Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain
Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain
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DOI：
10.1172/jci68996
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发表时间：
2013-07-01
影响因子：
15.9
通讯作者：
Decosterd, Isabelle
中科院分区：
文献类型：
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作者：
Laedermann, Cedric J.;Cachemaille, Matthieu;Decosterd, Isabelle
周围神经性疼痛是一种由神经损伤引起的致残状态。其特征是背根神经节（DRG）感觉神经元中表达的电压门控钠通道（Na(v)s）的失调。Na(v)s表达改变的机制尚不清楚。本研究探讨了E3泛素连接酶NEDD4-2在小鼠神经性疼痛发病机制中的作用，该酶已知能泛素化Na(v)s。采用外伤性神经损伤所致神经性疼痛的SNI模型，采用Na(v)1.7特异性抑制剂ProTxII，可分离Na(v)1.7介导的电流。SNI降低了DRG细胞内NEDD4-2的表达，增加了Na(v)1.7和Na(v)1.8电流的振幅。Na(v)1.7通道向外周轴突重新分布。在Nedd4L基因敲除小鼠（SNS-Nedd4L(-/-)）的伤害性DRG神经元中也观察到类似的变化。SNS-Nedd4L（-/-）小鼠在注射福尔马林后表现出热超敏反应和第二疼痛期增强。利用重组腺相关病毒（rAAV2/6）修复DRG神经元内NEDD4-2的表达，不仅降低了Na(v)1.7和Na(v)1.8电流幅值，而且减轻了sni诱导的机械异常性痛。这些发现表明NEDD4-2是Nays的一个有效的翻译后调节因子，NEDD4-2的下调可导致DRG神经元的高兴奋性，并参与病理性疼痛的发生。
Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Na(v)s) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Na(v)s, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1.7-specific inhibitor, ProTxII, allowed the isolation of Na(v)1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na(v)1.7 and Na(v)1.8 currents. The redistribution of Na(v)1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L(-/-)). SNS-Nedd4L(-/-) mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na(v)1.7 and Na(v)1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Nays and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.