Zheng Yang, Wan Xiaoping, Yang Dandan, Ramirez-Navarro Angelina, Liu Haiyan, Fu Ji-Dong, Deschênes Isabelle
Department of Physiology and Cell Biology, Frick Center for Heart Failure and Arrhythmias, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States.
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States.
Front Physiol. 2021 Mar 22;12:661429. doi: 10.3389/fphys.2021.661429. eCollection 2021.
Na1.5, encoded by the gene , is the predominant voltage-gated sodium channel expressed in the heart. It initiates the cardiac action potential and thus is crucial for normal heart rhythm and function. Dysfunctions in Na1.5 have been involved in multiple congenital or acquired cardiac pathological conditions such as Brugada syndrome (BrS), Long QT Syndrome Type 3, and heart failure (HF), all of which can lead to sudden cardiac death (SCD) - one of the leading causes of death worldwide. Our lab has previously reported that Na1.5 forms dimer channels with coupled gating. We also found that Na1.5 BrS mutants can exert a dominant-negative (DN) effect and impair the function of wildtype (WT) channels through coupled-gating with the WT. It was previously reported that reduction in cardiac sodium currents (I), observed in HF, could be due to the increased expression of an splice variant - E28D, which results in a truncated sodium channel (Na1.5-G1642X). In this study, we hypothesized that this splice variant leads to I reduction in HF through biophysical coupling with the WT. We showed that Na1.5-G1642X is a non-functional channel but can interact with the WT, resulting in a DN effect on the WT channel. We found that both WT and the truncated channel Na1.5-G1642X traffic at the cell surface, suggesting biophysical coupling. Indeed, we found that the DN effect can be abolished by difopein, an inhibitor of the biophysical coupling. Interestingly, the sodium channel polymorphism H558R, which has beneficial effect in HF patients, could also block the DN effect. In summary, the HF-associated splice variant Na1.5-G1642X suppresses sodium currents in heart failure patients through a mechanism involving coupled-gating with the wildtype sodium channel.
由该基因编码的Na1.5是心脏中表达的主要电压门控钠通道。它启动心脏动作电位，因此对正常心律和功能至关重要。Na1.5功能障碍与多种先天性或后天性心脏病理状况有关，如Brugada综合征（BrS）、3型长QT综合征和心力衰竭（HF），所有这些都可能导致心脏性猝死（SCD）——全球主要死因之一。我们实验室此前报道Na1.5形成具有耦合门控的二聚体通道。我们还发现，Na1.5 BrS突变体可发挥显性负性（DN）效应，并通过与野生型（WT）的耦合门控损害野生型通道的功能。此前有报道称，在HF中观察到的心脏钠电流（I）降低可能是由于一种剪接变体——E28D表达增加所致，该变体导致钠通道截短（Na1.5-G1642X）。在本研究中，我们假设这种剪接变体通过与WT的生物物理耦合导致HF中的I降低。我们表明，Na1.5-G1642X是一种无功能的通道，但可与WT相互作用，对WT通道产生DN效应。我们发现WT和截短通道Na1.5-G1642X都在细胞表面运输，提示存在生物物理耦合。事实上，我们发现DN效应可被生物物理耦合抑制剂difopein消除。有趣的是，对HF患者有有益作用的钠通道多态性H558R也可阻断DN效应。总之，与HF相关的剪接变体Na1.5-G1642X通过一种涉及与野生型钠通道耦合门控的机制抑制心力衰竭患者的钠电流。
