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Papers of the Week

Papers: 23 Nov 2019 - 29 Nov 2019

Animal Studies, Pharmacology/Drug Development

2019 Nov 20

Sci Transl Med



Editor's Pick

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


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, et al.
Sci Transl Med. 2019 Nov 20; 11(519).
PMID: 31748231.


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.