In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 11, No. 519 ( 2019-11-20)
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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aaw8434
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2019
detail.hit.zdb_id:
2518839-2
detail.hit.zdb_id:
2518854-9
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