Activation of peripheral KCNQ channels relieves gout pain
文献类型：期刊论文
| 作者 | Zheng, Yueming; Xu, Haiyan; Zhan, Li; Zhou, Xindi; Chen, Xueqin; Gao, Zhaobing
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| 刊名 | PAIN
 |
| 出版日期 | 2015-06 |
| 卷号 | 156期号:6页码:1025-1035 |
| 关键词 | KCNQ Benzbromarone Peripheral nervous system Gout Pain |
| ISSN号 | 0304-3959 |
| DOI | 10.1097/j.pain.0000000000000122 |
| 文献子类 | Article |
| 英文摘要 | Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK). Benzbromarone consistently attenuates BK-, formalin-, or monosodium urate induced inflammatory pain in rat and mouse models. Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout. |
| WOS关键词 | GATED POTASSIUM CHANNELS ; ANTICONVULSANT RETIGABINE ; SENSORY NEURONS ; VOLTAGE-SENSOR ; K+ CHANNELS ; URATE ARTHRITIS ; KV7 CHANNELS ; ANKLE JOINT ; RATS ; FLUPIRTINE |
| 资助项目 | State Key Program of Basic Research of China[2013CB910604] ; National Science and Technology Major Project on "Key New Drug Creation and Manufacturing Program"[2013ZX09103001-016] ; National Natural Science Foundation of China[81123004] ; National Natural Science Foundation of China[61327014] ; National Natural Science Foundation of China[61175103] ; Shanghai Municipal Science and Technology Commission[13JC1406700] ; External Cooperation Program of BIC, Chinese Academy of Sciences[1536631KYSB20130003] |
| WOS研究方向 | Anesthesiology ; Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000355642900009 |
| 出版者 | LIPPINCOTT WILLIAMS & WILKINS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276509]  |
| 专题 | 神经药理学研究国际科学家工作站 |
| 通讯作者 | Gao, Zhaobing |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zheng, Yueming,Xu, Haiyan,Zhan, Li,et al. Activation of peripheral KCNQ channels relieves gout pain[J]. PAIN,2015,156(6):1025-1035. |
| APA | Zheng, Yueming,Xu, Haiyan,Zhan, Li,Zhou, Xindi,Chen, Xueqin,&Gao, Zhaobing.(2015).Activation of peripheral KCNQ channels relieves gout pain.PAIN,156(6),1025-1035. |
| MLA | Zheng, Yueming,et al."Activation of peripheral KCNQ channels relieves gout pain".PAIN 156.6(2015):1025-1035. |
入库方式： OAI收割
来源：上海药物研究所
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