Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability
Abstract
BACKGROUND: Na V (voltage-gated sodium) channels drive cardiac excitability. Although Na V 1.5 is the primary cardiac isoform, the composition and functional contributions of non-Na V 1.5 isoforms in the heart remain unclear. METHODS: Here, we developed a chemical-genetic mouse model (Na V 1.5 GX/GX ) in which Na V 1.5 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: Na V 1.5 GX/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 Na V 1.5 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 Na V isoform-selective inhibitors showed that Na V 1.5 contributed 93% of sodium current in the left ventricle, 79% in the right ventricle, and 78% in the atria. Non-Na V 1.5 isoforms were differentially enriched across chambers: Na V 1.8 in the left ventricle, Na V 1.1/1.3…
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