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首页> 外文期刊>The European Journal of Neuroscience >Regulation of Na+/K+-ATPase by neuron-specific transcription factor Sp4: Implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons
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Regulation of Na+/K+-ATPase by neuron-specific transcription factor Sp4: Implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons

机译：神经元特异性转录因子Sp4对Na + / K + -ATPase的调节：暗示神经元的能量产生，神经元活动和能量消耗紧密耦合

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摘要

A major source of energy demand in neurons is the Na+/K+-ATPase pump that restores the ionic gradient across the plasma membrane subsequent to depolarizing neuronal activity. The energy comes primarily from mitochondrial oxidative metabolism, of which cytochrome c oxidase (COX) is a key enzyme. Recently, we found that all 13 subunits of COX are regulated by specificity (Sp) factors, and that the neuron-specific Sp4, but not Sp1 or Sp3, regulates the expression of key glutamatergic receptor subunits as well. The present study sought to test our hypothesis that Sp4 also regulates Na+/K+-ATPase subunit genes in neurons. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutational analysis, over-expression, and RNA interference studies, we found that Sp4, with minor contributions from Sp1 and Sp3, functionally regulate the Atp1a1, Atp1a3, and Atp1b1 subunit genes of Na+/K+-ATPase in neurons. Transcripts of all three genes were up-regulated by depolarizing KCl stimulation and down-regulated by the impulse blocker tetrodotoxin (TTX), indicating that their expression was activity-dependent. Silencing of Sp4 blocked the up-regulation of these genes induced by KCl, whereas over-expression of Sp4 rescued them from TTX-induced suppression. The effect of silencing or over-expressing Sp4 on primary neurons was much greater than those of Sp1 or Sp3. The binding sites of Sp factors on these genes are conserved among mice, rats and humans. Thus, Sp4 plays an important role in the transcriptional coupling of energy generation and energy consumption in neurons.
机译：神经元中能量需求的主要来源是Na + / K + -ATPase泵，该泵可在使神经元活性去极化后恢复跨质膜的离子梯度。能量主要来自线粒体的氧化代谢，其中细胞色素C氧化酶（COX）是关键酶。最近，我们发现COX的所有13个亚基均受特异性（Sp）因子调节，并且神经元特异性Sp4（而非Sp1或Sp3）也调节关键的谷氨酸能受体亚基的表达。本研究试图检验我们的假设，即Sp4还调节神经元中的Na + / K + -ATPase亚基基因。通过多种方法，包括计算机分析，电泳迁移率迁移和超迁移测定，染色质免疫沉淀，启动子​​突变分析，过表达和RNA干扰研究，我们发现Sp4在Sp1和Sp3的贡献很小，可以在功能上调节神经元中Na + / K + -ATPase的Atp1a1，Atp1a3和Atp1b1亚基基因。通过消极化KCl刺激上调所有三个基因的转录本，并通过脉冲阻断剂河豚毒素（TTX）下调所有三个基因的转录本，表明它们的表达是活性依赖性的。 Sp4的沉默阻止了由KCl诱导的这些基因的上调，而Sp4的过表达使它们摆脱了TTX诱导的抑制作用。 Sp4沉默或过表达对原代神经元的影响远大于Sp1或Sp3。 Sp因子在这些基因上的结合位点在小鼠，大鼠和人类之间是保守的。因此，Sp4在神经元的能量产生和能量消耗的转录偶联中起重要作用。

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