GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions
GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions
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癫痫发作和生酮饮食条件下 GAPDH 介导的钠通道 Scn1a 和 Scn3a 基因的转录后调控
DOI：
10.1016/j.neuropharm.2016.11.002
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发表时间：
2017-02-01
影响因子：
4.7
通讯作者：
Long, Yue-Sheng
中科院分区：
文献类型：
--
作者：
Lin, Guo-Wang;Lu, Ping;Long, Yue-Sheng
钠通道SCN1A和SCN3A基因的异常表达改变了神经兴奋性，这被认为是癫痫发病机制的一部分，具有复发性癫痫发作的长期风险。生酮饮食（KD）是一种高脂肪和低碳水化合物治疗儿童难以控制（难治性）癫痫的方法，已被认为可以逆转基因表达模式。在这里，我们揭示了GAPDH在癫痫和KD条件下对小鼠Scn1a和Scn3a表达的转录后调控中的新作用。我们发现GAPDH结合到人和小鼠SCN1A和SCN3A基因3' UTR的一个保守区域，分别通过SCN1A 3' UTR和SCN3A 3' UTR影响mRNA的稳定性，从而降低和增加基因的表达。在癫痫小鼠中，GAPDH的上调和磷酸化增强了其与3' UTR的结合，导致Scn1a下调，Scn3a上调。此外，给药KD会产生β -羟基丁酸，通过削弱GAPDH与Scn1a和Scn3a的结合来挽救Scn1a和Scn3a的异常表达。综上所述，这些数据表明gapdh介导的钠通道基因表达调控可能与癫痫和KD的抗惊厥作用有关。(C) 2016 Elsevier Ltd.版权所有。
Abnormal expressions of sodium channel SCN1A and SCN3A genes alter neural excitability that are believed to contribute to the pathogenesis of epilepsy, a long-term risk of recurrent seizures. Ketogenic diet (KD), a high-fat and low-carbohydrate treatment for difficult-to-control (refractory) epilepsy in children, has been suggested to reverse gene expression patterns. Here, we reveal a novel role of GAPDH on the posttranscriptional regulation of mouse Scn1a and Scn3a expressions under seizure and KD conditions. We show that GAPDH binds to a conserved region in the 3' UTRs of human and mouse SCN1A and SCN3A genes, which decreases and increases genes' expressions by affecting mRNA stability through SCN1A 3' UTR and SCN3A 3' UTR, respectively. In seizure mice, the upregulation and phosphorylation of GAPDH enhance its binding to the 3' UTR, which lead to downregulation of Scn1a and upregulation of Scn3a. Furthermore, administration of KD generates beta-hydroxybutyric acid which rescues the abnormal expressions of Scn1a and Scn3a by weakening the GAPDH's binding to the element. Taken together, these data suggest that GAPDH-mediated expression regulation of sodium channel genes may be associated with epilepsy and the anticonvulsant action of KD. (C) 2016 Elsevier Ltd. All rights reserved.