Journal article
Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability
Circulation research
03/25/2026
DOI: 10.1161/CIRCRESAHA.125.328159
PMID: 41878815
Abstract
BACKGROUND:
NaV (voltage-gated sodium) channels drive cardiac excitability. Although NaV1.5 is the primary cardiac isoform, the composition and functional contributions of non-NaV1.5 isoforms in the heart remain unclear.
METHODS:
Here, we developed a chemical-genetic mouse model (NaV1.5GX/GX) in which NaV1.5 can be selectively and reversibly inhibited by acyl- and aryl-sulfonamide compounds (GX [acyl- and aryl-sulfonamide compounds typically denoted by the name GX-### and associated items] drugs). Cardiac activity was assessed by electrocardiograms in vivo, and optical mapping was used for imaging of ex vivo hearts. Whole-cell voltage-clamp in tandem with validated toxins and isoform-selective inhibitors were used to examine sodium current composition.
RESULTS:
NaV1.5GX/GX mice exhibited normal cardiac function at baseline, but acute GX drug administration caused profound conduction defects and arrhythmias. Whole-heart optical mapping revealed dose-dependent chamber-specific sensitivity to NaV1.5 inhibition, with the right ventricle being the most sensitive, followed by the left ventricle, left atrium, and right atrium. Patch-clamp recordings of isolated cardiomyocytes with application of NaV isoform-selective inhibitors showed that NaV1.5 contributed 93% of sodium current in the left ventricle, 79% in the right ventricle, and 78% in the atria. Non-NaV1.5 isoforms were differentially enriched across chambers: NaV1.8 in the left ventricle, NaV1.1/1.3 in the right ventricle, and NaV1.2/1.6/1.7 in the atria.
CONCLUSIONS:
These results reveal a surprising chamber-specific isoform landscape of cardiac sodium currents, which may underlie the right ventricular predominant phenotype of Brugada syndrome. These data highlight non-NaV1.5 isoforms as potential mediators of chamber-specific cardiac pathologies and as pharmacological targets.
Details
- Title: Subtitle
- Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability
- Creators
- Colin J Clark - University of IowaChristian E Anderson - University of IowaAlex Dou - University of IowaJason M Dierdorff - University of IowaJason D Galpin - University of IowaLionel Gissot - University of IowaSamantha G Thompson - University of IowaHannah Choi - University of IowaJin-Young Yoon - University of IowaDaniel T Infield - University of IowaJared M McLendon - University of IowaJasmyn M Hoeger - University of IowaOmar Rabab'h - University of IowaPeter Bronk - Rhode Island HospitalKeane LeedsWilliam J Kutschke - University of IowaWilliam J Paradee - University of IowaRyan L Boudreau - University of IowaBum-Rak Choi - Rhode Island HospitalBarry London - University of IowaChristopher A Ahern - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Circulation research
- DOI
- 10.1161/CIRCRESAHA.125.328159
- PMID
- 41878815
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- R01 HL163979 / NHLBI NIH HHS
- Language
- English
- Electronic publication date
- 03/25/2026
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Medicine Administration; Internal Medicine
- Record Identifier
- 9985149086102771
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