Angsutararux Paweorn, Zhu Wandi, Voelker Taylor L, Silva Jonathan R
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States.
Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Front Pharmacol. 2021 Nov 19;12:761275. doi: 10.3389/fphar.2021.761275. eCollection 2021.
The voltage-gated Na channel regulates the initiation and propagation of the action potential in excitable cells. The major cardiac isoform Na1.5, encoded by , comprises a monomer with four homologous repeats (I-IV) that each contain a voltage sensing domain (VSD) and pore domain. In native myocytes, Na1.5 forms a macromolecular complex with Naβ subunits and other regulatory proteins within the myocyte membrane to maintain normal cardiac function. Disturbance of the Na complex may manifest as deadly cardiac arrhythmias. Although 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 Naβ1 and Naβ3 are linked to both AF and BrS. Here, we investigated the molecular pathologies of 8 variants in Naβ1 and Naβ3. Our results reveal that Naβ1 and Naβ3 variants contribute to AF and BrS disease phenotypes by modulating both Na1.5 expression and gating properties. Most AF-linked variants in the Naβ1 subunit do not alter the gating kinetics of the sodium channel, but rather modify the channel expression. In contrast, AF-related Naβ3 variants directly affect channel gating, altering voltage-dependent activation and the time course of recovery from inactivation via the modulation of VSD activation.
电压门控钠通道调节可兴奋细胞中动作电位的起始和传播。主要的心脏亚型Na1.5由[基因名称未给出]编码，它包含一个具有四个同源重复序列（I-IV）的单体，每个重复序列都包含一个电压传感结构域（VSD）和孔道结构域。在天然心肌细胞中，Na1.5与Naβ亚基和心肌细胞膜内的其他调节蛋白形成大分子复合物，以维持正常的心脏功能。钠复合物的紊乱可能表现为致命的心律失常。尽管[基因名称未给出]长期以来一直被认为是与家族性心房颤动（AF）和Brugada综合征（BrS）相关的基因，但其他遗传因素仍知之甚少。新出现的证据表明，非共价相互作用的Naβ1和Naβ3中的突变与AF和BrS都有关联。在这里，我们研究了Naβ1和Naβ3中8种变体的分子病理学。我们的结果表明，Naβ1和Naβ3变体通过调节Na1.5的表达和门控特性，导致AF和BrS疾病表型。Naβ1亚基中大多数与AF相关的变体不会改变钠通道的门控动力学，而是会改变通道的表达。相比之下，与AF相关的Naβ3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中恢复的时间进程。
