Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Neurochem Int. 2011 Oct;59(5):610-7. doi: 10.1016/j.neuint.2011.04.013. Epub 2011 Jun 6.
Methyl CpG-binding protein-2 (MeCP2) is a transcriptional regulator that binds to methylated DNA at CpG sites and functions to silence DNA transcription. MeCP2 is subject to the phosphorylation modification at serine 421 (S421), which releases MeCP2 from DNA and thus facilitates gene expression. As a transcriptional repressor densely expressed in limbic reward circuits of adult mammalian brains, MeCP2 is recently emerging as a critical epigenetic factor in experience-dependent neural plasticity and psychostimulant addiction. In this study, we investigated the regulation of MeCP2 phosphorylation in the rat striatum by the psychostimulant cocaine in vivo. We found that acute systemic injection of cocaine increased MeCP2 phosphorylation at S421 in the rat striatum, including both the caudate putamen and the nucleus accumbens, while cocaine did not affect MeCP2 phosphorylation in the medial prefrontal cortex. The cocaine-stimulated MeCP2 phosphorylation in the nucleus accumbens was a rapid and transient event, as it was evident at 20 min and returned to normal levels 3h after drug injection. The cocaine effect in the caudate putamen was however relatively delayed. Reliable induction of MeCP2 phosphorylation in this region was detected at 60 min. Pretreatment with an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist significantly reduced the cocaine-stimulated MeCP2 phosphorylation in the caudate putamen, although not in the nucleus accumbens. Our data support that MeCP2 is a sensitive target of psychostimulants. Its phosphorylation status is regulated by psychostimulant exposure. NMDA receptors play a region-specific role in linking cocaine to MeCP2 phosphorylation in striatal neurons in vivo.
甲基化 CpG 结合蛋白 2（MeCP2）是一种转录调节因子，它可以与 CpG 位点的甲基化 DNA 结合，并发挥沉默 DNA 转录的作用。MeCP2 可在丝氨酸 421（S421）处发生磷酸化修饰，这种修饰可以使 MeCP2 从 DNA 上释放，从而促进基因表达。MeCP2 在成年哺乳动物大脑的边缘奖赏回路中高度表达，作为一种转录抑制因子，它最近被认为是经验依赖性神经可塑性和精神兴奋剂成瘾的关键表观遗传因子。在这项研究中，我们研究了体内精神兴奋剂可卡因对大鼠纹状体中 MeCP2 磷酸化的调节。我们发现，急性全身注射可卡因可增加大鼠纹状体中 MeCP2 的 S421 磷酸化，包括尾状核和伏隔核，而可卡因对内侧前额叶皮层中的 MeCP2 磷酸化没有影响。可卡因刺激的伏隔核中 MeCP2 磷酸化是一个快速而短暂的事件，因为它在 20 分钟时明显，并在药物注射 3 小时后恢复到正常水平。然而，可卡因在尾状核中的作用相对延迟。在 60 分钟时可以检测到该区域中 MeCP2 磷酸化的可靠诱导。N-甲基-D-天冬氨酸（NMDA）谷氨酸受体拮抗剂的预处理显著降低了尾状核中可卡因刺激的 MeCP2 磷酸化，尽管对伏隔核没有影响。我们的数据支持 MeCP2 是精神兴奋剂的敏感靶点。其磷酸化状态受精神兴奋剂暴露的调节。NMDA 受体在体内纹状体神经元中发挥特定区域的作用，将可卡因与 MeCP2 磷酸化联系起来。
