Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel
Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel
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血清素以依赖于 ASIC3 通道的非质子配体传感域的方式促进外周疼痛敏感性
DOI：
10.1523/jneurosci.3376-12.2013
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发表时间：
2013
影响因子：
5.3
通讯作者：
Xu Tian-Le
中科院分区：
文献类型：
--
作者：
Wang Xiang;Li Wei-Guang;Yu Ye;Xiao Xian;Cheng Jin;Zeng Wei-Zheng;Peng Zhong;Zhu Michale Xi;Xu Tian-Le
组织酸中毒和炎症介质在炎症性疼痛中起关键作用。细胞外酸中毒激活酸敏感离子通道（asic）， asic是中枢和外周神经系统细胞外质子的关键传感器，在疼痛感觉和传递中起关键作用。此外，炎症介质，如5-羟色胺（5-HT），已知能增强痛觉。然而，质子、炎症介质和asic在痛觉中的功能相互作用尚不清楚。在本研究中，我们发现5-HT，一种经典的促炎介质，特异性地增强由同质ASIC3通道和异质ASIC3/1a和ASIC3/1b通道介导的质子诱发的持续电流，而不是瞬时电流。出乎意料的是，5-HT对ASIC3通道的影响并不涉及5-HT受体的激活，而是通过5-HT和ASIC3通道之间的功能相互作用介导的。我们进一步表明，5-HT对ASIC3通道的影响取决于新发现的非质子配体感应域。最后，通过小鼠舔爪实验发现，5-HT和酸的共同应用显著增加了小鼠的疼痛相关行为，而在ASIC3敲除小鼠中，这种行为在很大程度上被减弱，并被非选择性ASIC抑制剂阿米洛利抑制。总之，这些数据确定了ASIC3通道是5-HT在炎性疼痛感觉中急性作用的意想不到的分子靶点，并揭示了ASIC3通道通过同时检测细胞外质子和炎症介质在调节炎性疼痛中的重要作用。
Tissue acidosis and inflammatory mediators play critical roles in inflammatory pain. Extracellular acidosis activates acid-sensing ion channels (ASICs), which have emerged as key sensors for extracellular protons in the central and peripheral nervous systems and play key roles in pain sensation and transmission. Additionally, inflammatory mediators, such as serotonin (5-HT), are known to enhance pain sensation. However, functional interactions among protons, inflammatory mediators, and ASICs in pain sensation are poorly understood. In the present study, we show that 5-HT, a classical pro-inflammatory mediator, specifically enhances the proton-evoked sustained, but not transient, currents mediated by homomeric ASIC3 channels and heteromeric ASIC3/1a and ASIC3/1b channels. Unexpectedly, the effect of 5-HT on ASIC3 channels does not involve activation of 5-HT receptors, but is mediated via a functional interaction between 5-HT and ASIC3 channels. We further show that the effect of 5-HT on ASIC3 channels depends on the newly identified nonproton ligand sensing domain. Finally, coapplication of 5-HT and acid significantly increased pain-related behaviors as assayed by the paw-licking test in mice, which was largely attenuated in ASIC3 knock-out mice, and inhibited by the nonselective ASIC inhibitor amiloride. Together, these data identify ASIC3 channels as an unexpected molecular target for acute actions of 5-HT in inflammatory pain sensation and reveal an important role of ASIC3 channels in regulating inflammatory pain via coincident detection of extracellular protons and inflammatory mediators.