Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids
Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids
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DOI：
10.15252/embj.201592335
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发表时间：
2016-02-15
期刊：
影响因子：
11.4
通讯作者：
Deval, Emmanuel
中科院分区：
文献类型：
--
作者：
Marra, Sebastien;Ferru-Clement, Romain;Deval, Emmanuel
细胞外pH变化被视为触发酸敏感离子通道（ASIC）激活的主要内源性信号，酸敏感离子通道（ASIC）基本上被认为是质子传感器，并且参与与组织酸化相关的各种过程。在这里，我们表明，人类疼痛的炎性渗出物，显示非酸性pH值，诱导人ASIC 3通道的缓慢组成性激活。这种效应主要是由脂质驱动的，我们将溶血磷脂酰胆碱（LPC）和花生四烯酸（AA）确定为在没有任何细胞外酸化的情况下ASIC3的内源性激活剂。LPC和AA的组合在生理pH 7.4下在DRG神经元中引起稳健的去极化电流，增加伤害性C纤维放电，并诱导大鼠的疼痛行为，这些作用都被ASIC 3阻断剂阻止。在ASIC3基因敲除小鼠中，脂质诱导的疼痛也显著减少。这些发现为在没有组织pH变化的情况下ASIC3的作用以及这些通道对脂质介导的信号传导的贡献开辟了新的视角。
Extracellular pH variations are seen as the principal endogenous signal that triggers activation of Acid-Sensing Ion Channels (ASICs), which are basically considered as proton sensors, and are involved in various processes associated with tissue acidification. Here, we show that human painful inflammatory exudates, displaying nonacidic pH, induce a slow constitutive activation of human ASIC3 channels. This effect is largely driven by lipids, and we identify lysophosphatidylcholine (LPC) and arachidonic acid (AA) as endogenous activators of ASIC3 in the absence of any extracellular acidification. The combination of LPC and AA evokes robust depolarizing current in DRG neurons at physiological pH 7.4, increases nociceptive C-fiber firing, and induces pain behavior in rats, effects that are all prevented by ASIC3 blockers. Lipid-induced pain is also significantly reduced in ASIC3 knockout mice. These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid-mediated signaling.