Methylation-related metabolic effects of D4 dopamine receptor expression and activation.,Translational Psychiatry

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Methylation-related metabolic effects of D4 dopamine receptor expression and activation.
Translational Psychiatry ( IF 5.8 ) Pub Date : 2019-11-12 , DOI: 10.1038/s41398-019-0630-3
Nathaniel W Hodgson ₁ , Mostafa I Waly ₂ , Malav S Trivedi ₃ , Verna-Ann Power-Charnitsky ₄ , Richard C Deth ₃

Affiliation

D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine synthase (MS). We evaluated the impact of D4R expression on folate-dependent phospholipid methylation (PLM) and MS activity, as well as cellular redox and methylation status, in transfected CHO cells expressing human D4R variants containing 2, 4, or 7 exon III repeats (D4.2R, D4.4R, D4.7R). Dopamine had no effect in non-transfected CHO cells, but increased PLM to a similar extent for both D4.2R- and D4.4R-expressing cells, while the maximal increase was for D4.7R was significantly lower. D4R expression in CHO cells decreased basal MS activity for all receptor subtypes and conferred dopamine-sensitive MS activity, which was greater with a higher number of repeats. Consistent with decreased MS activity, D4R expression decreased basal levels of methylation cycle intermediates methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), as well as cysteine and glutathione (GSH). Conversely, dopamine stimulation increased GSH, SAM, and the SAM/SAH ratio, which was associated with a more than 2-fold increase in global DNA methylation. Our findings illustrate a profound influence of D4R expression and activation on MS activity, coupled with the ability of dopamine to modulate cellular redox and methylation status. These previously unrecognized signaling activities of the D4R provide a unique link between neurotransmission and metabolism.

中文翻译：

D4多巴胺受体表达和激活的甲基化相关代谢作用。

D4多巴胺受体（D4R）激活利用蛋氨酸合酶（MS）提供的叶酸衍生的甲基来独特地促进质膜磷脂的甲基化。我们评估了D4R表达对叶酸依赖性磷脂甲基化（PLM）和MS活性以及细胞氧化还原和甲基化状态的影响，在转染表达含有2、4或7个外显子III重复的人D4R变体的CHO细胞中（D4。 2R，D4.4R，D4.7R）。多巴胺对未转染的CHO细胞无影响，但对于D4.2R和D4.4R表达细胞，PLM均以相似的程度增加，而D4.7R的最大增加则明显更低。CHO细胞中的D4R表达降低了所有受体亚型的基础MS活性，并赋予了多巴胺敏感性MS活性，随着重复次数的增加，这种活性会更高。与MS活性降低一致，D4R表达降低了甲基化循环中间体蛋氨酸，S-腺苷甲硫氨酸（SAM）和S-腺苷同型半胱氨酸（SAH）以及半胱氨酸和谷胱甘肽（GSH）的基础水平。相反，多巴胺刺激可增加GSH，SAM和SAM / SAH比，这与总体DNA甲基化增加2倍以上有关。我们的发现说明了D4R表达和激活对MS活性的深刻影响，以及多巴胺调节细胞氧化还原和甲基化状态的能力。D4R的这些先前无法识别的信号传导活性在神经传递与代谢之间提供了独特的联系。以及半胱氨酸和谷胱甘肽（GSH）。相反，多巴胺刺激可增加GSH，SAM和SAM / SAH比，这与总体DNA甲基化增加2倍以上有关。我们的发现说明了D4R表达和激活对MS活性的深刻影响，以及多巴胺调节细胞氧化还原和甲基化状态的能力。D4R的这些先前无法识别的信号传导活性在神经传递与代谢之间提供了独特的联系。以及半胱氨酸和谷胱甘肽（GSH）。相反，多巴胺刺激可增加GSH，SAM和SAM / SAH比，这与总体DNA甲基化增加2倍以上有关。我们的发现说明了D4R表达和激活对MS活性的深刻影响，以及多巴胺调节细胞氧化还原和甲基化状态的能力。D4R的这些先前无法识别的信号传导活性在神经传递与代谢之间提供了独特的联系。加上多巴胺调节细胞氧化还原和甲基化状态的能力。D4R的这些先前无法识别的信号传导活性在神经传递与代谢之间提供了独特的联系。加上多巴胺调节细胞氧化还原和甲基化状态的能力。D4R的这些先前无法识别的信号传导活性在神经传递与代谢之间提供了独特的联系。

更新日期：2019-11-13

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