Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Gunma, Japan.
J Neurochem. 2013 Oct;127(1):66-77. doi: 10.1111/jnc.12362. Epub 2013 Jul 29.
Growth factors and nutrients, such as amino acids and glucose, regulate mammalian target of rapamycin complex 1 (mTORC1) signaling and subsequent translational control in a coordinated manner. Brain-derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, activates mTORC1 and induces phosphorylation of its target, p70S6 kinase (p70S6K), at Thr389 in neurons. BDNF also increases mammalian target of rapamycin-dependent novel protein synthesis in neurons. Here, we report that BDNF-induced p70S6K activation is dependent on glucose, but not amino acids, sufficiency in cultured cortical neurons. AMP-activated protein kinase (AMPK) is the molecular background to this specific nutrient dependency. Activation of AMPK, which is induced by glucose deprivation, treatment with pharmacological agents such as 2-deoxy-D-glucose, metformin, and 5-aminoimidazole-4-carboxamide ribonucleoside or forced expression of a constitutively active AMPKα subunit, counteracts BDNF-induced phosphorylation of p70S6K and enhanced protein synthesis in cortical neurons. These results indicate that AMPK inhibits the effects of BDNF on mTORC1-mediated translation in neurons.
生长因子和营养物质，如氨基酸和葡萄糖，以协调的方式调节哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号及其随后的翻译控制。脑源性神经营养因子（BDNF）是大脑中最突出的神经营养因子，可激活 mTORC1，并在神经元中诱导其靶标 p70S6 激酶（p70S6K）的 Thr389 磷酸化。BDNF 还增加了神经元中哺乳动物雷帕霉素依赖性新蛋白质的合成。在这里，我们报告 BDNF 诱导的 p70S6K 激活依赖于培养的皮质神经元中葡萄糖的充足，但不依赖于氨基酸。 AMP 激活的蛋白激酶（AMPK）是这种特定营养依赖性的分子基础。葡萄糖剥夺诱导的 AMPK 激活、用 2-脱氧-D-葡萄糖、二甲双胍和 5-氨基咪唑-4-羧酰胺核苷等药物处理或强制表达组成型激活的 AMPKα亚单位，可拮抗 BDNF 诱导的 p70S6K 磷酸化和增强皮质神经元中的蛋白质合成。这些结果表明 AMPK 抑制了 BDNF 对神经元中 mTORC1 介导的翻译的影响。
