Ghosh Krishna, Huang Yuying, Chen Shao-Rui, Pan Hui-Lin
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Biol Chem. 2024 Nov;300(11):107848. doi: 10.1016/j.jbc.2024.107848. Epub 2024 Sep 30.
The development of chronic neuropathic pain involves complex synaptic and epigenetic mechanisms. Nerve injury causes sustained upregulation of α2δ-1 (encoded by the Cacna2d1 gene) in the dorsal root ganglion (DRG), contributing to pain hypersensitivity by directly interacting with and augmenting presynaptic NMDA receptor activity in the spinal dorsal horn. Under normal conditions, histone deacetylase 2 (HDAC2) is highly enriched at the Cacna2d1 gene promoter in the DRG, which constitutively suppresses Cacna2d1 transcription. However, nerve injury leads to HDAC2 dissociation from the Cacna2d1 promoter, promoting the enrichment of active histone marks and Cacna2d1 transcription in primary sensory neurons. In this study, we determined the mechanism by which nerve injury diminishes HDAC2 occupancy at the Cacna2d1 promoter in the DRG. Spinal nerve injury in rats increased serine-394 phosphorylation of HDAC2 in the DRG. Coimmunoprecipitation showed that nerve injury enhanced the physical interaction between HDAC2 and casein kinase II (CK2) in the DRG. Furthermore, repeated intrathecal treatment with CX-4945, a potent and specific CK2 inhibitor, markedly reversed nerve injury-induced pain hypersensitivity, HDAC2 phosphorylation, and α2δ-1 expression levels in the DRG. In addition, treatment with CX-4945 largely restored HDAC2 enrichment at the Cacna2d1 promoter and reduced the elevated levels of acetylated H3 and H4 histones, particularly H3K9ac and H4K5ac, at the Cacna2d1 promoter in the injured DRG. These findings suggest that nerve injury increases CK2 activity and CK2-HDAC2 interactions, which enhance HDAC2 phosphorylation in the DRG. This, in turn, diminishes HDAC2 enrichment at the Cacna2d1 promoter, thereby promoting Cacna2d1 transcription.
慢性神经性疼痛的发展涉及复杂的突触和表观遗传机制。神经损伤导致背根神经节（DRG）中α2δ-1（由Cacna2d1基因编码）持续上调，通过直接与脊髓背角的突触前NMDA受体活性相互作用并增强其活性，导致疼痛超敏反应。在正常情况下，组蛋白脱乙酰酶2（HDAC2）在DRG中的Cacna2d1基因启动子处高度富集，其组成性抑制Cacna2d1转录。然而，神经损伤导致HDAC2从Cacna2d1启动子解离，促进活性组蛋白标记的富集和初级感觉神经元中Cacna2d1的转录。在本研究中，我们确定了神经损伤减少DRG中Cacna2d1启动子处HDAC2占据的机制。大鼠脊髓神经损伤增加了DRG中HDAC2的丝氨酸-394磷酸化。免疫共沉淀显示神经损伤增强了DRG中HDAC2与酪蛋白激酶II（CK2）之间的物理相互作用。此外，用强效特异性CK2抑制剂CX-4945进行反复鞘内治疗，可显著逆转神经损伤诱导的疼痛超敏反应、HDAC2磷酸化以及DRG中α2δ-1的表达水平。此外，CX-4945治疗在很大程度上恢复了HDAC2在Cacna2d1启动子处的富集，并降低了损伤DRG中Cacna2d1启动子处乙酰化H3和H4组蛋白，特别是H3K9ac和H4K5ac的升高水平。这些发现表明，神经损伤增加了CK2活性和CK2-HDAC2相互作用，从而增强了DRG中HDAC2的磷酸化。这反过来又减少了HDAC2在Cacna2d1启动子处的富集，从而促进Cacna2d1转录。
