Epigenetic restoration of voltage‐gated potassium channel Kv1.2 alleviates nerve injury‐induced neuropathic pain,Journal of Neurochemistry

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Epigenetic restoration of voltage‐gated potassium channel Kv1.2 alleviates nerve injury‐induced neuropathic pain
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-07-03 , DOI: 10.1111/jnc.15117
Jingjing Zhang ₁ , Lina Rong ₁ , Jinping Shao ₁ , Yidan Zhang ₁ , Yaping Liu ₁ , Sen Zhao ₁ , Lei Li ₁ , Wenli Yu ₁ , Mengya Zhang ₁ , Xiuhua Ren ₁ , Qingzan Zhao ₁ , Changlian Zhu _{2,

3,

4,

5} , Huan Luo _{1,

6} , Weidong Zang _{1,

2} , Jing Cao _{1,

2}

Affiliation

Voltage‐gated potassium channels (Kv) are important regulators of neuronal excitability for its role of regulating resting membrane potential and repolarization. Recent studies show that Kv channels participate in neuropathic pain, but the detailed underlying mechanisms are far from being clear. In this study, we used siRNA, miR‐137 agomir, and antagomir to regulate the expression of Kv1.2 in spinal cord and dorsal root ganglia (DRG) of naïve and chronic constriction injury (CCI) rats. Kv currents and neuron excitability in DRG neurons were examined by patch‐clamp whole‐cell recording to verify the change in Kv1.2 function. The results showed that Kv1.2 was down‐regulated in DRG and spinal dorsal horn (SDH) by CCI. Knockdown of Kv1.2 by intrathecally injecting Kcna2 siRNA induced significant mechanical and thermal hypersensitivity in naïve rats. Concomitant with the down‐regulation of Kv1.2 was an increase in the expression of the miR‐137. The targeting and regulating of miR‐137 on Kcna2 was verified by dual‐luciferase reporter system and intrathecal injecting miR‐137 agomir. Furthermore, rescuing the expression of Kv1.2 in CCI rats, achieved through inhibiting miR‐137, restored the abnormal Kv currents and excitability in DRG neurons, and alleviated mechanical allodynia and thermal hyperalgesia. These results indicate that the miR‐137‐mediated Kv1.2 impairment is a crucial etiopathogenesis for the nerve injury‐induced neuropathic pain and can be a novel potential therapeutic target for neuropathic pain management.

中文翻译：

电压门控钾通道 Kv1.2 的表观遗传修复可减轻神经损伤引起的神经性疼痛

电压门控钾通道 (Kv) 是神经元兴奋性的重要调节剂，因为它具有调节静息膜电位和复极化的作用。最近的研究表明，Kv 通道参与了神经性疼痛，但详细的潜在机制还远未清楚。在本研究中，我们使用 siRNA、miR-137 agomir 和 antagomir 来调节幼稚和慢性缩窄性损伤 (CCI) 大鼠脊髓和背根神经节 (DRG) 中 Kv1.2 的表达。通过膜片钳全细胞记录检查 DRG 神经元中的 Kv 电流和神经元兴奋性，以验证 Kv1.2 功能的变化。结果表明，Kv1.2 在 DRG 和脊髓背角 (SDH) 中被 CCI 下调。通过鞘内注射 Kcna2 击倒Kv1.2siRNA 在幼稚大鼠中引起显着的机械和热超敏反应。伴随 Kv1.2 下调的是 miR-137 表达的增加。通过双荧光素酶报告系统和鞘内注射 miR-137 agomir 验证了miR-137 对Kcna2的靶向和调节。此外，通过抑制 miR-137 来挽救 CCI 大鼠中 Kv1.2 的表达，恢复 DRG 神经元的异常 Kv 电流和兴奋性，并缓解机械性异常性疼痛和热痛觉过敏。这些结果表明 miR-137 介导的 Kv1.2 损伤是神经损伤诱导的神经性疼痛的关键发病机制，并且可以成为神经性疼痛管理的新潜在治疗靶点。

更新日期：2020-07-03

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