DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

被引：176

作者：

Zhao, Jian-Yuan ^{[1
,2
]}

Liang, Lingli ^{[1
]}

Gu, Xiyao ^{[1
]}

Li, Zhisong ^{[1
,3
]}

Wu, Shaogen ^{[1
]}

Sun, Linlin ^{[1
]}

Atianjoh, Fidelis E. ^{[1
,4
]}

Feng, Jian ^{[5
,6
]}

Mo, Kai ^{[1
]}

Jia, Shushan ^{[1
]}

Lutz, Brianna Marie ^{[1
]}

Bekker, Alex ^{[1
]}

Nestler, Eric J. ^{[5
,6
]}

Tao, Yuan-Xiang ^{[1
,3
,7
,8
]}

机构：

[1] Rutgers State Univ, New Jersey Med Sch, Dept Anesthesiol, Newark, NJ 07103 USA

[2] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200438, Peoples R China

[3] Zhengzhou Univ, Affiliated Hosp 1, Dept Anesthesiol, Zhengzhou 450052, Henan, Peoples R China

[4] Howard Univ, Coll Med, Dept Anat, Washington, DC 20059 USA

[5] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[7] Rutgers State Univ, New Jersey Med Sch, Dept Cell Biol, Newark, NJ 07103 USA

[8] Rutgers State Univ, New Jersey Med Sch, Dept Mol Med & Physiol, Dept Pharmacol & Neurosci, Newark, NJ 07103 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

中国国家自然科学基金;

关键词：

PRIMARY SENSORY NEURONS; PERIPHERAL-NERVE INJURY; ROOT GANGLION NEURONS; POSTSYNAPTIC DENSITY-93 PROTEIN; ALPHA-GENE EXPRESSION; RAT SCIATIC-NERVE; POTASSIUM CHANNELS; EPIGENETIC REGULATION; PERSISTENT PAIN; DOWN-REGULATION;

D O I：

10.1038/ncomms14712

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. DNA methylation represses gene expression. Here, we report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna2 promoter region and rescues Kcna2 expression in the injured DRG and attenuates neuropathic pain. Conversely, in the absence of nerve injury, mimicking this increase reduces the Kcna2 promoter activity, diminishes Kcna2 expression, decreases Kv current, increases excitability in DRG neurons and leads to spinal cord central sensitization and neuropathic pain symptoms. These findings suggest that DNMT3a may contribute to neuropathic pain by repressing Kcna2 expression in the DRG.

引用

页数：15

共 57 条

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Spinal cord protein interacting with C kinase 1 is required for the maintenance of complete Freund's adjuvant-induced inflammatory pain but not for incision-induced post-operative pain [J].