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Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability [bulk RNA-seq]

ABSTRACT: Sodium channels are essential for cardiac conduction and excitability. The sodium current is primarily carried by the voltage gated sodium channel isoform NaV1.5. Using a novel NaV1.5 chimeric construct (NaV1.5-GX), our study reveals a unique chamber-specific distribution of non-NaV1.5 sodium channel isoforms, and we performed bulk RNA sequencing of murine ventricles to assess if acute NaV1.5 inhibition changed the trascriptional profile of the ventricular myocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE319426 | GEO | 2026/04/09

REPOSITORIES: GEO

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Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability [Spatial Transcriptomics]

Project description:Sodium channels are essential for cardiac conduction and excitability. The sodium current is primarily carried by the voltage gated sodium channel isoform NaV1.5. Using a novel NaV1.5 chimeric construct, our study reveals a unique chamber-specific distribution of non-NaV1.5 sodium channel isoforms, and we performed spatial sequencing of murine hearts to assess the transcriptional changes associated with our chimeric channel.

2026-04-09 | GSE319481 | GEO

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Project description:Scn2a encodes voltage-gated sodium channel NaV1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs excitability contributing to autism. This paradigm, however, does not explain why 20~30% of patients with NaV1.2 deficiency still develop seizures. Here we report a counterintuitive finding that severe NaV1.2 deficiency results in increased neuronal excitability. Using a unique NaV1.2-deficient mouse model, we found enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by the genetic restoration of Scn2a expression in adult mice. RNA-sequencing revealed that the downregulation of multiple potassium channels including KV1.1, and KV channel openers alleviated hyperexcitability of NaV1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying NaV1.2 deficiency-related seizures.

2021-07-13 | GSE179818 | GEO

Genetic background effect on Scn5a mutant cardiac right ventricle gene expression

Project description:Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel alpha subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity among mutation carriers is highly variable. We hypothesized that genetic modifiers underlie the variability in conduction slowing and disease severity. With the aim of identifying such modifiers, we studied the Scn5a(1798insD/+) mutation in 2 distinct mouse strains, FVB/N and 129P2. In 129P2 mice, the mutation resulted in more severe conduction slowing particularly in the right ventricle (RV) compared to FVB/N. Pan-genomic mRNA expression profiling in the 2 mouse strains uncovered a drastic reduction in mRNA encoding the sodium channel auxiliary subunit beta4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta4 protein levels in 129P2 ventricular tissue, whereas abundant beta4 protein was detected in FVB/N. Sodium current measurements in isolated myocytes from the 2 mouse strains indicated that sodium channel activation in myocytes from 129P2 mice occurred at more positive potentials compared to FVB/N. Using computer simulations, this difference in activation kinetics was predicted to explain the observed differences in conduction disease severity between the 2 strains. In conclusion, genetically determined differences in sodium current characteristics on the myocyte level modulate disease severity in cardiac sodium channelopathies. In particular, the sodium channel subunit beta4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease.

2010-01-12 | GSE19741 | GEO

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Project description:Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

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Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene targeted mice

Project description:The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. As well as action potential propagation, NaV1.7 regulates neurotransmitter release, integrates depolarizing inputs over long periods and regulates transcription. In order to better understand these functions, we generated an epitope-tagged NaV1.7 mouse that showed normal NaV1.7 channel activity and normal pain behavior. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 NaV1.7 associated proteins including known and novel interactors such as sodium channel β3 subunit (Scn3b) and collapsin response mediator protein (Crmp2). Selected NaV1.7 protein interactors, such as Crmp2, membrane-trafficking protein synapototagmin-2 (Syt2), G protein-regulated inducer of neurite outgrowth 1 (Gprin1), L-type amino acid transporter 1 (Lat1) and transmembrane P24 trafficking protein 10 (Tmed10) were validated using co-immunoprecipitation and functional assays. The information provided with this physiologically normal epitope-tagged mouse should provide useful insights into the downstream mechanisms associated with NaV1.7 channel function.

2018-01-15 | PXD005155 | Pride

Regulation of fin regeneration by a voltage-gated sodium channel

Project description:Regulation of fin regeneration by a voltage-gated sodium channel

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Epithelial sodium channel inhibition as a targeted therapy for skin inflammation

Project description:Epithelial sodium channel inhibition as a targeted therapy for skin inflammation

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Loss of schizophrenia risk gene XPO7 disrupts neuronal excitability and network regularity via altered Na+ channel dynamics in human neurons

Project description:Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional consequences of XPO7 loss of function (LoF) in human induced pluripotent stem cell (iPSC)-derived neurons, focusing on its role as a schizophrenia risk gene identified through recent large-scale exome sequencing analyses. By integrating high-precision electrophysiological measurements with transcriptomic, proteomic, and imaging approaches, we demonstrate that XPO7 LoF alters Na+ channel properties and availability, disrupts neuronal excitability, and impairs the synchrony and regularity of network activity. These functional deficits are accompanied by widespread molecular dysregulation affecting nucleocytoplasmic transport, ion channel function, and synaptic composition. Among the dysregulated proteins is Nav1.2, a voltage-gated sodium channel encoded by the schizophrenia-associated gene SCN2A, which exhibits aberrant subcellular distribution in XPO7 LoF neurons, characterized by increased somatic accumulation and reduced synaptic localization. Together, these findings position XPO7 as a critical regulator of neuronal excitability and connectivity, linking channelopathy to cellular phenotypes relevant to schizophrenia pathophysiology.

2026-04-09 | GSE301134 | GEO

Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)

Project description:Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC)

| PRJNA544464 | ENA

Larval application of sodium channel homologous dsRNA restores pyrethroid insecticide susceptibility in a resistant adult mosquito population

Project description:Mosquitoes host and pass on to humans a variety of disease-causing pathogens such as infectious viruses and other parasitic microorganisms. The emergence and spread of insecticide resistance is threatening the effectiveness of current control measures for common mosquito vector borne diseases, such as malaria, dengue and Zika. Therefore, the emerging resistance to the widely used pyrethroid insecticides is an alarming problem for public health. Among the new approaches implemented for pest control, one of the most promising is RNA interference (RNAi). The aim of this study was to provide a feasible RNAi solution that can be applied on wild pyrethroid resistant mosquito populations in the near future. To achieve this, high dsRNA efficacy at economic quantities is required. It is recognized that the sodium channel transcript variability governs its functional diversity including the emergence of insecticide resistance. Therefore, to maximize the RNAi effect, we tiled a number of overlapping dsRNA constructs that together target about half of the voltage-gated sodium channel (VGSC) transcript variants annotated in this work. This strategy provided a refined dsRNA trigger that increased mortality with a three-fold decrease in dsRNA amounts compared to the primary VGSC dsRNA construct. Thus, we demonstrated the use of RNA interference (RNAi) to increase susceptibility of adult mosquitoes to a widely used pyrethroid insecticide.

2016-07-06 | GSE84030 | GEO

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