Neurobiology Division, Cell Biology & Physiology Department, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032, India.
Mol Neurobiol. 2019 Apr;56(4):2685-2702. doi: 10.1007/s12035-018-1260-0. Epub 2018 Jul 27.
Docosahexaenoic acid (DHA), an important ω-3 fatty acid, is abundantly present in the central nervous system and is important in every step of brain development. Much of this knowledge has been based on studies of the role of DHA in the function of the neurons, and reports on its effect on the glial cells are few and far between. We have previously reported that DHA facilitates astrocyte differentiation in primary culture. We have further explored the signaling mechanism associated with this event. It was observed that a sustained activation of the extracellular signal-regulated kinase (ERK) appeared to be critical for DHA-induced differentiation of the cultured astrocytes. Prior exposure to different endocytic inhibitors blocked both ERK activation and differentiation of the astrocytes during DHA treatment suggesting that the observed induction of ERK-2 was purely endosomal. Unlike the β-adrenergic receptor (β-AR) antagonist, atenolol, pre-treatment of the cells with the β-adrenergic receptor (β-AR) antagonist, ICI-118,551 inhibited the DHA-induced differentiation process, indicating a downstream involvement of β-AR in the differentiation process. qRT-PCR and western blot analysis demonstrated a significant induction in the mRNA and protein expression of β-AR at 18-24 h of DHA treatment, suggesting that the induction of β-AR may be due to transcriptional upregulation. Moreover, DHA caused activation of PKA at 6 h, followed by activation of downstream cAMP response element-binding protein, a known transcription factor for β-AR. Altogether, the observations suggest that DHA upregulates β-AR in astrocytes, which undergo endocytosis and signals for sustained endosomal ERK activation to drive the differentiation process.
二十二碳六烯酸（DHA），一种重要的ω-3 脂肪酸，在中枢神经系统中大量存在，对大脑发育的每一个步骤都很重要。这方面的大部分知识是基于 DHA 对神经元功能的作用研究得出的，而关于其对神经胶质细胞的影响的报道却很少。我们之前曾报道过 DHA 可促进原代培养的星形胶质细胞分化。我们进一步探讨了与这一事件相关的信号机制。结果表明，细胞外信号调节激酶（ERK）的持续激活对于 DHA 诱导的培养星形胶质细胞分化似乎是至关重要的。先前的研究表明，不同的内吞作用抑制剂的预先暴露会阻断 DHA 处理期间 ERK 的激活和星形胶质细胞的分化，这表明观察到的 ERK-2 的诱导是纯粹的内体。与β-肾上腺素能受体（β-AR）拮抗剂，阿替洛尔不同，细胞先用β-肾上腺素能受体（β-AR）拮抗剂，ICI-118,551 预处理，可抑制 DHA 诱导的分化过程，这表明β-AR 在下游参与了分化过程。qRT-PCR 和 Western blot 分析表明，在 DHA 处理 18-24 小时后，β-AR 的 mRNA 和蛋白表达显著增加，表明β-AR 的诱导可能是由于转录上调。此外，DHA 在 6 小时引起 PKA 的激活，随后激活下游 cAMP 反应元件结合蛋白，这是β-AR 的已知转录因子。总的来说，这些观察结果表明，DHA 在星形胶质细胞中上调β-AR，β-AR 发生内吞作用并发出持续的内体 ERK 激活信号，从而驱动分化过程。
