Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models
Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models
复制标题
选择性激活 TWIK 相关酸敏感 K 3 亚基通道在啮齿动物模型中具有镇痛作用
DOI：
10.1126/scitranslmed.aaw8434
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发表时间：
2019-11-20
影响因子：
17.1
通讯作者：
Yang, Huaiyu
中科院分区：
文献类型：
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作者：
Liao, Ping;Qiu, Yunguang;Yang, Huaiyu
TRAK相关酸敏K+3(TASK-3)通道是两孔结构域K+(K2P)通道的一员，由于缺乏选择性激动剂，导致我们对其生物学功能的了解有限。通过使用基于结构的药物设计方法来定位一个可药物的跨膜腔，我们发现了一种双胍化合物CHET3，它是含有TASK-3的K2P通道的高选择性变构激活剂，包括TASK-3同分异构体和TASK-3/TASK-1异构体。CHET3在各种啮齿动物的急性和慢性疼痛模型中显示出强大的体内止痛作用，这些模型可以通过药物作用或通过基因消融TASK-3来消除。我们进一步发现，包含TASK-3的通道在解剖学上定义了一个独特的小型、瞬时受体势阳离子通道亚家族M成员8(TRPM8)-、瞬时受体势阳离子通道亚家族V成员1(TRPV1)-或酪氨酸羟基酶(TH)阳性的伤害性感觉神经元，并在功能上调节它们的膜兴奋性，支持CHET3在慢性疼痛下的热痛过敏和机械性痛觉过敏中的镇痛作用。总体而言，我们的概念验证研究揭示了包含任务3的K2P通道是治疗疼痛的可用药靶点。
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.