Tandem Promoters and Developmentally Regulated 5′- and 3′-mRNA Untranslated Regions of the Mouse Scn5a Cardiac Sodium Channel

Abstract

The SCN5A gene encodes a voltage-sensitive sodium channel expressed in cardiac and skeletal muscle. Coding region mutations cause cardiac sudden death syndromes and conduction system failure. Polymorphisms in the 5-sequence adjacent to the SCN5A gene have been linked to cardiac arrhythmias. We identified three alternative 5-splice variants (1A, 1B, and 1C) of the untranslated exon 1 and two 3-variants in the murine Scn5a mRNA. Two of the exon 1 isoforms (1B and 1C) were novel when compared with the published human and rat SCN5A sequences. Quantitative real time PCR results showed that the abundance of the isoforms varied during cardiac development. The 1A, 1B, and 1C mRNA splice variants increased 7.8 ؎ 1.7-fold (E1A), 6.0 ؎ 1.0-fold (E1B), and 20.6 ؎ 3.7-fold (E1C) from fetal to adult heart, respectively. Promoter deletion and luciferase reporter gene analysis using cardiac and skeletal muscle cell lines demonstrated a pattern of distinct cardiac-specific enhancer elements associated with exons 1A and 1C. In the case of exon 1C, the enhancer element appeared to be within the exon. A 5-repressor preceded each cardiac enhancer element. We concluded that the murine Na ؉ channel has both 5-and 3-untranslated region mRNA variants that are developmentally regulated and that the promoter region contains two distinct cardiac-specific enhancer regions. The presence of homologous human splicing suggests that that these regions may be fruitful new areas of study in understanding cardiac sodium channel regulation and the genetic susceptibility to sudden death.

Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

“…To reveal the functional role of Nav1.7 channel expression in IDC, we demonstrated that expression of the Nav1.7 channel in (38,39). Furthermore, they are also implicated as key regulators of intracellular pH and cell migration (40,41).…”

Oxidative Stress Markers Are Associated with Persistent Atrial Fibrillation

“…Recently, we have shown that the cardiac sodium channel (SCN5a) promoter region contains an NF-B response element that could lead to Na ϩ channel transcriptional regulation by an NF-B-dependent mechanism (16 ).…”

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

“…Previously, we have defined the scn5a promoter region (36). For these experiments, a new promoter construct that contained the NF-B consensus binding site was used to test the effect of treatments on scn5a transcription.…”

“…NF-B is a known redox-sensitive transcription factor (50). Previously, we have shown that the promoter region of the cardiac Na ϩ channel contains one NF-B consensus binding sequence (36). Therefore, we investigated whether NF-B might be involved in the ANG II-or H 2 O 2 -mediated Na ϩ channel transcriptional regulation.…”

“…Recently, we (36) described the cardiac Na ϩ channel promoter region, and sequence examination showed a consensus binding site for NF-B. Therefore, we hypothesized that ANG II may contribute to arrhythmic risk by altering Na ϩ channel transcriptional regulation through an oxidative stress and NF-B-mediated mechanism.…”