 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 homomer and TASK-3/TASK-1 heteromer. CHET3 displayed unexpectedly potent analgesic effects 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 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.\n\nOne Sentence SummaryIdentification of a novel drug target and its new hit compounds for developing new-generation non-opioid analgesics.

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Liao, P., Qiu, Y., Mo, Y., Fu, J., Song, Z., Huang, L., Bai, S., Wang, Y., Zhu, J. J., Tian, F., Chen, Z., Pan, N., Sun, E. Y., Yang, L., Lan, X., Chen, Y., Huang, D., Sun, P., Zhao, L., Yang, D., Lu, W., Yang, T., Xiao, J., Li, W. G., Gao, Z., Shen, B., Zhang, Q., Liu, J., Jiang, H., Jiang, R., Yang, H.. 2019-06-05. Selective Activation of TASK-3-containing K+ Channels Reveals Their Therapeutic Potentials in Analgesia. https://doi.org/10.1101/657387

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