PDF(Pubmed)
Abstract：
The voltage-gated Na+ channel regulates the initiation and propagation of the action potential in excitable cells. The major cardiac isoform NaV1.5, encoded by SCN5A, comprises a monomer with four homologous repeats (I-IV) that each contain a voltage sensing domain (VSD) and pore domain. In native myocytes, NaV1.5 forms a macromolecular complex with NaVβ subunits and other regulatory proteins within the myocyte membrane to maintain normal cardiac function. Disturbance of the NaV complex may manifest as deadly cardiac arrhythmias. Although SCN5A has long been identified as a gene associated with familial atrial fibrillation (AF) and Brugada Syndrome (BrS), other genetic contributors remain poorly understood. Emerging evidence suggests that mutations in the non-covalently interacting NaVβ1 and NaVβ3 are linked to both AF and BrS. Here, we investigated the molecular pathologies of 8 variants in NaVβ1 and NaVβ3. Our results reveal that NaVβ1 and NaVβ3 variants contribute to AF and BrS disease phenotypes by modulating both NaV1.5 expression and gating properties. Most AF-linked variants in the NaVβ1 subunit do not alter the gating kinetics of the sodium channel, but rather modify the channel expression. In contrast, AF-related NaVβ3 variants directly affect channel gating, altering voltage-dependent activation and the time course of recovery from inactivation via the modulation of VSD activation.
摘要：
电压门控Na通道调节可兴奋细胞中动作电位的启动和传播。主要心脏同工型NaV1.5，由SCN5A编码，包含具有四个同源重复(I-IV)的单体,每个同源重复含有电压感测结构域(VSD)和孔结构域。在天然肌细胞中，NaV1.5与肌细胞膜内的NaVβ亚基和其他调节蛋白形成大分子复合物，以维持正常的心脏功能。NaV复合物的紊乱可能表现为致命的心律失常。尽管SCN5A早已被确定为与家族性心房颤动（AF）和Brugada综合征（BrS）相关的基因，其他遗传因素仍然知之甚少。新出现的证据表明，非共价相互作用的NaVβ1和NaVβ3中的突变与AF和BrS均相关。这里,我们研究了NaVβ1和NaVβ3中8种变体的分子病理学。我们的结果表明，NaVβ1和NaVβ3变体通过调节NaV1.5表达和门控特性而导致AF和BrS疾病表型。在NaVβ1亚单位中的大多数AF连锁变体不改变钠通道的门控动力学,而是修改通道表达式。相比之下,AF相关的NaVβ3变体直接影响通道门控，通过调节VSD激活来改变电压依赖性激活和从失活恢复的时间过程。
