title: Transcription of the human sodium channel SCN1A gene is repressed by a scaffolding protein RACK1.
abstract: Voltage-gated sodium channel α subunit type I (Nav1.1, encoded by SCN1A gene) plays a critical role in the initiation of action potential in the central nervous system. Downregulated expression of SCN1A is believed to be associated with epilepsy. Here, we found that the SCN1A promoter (P1c), located at the 5' untranslated exon 1c, drove the reporter gene expression in human NT2 cells, and a region between nt +53 and +62 downstream of the P1c promoter repressed the promoter activity. Further analyses showed that a scaffolding protein RACK1 (receptor for activated C kinase 1) was involved in binding to this silencer. Knockdown of RACK1 expression in NT2 cells deprived the repressive role of the silencer on the P1c promoter and increased SCN1A transcription, suggesting the potential involvement of RACK1 in negatively regulating SCN1A transcription via interaction with the silencer. Furthermore, we demonstrated that the binding of the protein complex including RACK1 to the SCN1A promoter motif was decreased in neuron-like differentiation of the NT2 cells induced by retinoic acid and resulted in the upregulation of SCN1A transcription. Taken together, this study reports a novel role of RACK1 in regulating SCN1A expression that participates in retinoic acid-induced neuronal differentiation of NT2 cells.
authors.affiliation: Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, 510260, China.
authors.forename: Zhao-Fei
authors.initials: ZF
authors.lastname: Dong
authors.forename: Ling-Jia
authors.initials: LJ
authors.lastname: Tang
authors.forename: Guang-Fei
authors.initials: GF
authors.lastname: Deng
authors.forename: Tao
authors.initials: T
authors.lastname: Zeng
authors.forename: Shu-Jing
authors.initials: SJ
authors.lastname: Liu
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Wan
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Qi-Hua
authors.initials: QH
authors.lastname: Zhao
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Yi
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Liao
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Long
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C419368:RACK1 protein, human; D012333:RNA, Messenger; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C568242:SCN1A protein, human; D014212:Tretinoin; D019204:GTP-Binding Proteins