Chen Zhong-Guo, Wang Yu-Jun, Chen Ruo-Song, Geng Fan, Gan Chen-Ling, Wang Wei-Sheng, Liu Xing, Zhou Hu, He Ling, Hu Gang, Liu Jing-Gen
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Department of Pharmacology, China Pharmaceutical University, Nanjing, 210008, China.
Mol Psychiatry. 2021 Apr;26(4):1162-1177. doi: 10.1038/s41380-019-0533-y. Epub 2019 Oct 1.
Compelling evidence suggests that synaptic structural plasticity, driven by remodeling of the actin cytoskeleton, underlies addictive drugs-induced long-lasting behavioral plasticity. However, the signaling mechanisms leading to actin cytoskeleton remodeling remain poorly defined. DNA methylation is a critical mechanism used to control activity-dependent gene expression essential for long-lasting synaptic plasticity. Here, we provide evidence that DNA methyltransferase DNMT3a is degraded by the E2 ubiquitin-conjugating enzyme Ube2b-mediated ubiquitination in dorsal hippocampus (DH) of rats that repeatedly self-administrated heroin. DNMT3a degradation leads to demethylation in CaMKK1 gene promotor, thereby facilitating CaMKK1 expression and consequent activation of its downstream target CaMKIα, an essential regulator of spinogenesis. CaMKK1/CaMKIα signaling regulates actin cytoskeleton remodeling in the DH and behavioral plasticity by activation of Rac1 via acting Rac guanine-nucleotide-exchange factor βPIX. These data suggest that Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on CaMKK1 gene and thus activates CaMKK1/CaMKIα/βPIX/Rac1 cascade, leading to drug use-induced actin polymerization and behavior plasticity.
有力证据表明，由肌动蛋白细胞骨架重塑驱动的突触结构可塑性是成瘾性药物诱导的持久行为可塑性的基础。然而，导致肌动蛋白细胞骨架重塑的信号机制仍不清楚。DNA甲基化是一种关键机制，用于控制对持久突触可塑性至关重要的活动依赖性基因表达。在这里，我们提供证据表明，在反复自我给药海洛因的大鼠背侧海马（DH）中，DNA甲基转移酶DNMT3a被E2泛素结合酶Ube2b介导的泛素化降解。DNMT3a降解导致CaMKK1基因启动子去甲基化，从而促进CaMKK1表达及其下游靶点CaMKIα的激活，CaMKIα是成棘作用的重要调节因子。CaMKK1/CaMKIα信号通过激活Rac鸟嘌呤核苷酸交换因子βPIX激活Rac1，从而调节DH中的肌动蛋白细胞骨架重塑和行为可塑性。这些数据表明，Ube2b依赖的DNMT3a降解解除了对CaMKK1基因的转录抑制，从而激活CaMKK1/CaMKIα/βPIX/Rac1级联反应，导致药物使用诱导的肌动蛋白聚合和行为可塑性。
