ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain.
ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain.
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DOI：
10.1126/sciadv.ade9931
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发表时间：
2023-03-29
期刊：
影响因子：
13.6
通讯作者：
Qiu, Zhaozhu
中科院分区：
文献类型：
--
作者：
Chu, Jiachen;Yang, Junhua;Zhou, Yuan;Chen, Jianan;Chen, Kevin Hong;Zhang, Chi;Cheng, Henry Yi;Koylass, Nicholas;Liu, Jun O.;Guan, Yun;Qiu, Zhaozhu
周围神经损伤后，细胞外5‘-三磷酸腺苷(ATP)介导的嘌呤能信号转导通路在脊髓小胶质细胞激活和神经病理性疼痛中起关键作用。然而，对ATP释放的机制仍知之甚少。在这里，我们发现体积调节的阴离子通道(Vrac)是一种ATP释放通道，并被小胶质细胞中的炎性介质1-磷酸鞘氨醇(S1P)激活。小胶质细胞特异性缺失Swell1(也称为Lrrc8a)的小鼠，vrac的一个基本亚基，减少了周围神经损伤引起的脊髓细胞外ATP的增加。突变小鼠还表现出脊髓小胶质细胞减少，背角神经元过度活跃，以及诱发和自发的神经病理性疼痛行为。我们进一步进行了高通量筛选，并确定FDA批准的药物地库马洛尔是一种新的、有效的vrac抑制剂。鞘内注射Diumarol可减轻小鼠神经损伤所致的机械性痛觉过敏。我们的发现表明，小胶质细胞中释放ATP的vrac是神经病理性疼痛的关键脊髓决定因素，也是这种衰弱疾病的潜在治疗靶点。小胶质细胞中的大孔离子通道SWELL1释放三磷酸腺苷，调节小鼠的神经病理性疼痛行为。
Following peripheral nerve injury, extracellular adenosine 5′-triphosphate (ATP)–mediated purinergic signaling is crucial for spinal cord microglia activation and neuropathic pain. However, the mechanisms of ATP release remain poorly understood. Here, we show that volume-regulated anion channel (VRAC) is an ATP-releasing channel and is activated by inflammatory mediator sphingosine-1-phosphate (S1P) in microglia. Mice with microglia-specific deletion of Swell1 (also known as Lrrc8a), a VRAC essential subunit, had reduced peripheral nerve injury–induced increase in extracellular ATP in spinal cord. The mutant mice also exhibited decreased spinal microgliosis, dorsal horn neuronal hyperactivity, and both evoked and spontaneous neuropathic pain–like behaviors. We further performed high-throughput screens and identified an FDA-approved drug dicumarol as a novel and potent VRAC inhibitor. Intrathecal administration of dicumarol alleviated nerve injury–induced mechanical allodynia in mice. Our findings suggest that ATP-releasing VRAC in microglia is a key spinal cord determinant of neuropathic pain and a potential therapeutic target for this debilitating disease. SWELL1, a large-pore ion channel, in microglia releases ATP and regulates neuropathic pain-like behaviors in mice.
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影响因子：
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作者：
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DOI：
10.1007/s00424-016-1794-9
发表时间：
2016-05
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
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作者：
Deng W;Mahajan R;Baumgarten CM;Logothetis DE
通讯作者：
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