Shao Dongmin, Okuse Kenji, Djamgoz Mustafa B A
Division of Cell and Molecular Biology, Neuroscience Solutions to Cancer Research Group, Imperial College London, South Kensington Campus, London, UK.
Int J Biochem Cell Biol. 2009 Jul;41(7):1471-81. doi: 10.1016/j.biocel.2009.01.016. Epub 2009 Feb 2.
Voltage-gated sodium channels (VGSCs), classically known to play a central role in excitability and signalling in nerves and muscles, have also been found to be expressed in a range of 'non-excitable' cells, including lymphocytes, fibroblasts and endothelia. VGSC abnormalities are associated with various diseases including epilepsy, long-QT syndrome 3, Brugada syndrome, sudden infant death syndrome and, more recently, various human cancers. Given their pivotal role in a wide range of physiological and pathophysiological processes, regulation of functional VGSC expression has been the subject of intense study. An emerging theme is post-translational regulation and macro-molecular complexing by protein-protein interactions and intracellular trafficking, leading to changes in functional VGSC expression in plasma membrane. This partially involves endoplasmic reticulum associated degradation and ubiquitin-proteasome system. Several proteins have been shown to associate with VGSCs. Here, we review the interactions involving VGSCs and the following proteins: p11, ankyrin, syntrophin, beta-subunit of VGSC, papin, ERM and Nedd4 proteins. Protein kinases A and C, as well as Ca(2+)-calmodulin dependent kinase II that have also been shown to regulate intracellular trafficking of VGSCs by changing the balance of externalization vs. internalization, and an effort is made to separate these effects from the short-term phosphorylation of mature proteins in plasma membrane. Two further modulatory mechanisms are reciprocal interactions with the cytoskeleton and, late-stage, activity-dependent regulation. Thus, the review gives an updated account of the range of post-translational molecular mechanisms regulating functional VGSC expression. However, many details of VGSC subtype-specific regulation and pathophysiological aspects remain unknown and these are highlighted throughout for completeness.
电压门控钠通道（VGSCs），传统上已知其在神经和肌肉的兴奋性及信号传导中起核心作用，现已发现其也在一系列“非兴奋性”细胞中表达，包括淋巴细胞、成纤维细胞和内皮细胞。VGSC异常与多种疾病相关，包括癫痫、长QT综合征3型、Brugada综合征、婴儿猝死综合征，以及最近发现的各种人类癌症。鉴于其在广泛的生理和病理生理过程中的关键作用，功能性VGSC表达的调控一直是深入研究的主题。一个新出现的主题是通过蛋白质-蛋白质相互作用和细胞内运输进行的翻译后调控和大分子复合，导致质膜中功能性VGSC表达发生变化。这部分涉及内质网相关降解和泛素-蛋白酶体系统。已有几种蛋白质被证明与VGSCs相关。在此，我们综述涉及VGSCs与以下蛋白质的相互作用：p11、锚蛋白、肌营养不良素、VGSC的β亚基、木瓜蛋白酶、ERM和Nedd4蛋白。蛋白激酶A和C，以及钙调蛋白依赖性激酶II也已被证明可通过改变外向化与内化的平衡来调节VGSCs的细胞内运输，并努力将这些作用与质膜中成熟蛋白质的短期磷酸化作用区分开来。另外两种调节机制是与细胞骨架的相互作用以及后期的活性依赖性调节。因此，本综述更新了对调节功能性VGSC表达的翻译后分子机制范围的阐述。然而，VGSC亚型特异性调节和病理生理方面的许多细节仍不清楚，为了完整性，这些在全文中都有强调。
