Research ArticlePain

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

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Science Translational Medicine  20 Nov 2019:
Vol. 11, Issue 519, eaaw8434
DOI: 10.1126/scitranslmed.aaw8434

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A pain-relieving task(3)

Potassium channels play a major role in determining neuronal excitability, and recent evidence suggests a major role for potassium currents in the pathophysiology of acute and chronic pain. In a new study, Liao et al. developed and characterized a selective agonist for TWIK-related acid-sensitive K+ 3 (TASK-3) channel called CHET3, with analgesic properties. Systemic administration of CHET3 in rodent models of acute and chronic pain had potent analgesic activity by reducing nociceptive neuron excitability. The results suggest that TASK-3 might be an effective therapeutic target for treating acute and chronic pain.

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.

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