GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions.
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 β-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.
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Guo-Wang
GW
Lin
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Ping
P
Lu
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Tao
T
Zeng
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Hui-Ling
HL
Tang
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Yong-Hong
YH
Chen
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Shu-Jing
SJ
Liu
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Mei-Mei
MM
Gao
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Qi-Hua
QH
Zhao
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China.
Yong-Hong
YH
Yi
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 501260, China. Electronic address: longyuesheng@gzhmu.edu.cn.
Yue-Sheng
YS
Long
D000818:Animals; D045744:Cell Line, Tumor; D055423:Diet, Ketogenic / Q000379:methods; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000235:genetics*; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000235:genetics*; D011485:Protein Binding / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012640:Seizures / Q000178:diet therapy* / Q000235:genetics* / Q000378:metabolism; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C424715:SCN3A protein, human; D015222:Sodium Channels; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases
Glyceraldehyde-3-phosphate dehydrogenase; Ketogenic diet; Posttranscriptional regulation; Seizure; Sodium channel