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The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology.

ABSTRACT: The gene SCN5A encodes the main cardiac sodium channel NaV1.5. This channel predominates the cardiac sodium current, INa, which underlies the fast upstroke of the cardiac action potential. As such, it plays a crucial role in cardiac electrophysiology. Over the last 60years a tremendous amount of knowledge regarding its function at the electrophysiological and molecular level has been acquired. Furthermore, genetic studies have shown that mutations in SCN5A are associated with multiple cardiac diseases (e.g. Brugada syndrome, Long QT syndrome, conduction disease and cardiomyopathy), while genetic variation in the general population has been associated with differences in cardiac conduction and risk of arrhythmia through genome wide association studies. In this review we aim to give an overview of the current knowledge (and the gaps therein) on SCN5A and NaV1.5.

SUBMITTER: Veerman CC

PROVIDER: S-EPMC6636349 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology.

Veerman Christiaan C CC Wilde Arthur A M AA Lodder Elisabeth M EM

Gene 20150908 2

The gene SCN5A encodes the main cardiac sodium channel NaV1.5. This channel predominates the cardiac sodium current, INa, which underlies the fast upstroke of the cardiac action potential. As such, it plays a crucial role in cardiac electrophysiology. Over the last 60years a tremendous amount of knowledge regarding its function at the electrophysiological and molecular level has been acquired. Furthermore, genetic studies have shown that mutations in SCN5A are associated with multiple cardiac di ...[more]

PMID: 26361848

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Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p.

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Small GTPases SAR1A and SAR1B regulate the trafficking of the cardiac sodium channel Nav1.5.

Project description:BACKGROUND:The cardiac sodium channel Nav1.5 is essential for the physiological function of the heart and causes cardiac arrhythmias and sudden death when mutated. Many disease-causing mutations in Nav1.5 cause defects in protein trafficking, a cellular process critical to the targeting of Nav1.5 to cell surface. However, the molecular mechanisms underlying the trafficking of Nav1.5, in particular, the exit from the endoplasmic reticulum (ER) for cell surface trafficking, remain poorly understood. METHODS AND RESULTS:Here we investigated the role of the SAR1 GTPases in trafficking of Nav1.5. Overexpression of dominant-negative mutant SAR1A (T39N or H79G) or SAR1B (T39N or H79G) significantly reduces the expression level of Nav1.5 on cell surface, and decreases the peak sodium current density (INa) in HEK/Nav1.5 cells and neonatal rat cardiomyocytes. Simultaneous knockdown of SAR1A and SAR1B expression by siRNAs significantly reduces the INa density, whereas single knockdown of either SAR1A or SAR1B has minimal effect. Computer modeling showed that the three-dimensional structure of SAR1 is similar to RAN. RAN was reported to interact with MOG1, a small protein involved in regulation of the ER exit of Nav1.5. Co-immunoprecipitation showed that SAR1A or SAR1B interacted with MOG1. Interestingly, knockdown of SAR1A and SAR1B expression abolished the MOG1-mediated increases in both cell surface trafficking of Nav1.5 and the density of INa. CONCLUSIONS:These data suggest that SAR1A and SAR1B are the critical regulators of trafficking of Nav1.5. Moreover, SAR1A and SAR1B interact with MOG1, and are required for MOG1-mediated cell surface expression and function of Nav1.5.

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Characterization of the cardiac sodium channel SCN5A mutation, N1325S, in single murine ventricular myocytes.

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| S-EPMC1773013 | biostudies-literature

NF-kappaB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II.

Project description:Angiotensin II (ANG II) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac Na(+) channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that ANG II-mediated oxidative stress may modulate Na(+) channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with ANG II (100 nmol/l) or H(2)O(2) (10 micromol/l) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in Na(+) current, respectively (P < or = 0.01). By quantitative real-time RT-PCR, the cardiac Na(+) channel (scn5a) mRNA abundance declined by 47.3% (P < 0.01) in H9c2 myocytes treated for 48 h with 100 nmol/l ANG II. A similar change occurred with 20 micromol/l H(2)O(2) (46.9%, P < 0.01) after 48 h. Comparable effects were seen in acutely isolated ventricular myocytes. The effects of ANG II could be inhibited by prior treatment of H9c2 cells with scavengers of reactive oxygen species or an inhibitor of the NADPH oxidase. Mutation of the scn5a promoter NF-kappaB binding site prevented decreased activity in response to ANG II and H(2)O(2). Gel shift and chromosomal immunoprecipitation assays confirmed that nuclear factor (NF)-kappaB bound to the scn5a promoter in response to ANG II and H(2)O(2). Overexpression of the p50 subunit of NF-kappaB in H9c2 cells reduced scn5a mRNA (77.3%, P < 0.01). In conclusion, ANG II can decrease scn5a transcription and current. This effect appears to be through production of H(2)O(2) resulting in NF-kappaB binding to the Na(+) channel promoter.

| S-EPMC3150844 | biostudies-literature

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