HDAC2, but not HDAC1, regulates Kv1.2 expression to mediate neuropathic pain in CCI rats
HDAC2, but not HDAC1, regulates Kv1.2 expression to mediate neuropathic pain in CCI rats
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HDAC2（而非 HDAC1）调节 Kv1.2 表达以介导 CCI 大鼠的神经性疼痛
DOI：
10.1016/j.neuroscience.2019.03.033
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发表时间：
2019-06-01
期刊：
影响因子：
3.3
通讯作者：
Zang, Weidong
中科院分区：
文献类型：
--
作者：
Li, Zhihua;Guo, Yanyan;Zang, Weidong
钾离子通道亚基1.2（Kv1.2）在背根神经节（DRG）的表达影响神经元的兴奋性，参与神经病理性疼痛（NPP）的诱导和发展，但Kv1.2在NPP中下调的分子机制尚不清楚。组蛋白去乙酰化酶（HDAC）抑制剂的报告，以减轻与NPP大鼠的疼痛超敏反应的发展。HDAC抑制剂是否有助于调节Kv1.2的表达，以及哪种特定的HDAC亚基参与NPP，仍有待研究。本研究通过建立慢性缩窄性损伤（CCI）模型，采用Western blot、实时荧光定量PCR、免疫组化、鞘内注射和siRNA等方法，探讨HDAC亚基参与调控Kv1.2表达从而介导NPP的机制。我们的研究结果表明，神经损伤导致HDAC1在DRG中的表达上调，以及HDAC2在DRG和脊髓中的表达上调。双标记免疫荧光组织化学显示，Kv1.2主要与HDAC2共定位，但不是HDAC1，在NF200阳性的大神经元的DRG。鞘内注射HDAC抑制剂辛二酰苯胺异羟肟酸可减轻CCI大鼠的机械和热过敏反应，并逆转CCI大鼠Kv1.2表达的下降。此外，在该模型中，用HDAC2而不是HDAC1 siRNA治疗也减轻了机械和热超敏反应，并上调了Kv1.2表达。体外转染PC12细胞证实，只有HDAC2 siRNA能调控Kv1.2的表达。这些发现表明，HDAC2，而不是HDAC1，参与NPP通过调节Kv1.2的表达。(C)2019作者（S）由Elsevier Ltd代表IBRO出版。
The expression of potassium ion channel subunit 1.2 (Kv1.2) in the dorsal root ganglion (DRG) influences the excitability of neurons, which contributes to the induction and development of neuropathic pain (NPP); however, the molecular mechanisms underlying the downregulation of Kv1.2 in NPP remain unknown. Histone deacetylase (HDAC) inhibitors are reported to attenuate the development of pain hypersensitivity in rats with NPP. Whether HDAC inhibitors contribute to regulation of Kv1.2 expression, and which specific HDAC subunit is involved in NPP, remain unexplored. In this study we established a chronic constrictive injury (CCI) model and used western blot, quantitative real-time PCR, immunostaining, intrathecal injection, and siRNA methods to explore which HDAC subunit is involved in regulating Kv1.2 expression to mediate NPP. Our results demonstrated that nerve injury led to upregulation of HDAC1 expression in the DRG, and of HDAC2 in the DRG and spinal cord. Double-labeling immunofluorescence histochemistry showed that Kv1.2 principally co-localized with HDAC2, but not HDAC1, in NF200-positive large neurons of the DRG. Intrathecal injection with the HDAC inhibitor, suberoylanilide hydroxamic acid, attenuated mechanical and thermal hypersensitivity and reversed the decreased expression of Kv1.2 in rats with CCI. Furthermore, treatment with HDAC2, but not HDAC1, siRNA also relieved mechanical and thermal hypersensitivity and upregulated the Kv1.2 expression in this model. In vitro trans-fection of PC12 cells with HDAC2 and HDAC1 siRNA confirmed that only HDAC2 siRNA could regulate the expression of Kv1.2. These findings suggest that HDAC2, but not HDAC1, is involved in NPP through regulation of Kv1.2 expression. (C) 2019 The Author(s). Published by Elsevier Ltd on behalf of IBRO.