| First Author | Liao P | Year | 2019 |
| Journal | Sci Transl Med | Volume | 11 |
| Issue | 519 | PubMed ID | 31748231 |
| Mgi Jnum | J:283506 | Mgi Id | MGI:6385738 |
| Doi | 10.1126/scitranslmed.aaw8434 | Citation | Liao P, et al. (2019) Selective activation of TWIK-related acid-sensitive K(+) 3 subunit-containing channels is analgesic in rodent models. Sci Transl Med 11(519) |
| abstractText | 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. |
