ASIC3, a sensor of acidic and primary inflammatory pain
ASIC3, a sensor of acidic and primary inflammatory pain
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DOI：
10.1038/emboj.2008.213
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发表时间：
2008-11-19
期刊：
影响因子：
11.4
通讯作者：
Lingueglia, Eric
中科院分区：
文献类型：
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作者：
Deval, Emmanuel;Noel, Jacques;Lingueglia, Eric
酸敏感离子通道（ASIC）是由细胞外酸中毒激活的阳离子通道，在中枢和外周神经系统中表达。尽管外周ASIC似乎是酸性疼痛的天然传感器（例如，在炎症、局部缺血、病变或肿瘤中），仍然缺乏直接的证明。我们发现，类似60%的大鼠皮肤感觉神经元表达ASIC3样电流。天然以及重组ASIC3协同响应三种不同的炎症信号，即轻微酸化（类似于pH 7.0），高渗和花生四烯酸（AA）。中度pH，单独或与高渗和AA组合，增加伤害感受器兴奋性并产生由毒素APETx 2（ASIC3的特异性阻断剂）抑制的疼痛。APETx2和用特异性siRNA体内敲低ASIC3也对大鼠中原发性炎症诱导的痛觉过敏具有有效的镇痛作用。因此，外周ASIC 3通道是酸性疼痛的重要传感器和炎症期间产生的分子信号的整合剂，在炎症期间它们促成原发性痛觉过敏。
Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular acidosis that are expressed in both central and peripheral nervous systems. Although peripheral ASICs seem to be natural sensors of acidic pain (e.g., in inflammation, ischaemia, lesions or tumours), a direct demonstration is still lacking. We show that similar to 60% of rat cutaneous sensory neurons express ASIC3-like currents. Native as well as recombinant ASIC3 respond synergistically to three different inflammatory signals that are slight acidifications (similar to pH 7.0), hypertonicity and arachidonic acid (AA). Moderate pH, alone or in combination with hypertonicity and AA, increases nociceptors excitability and produces pain suppressed by the toxin APETx2, a specific blocker of ASIC3. Both APETx2 and the in vivo knockdown of ASIC3 with a specific siRNA also have potent analgesic effects against primary inflammation-induced hyperalgesia in rat. Peripheral ASIC3 channels are thus essential sensors of acidic pain and integrators of molecular signals produced during inflammation where they contribute to primary hyperalgesia.