Using fluorescence to understand β subunit-NaV channel interactions.
Using fluorescence to understand β subunit-NaV channel interactions.
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使用荧光来了解 β 亚基-NaV 通道相互作用。
DOI：
10.1085/jgp.201711843
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Larsson,HPeter
中科院分区：
文献类型：
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作者：
Barro-Soria,Rene;Liin,SaraI;Larsson,HPeter
人类电压门控钠通道NaV 1。5在人类心脏中起着关键作用，在其中它产生心肌细胞去极化的基础的内向钠电流。NAV1。5蛋白由2，000多个氨基酸组成，组织成四个同源结构域（卡特拉尔等人，2017），其使通道配备有一个中心孔域和四个外围电压传感器域。在人类心脏中，Nav 1。5与其他几种蛋白质相互作用形成大分子复合物。重要的相互作用伴侣是四个β亚基（β1-4），每个亚基都有一个跨膜片段、一个细胞外N末端和一个细胞内C末端（Abriel，2010）。所有四种β亚基都在心脏中表达，并调节NaV 1的运输和生物物理特性。5，尽管不同β亚基的功能作用仍存在争议（Abriel，2010）。校正NaV 1的电压依赖性和动力学。5通道激活和失活，以及正确的NaV 1。5通道密度，对心脏功能至关重要。因此，编码NaV 1的基因中的突变。5与心律失常有关，包括Brugada综合征、3型长QT综合征和心脏传导疾病（Veerman等人，2015）。此外，编码β1-4的基因中的多个突变与改变的NaV 1相关。5功能和心律失常（Abriel，2010）。在这个问题上，Silva及其同事研究了β1和β3调节NaV 1活性的机制。5.β1和β3与NaV 1非共价结合。5（与共价结合的β2和β4相反），并且先前已显示改变通道失活的电压依赖性。然而，这些变化的方向和幅度并不是决定性的，并且似乎随表达系统而变化（Abriel，2010）。此外，对β1和β3如何与NaV 1相互作用的分子理解。5改变电压依赖性仍然很差。在他们的工作在这个问题上，朱等。使用光学方法来解决其中的一些问题。β亚基如何调节NaV 1的分子见解。5通道功能对于我们理解每个β亚基的生理相关性以及突变如何干扰NaV 1非常重要。5-β亚基相互作用。
The human voltage-gated sodium channel NaV1. 5 plays a critical role in the human heart, in which it generates inward sodium currents that underlie cardiomyocyte depolarization. The NaV1. 5 protein is composed of more than 2,000 amino acids, organized into four homologous domains (Catterall et al., 2017), which equip the channel with one central pore domain and four peripheral voltage sensor domains. In the human heart, NaV1. 5 interacts with several other proteins to form a macromolecular complex. Among important interaction partners are the four β subunits (β1–4), which each have one transmembrane segment, an extracellular N terminus, and an intracellular C terminus (Abriel, 2010). All four β subunits are expressed in the heart and modulate the trafficking and biophysical properties of NaV1. 5, although the functional effect of the different β subunits are still debated (Abriel, 2010). Correct voltage dependence and kinetics of NaV1. 5 channel activation and inactivation, together with correct NaV1. 5 channel density in the plasma membrane, are critical for cardiac function. As a consequence, mutations in the gene encoding NaV1. 5 have been linked to cardiac arrhythmias, including Brugada syndrome, Long QT Syndrome type 3, and cardiac conduction disease (Veerman et al., 2015). Moreover, multiple mutations in the genes encoding β1–4 have been associated with altered NaV1. 5 function and cardiac arrhythmias (Abriel, 2010). In this issue, Silva and co-workers study the mechanism by which β1 and β3 modulate the activity of NaV1. 5. β1 and β3 are noncovalently bound to NaV1. 5 (in contrast to β2 and β4, which are covalently bound) and have previously been shown to shift the voltage dependence of channel inactivation. However, the direction and magnitude of these shifts are not conclusive and appear to vary with expression system (Abriel, 2010). Moreover, the molecular understanding of how β1 and β3 interact with NaV1. 5 to alter voltage dependence has remained poor. In their work in this issue, Zhu et al. use optical approaches to resolve some of these questions. Molecular insights into how β subunits modulate NaV1. 5 channel function are important for our understanding of the physiological relevance of each β subunit and how mutations interfere with NaV1. 5–β subunit interactions.