Wu Xin, Li Yawei, Hong Liang
Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.
Department of Preventive Medicine, Northwestern University, Chicago, IL, United States.
Front Physiol. 2022 Jul 5;13:904664. doi: 10.3389/fphys.2022.904664. eCollection 2022.
The voltage-gated sodium channel Na1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Na1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Na1.5 mutations vary across race-ethnic groups. Here we investigated an Asian-specific mutation Na1.5-P1090L associated with LQT syndrome. We found that Na1.5-P1090L mutation perturbed the sodium channel function. It altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by P1090L. Mexiletine also modified the recovery from steady-state inactivation and the development of inactivation of P1090L. It rescued the dysfunctional inactivation of P1090L and reduced the P1090L channel's availability.
电压门控钠通道Na1.5在心肌细胞动作电位的产生和传导中起着至关重要的作用。Na1.5的突变与长QT综合征、Brugada综合征和心律失常性猝死综合征有关。遗传学研究表明，Na1.5突变在不同种族群体中存在差异。在此，我们研究了一种与长QT综合征相关的亚洲特异性突变Na1.5-P1090L。我们发现，Na1.5-P1090L突变扰乱了钠通道功能。它改变了通道的门控过程，并表现出增强的窗电流。美西律治疗可逆转由P1090L产生的稳态失活的去极化偏移。美西律还改变了P1090L从稳态失活中的恢复以及失活的发展。它挽救了P1090L功能失调的失活，并降低了P1090L通道的可用性。
