Voltage-gated sodium channel β1 subunit processing: downstream roles in regulating cardiac excitability

德拉韦综合征(DS)是一种严重的儿童癫痫性脑病(EE)，典型的表现为 在生命的第一年。除了癫痫发作，患者还患有行为和发育障碍 延迟、共济失调、智力残疾以及猝死风险增加(约18%) 癫痫(SUDEP)。SUDEP的发病机制尚不清楚，目前尚无生物标志物 目前已知可以识别高危患者。我们研究DS是因为它的SUDEP发生率很高 以更好地了解SUDEP机制。在大多数情况下(&gt；80%)DS与 编码电压门控钠通道(VGSC)亚单位的基因SCN1A和SCN1B 分别编码Nav1.1α亚基和VGSCβ1亚基。SCN1A和SCN1B是 在大脑和心脏中都有表达。β1调节离子通道孔的门控和动力学， 发挥细胞黏附分子(CAM)的作用，启动细胞信号转导。在心室肌细胞中， 磷酸化的β1定位于插入盘并与河豚毒素(TTx)- 不敏感的VGSCα亚单位NaV1.5，而非磷酸化的β1定位于它所在的T管 与TTX敏感的VGSCα亚基、Nav1.1、Nav1.3和Nav1.6相关联。我们建议 DS患者SUDEP的高发生率与神经元兴奋性和心脏 脑和心脏VGSC亚基突变表达所致的心律失常。Scn1b基因缺失小鼠模型 DS.Scn1b基因缺失小鼠心电图QT间期延长，钙离子异常 对TTX敏感的处理，以及增加的瞬变和持续钠电流 急性分离的心室肌细胞。Scn1b基因缺失小鼠的Scn3a和Scn3a表达增加 SCN5A，分别编码Nav1.3和NaV1.5。β亚基是序列的底物 β位点APP裂解酶1(BACE1)和γ分泌酶。序贯卵裂 产生一个可溶性的胞内结构域(ICD)。我们假设β1在心脏中裂解， 其次是β1-icd转位到细胞核，对转录调控是至关重要的 VGSCα亚单位和可能在调节心脏兴奋性方面重要的其他基因。什么时候 β1不像DS那样具有功能，β1介导的转录调节和β1介导的电流 调制被打乱，导致兴奋性和心律失常的变化。了解 β-1介导的心脏信号转导机制可能为治疗心肌梗死提供新的途径 识别和治疗有SUDEP风险的患者。

Dravet syndrome (DS) is a severe, pediatric epileptic encephalopathy (EE) that typically presents in the first year of life. In addition to seizures, patients suffer from behavioral and developmental delay, ataxia, intellectual disability, and an increased risk (~18%) of Sudden Unexpected Death in EPilepsy (SUDEP). The mechanism of SUDEP is not clear and there are no biomarkers currently known to identify at risk patients. We study DS because of its high incidence of SUDEP to better understand SUDEP mechanisms. In most cases (>80%) DS is linked to mutations in genes which encode voltage-gated sodium channel (VGSC) subunits, SCN1A and SCN1B, which encode the Nav1.1 α subunit and the VGSC β1 subunit, respectively. SCN1A and SCN1B are expressed in both brain and heart. β1 regulates gating and kinetics of the ion channel pore, functions as a cell adhesion molecule (CAM), and initiates cell signaling. In ventricular myocytes, phosphorylated β1 localizes to intercalated disks and associates with the tetrodotoxin (TTX)- insensitive VGSC α subunit Nav1.5, while non-phosphorylated β1 localizes to t-tubules where it associates with the TTX-sensitive VGSC α subunits, Nav1.1, Nav1.3 and Nav1.6. We propose the high incidence of SUDEP in DS patients results from neuronal hyperexcitability and cardiac arrhythmia due to expression of mutant VGSC subunits in brain and heart. Scn1b null mice model DS. Scn1b null mice display prolonged QT intervals by electrocardiogram, abnormal calcium handling that is sensitive to TTX, and increased transient and persistent sodium currents in acutely isolated ventricular myocytes. Scn1b null mice show increased expression of Scn3a and Scn5a, encoding Nav1.3 and Nav1.5, respectively. β subunits are substrates for sequential cleavage by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Sequential cleavage generates a soluble intracellular domain (ICD). We hypothesize that β1 cleavage in heart, followed by β1-ICD translocation to the nucleus, is critical for the transcriptional regulation of VGSC α subunits and potentially other genes important in regulating cardiac excitability. When β1 is not functional, as in DS, β1-mediated transcriptional regulation and β1-mediated current modulation are disrupted, resulting in changes in excitability and arrhythmias. Understanding the mechanism of β1-mediated signal transduction in heart may lead to new methods for the identification and treatment of patients at risk of SUDEP.