Non-canonical Sodium Channel Isoforms Underlie Chamber Specific Cardiac Excitability

Clark, C. J.; Anderson, C.; Dou, A.; Dierdorff, J.; Galpin, J. D.; Gissot, L.; Thompson, S.; Choi, H.; Yoon, J.-Y.; Infield, D. T.; Leeds, K.; Bronk, P.; McLendon, J. M.; Boudreau, R. L.; Choi, B.-R.; London, B.; Ahern, C. A.

doi:10.1101/2025.08.27.672688

bioRxiv · 10.1101/2025.08.27.672688

Non-canonical Sodium Channel Isoforms Underlie Chamber Specific Cardiac Excitability

Clark, C. J.·Anderson, C.·Dou, A.·Dierdorff, J.·Galpin, J. D.·Gissot, L.·Thompson, S.·Choi, H.·Yoon, J.-Y.·Infield, D. T.·Leeds, K.·Bronk, P.·McLendon, J. M.·Boudreau, R. L.·Choi, B.-R.·London, B.·Ahern, C. A.

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Abstract

Voltage-gated sodium (NaV) channels drive cardiac excitability. While NaV1.5 is the primary cardiac isoform, the composition and functional contributions of non-NaV1.5 isoforms in the heart remain unclear. Here, we developed a chemical-genetic mouse model (NaV1.5-GX) in which NaV1.5 can be selectively and reversibly inhibited by acyl- and aryl-sulfonamide compounds (GX drugs). NaV1.5-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 (RV) being the most sensitive, followed by the left ventricle (LV), left atrium (LA), and right atrium (RA). Patch-clamp recordings of isolated cardiomyocytes with application of NaV isoform-selective inhibitors showed that NaV1.5 contributed 93% of sodium current in the LV, 81% in the RV and 78% in the LA. Non-NaV1.5 isoforms were differentially enriched across chambers: NaV1.8 in the LV, NaV1.1/1.3 in the RV, and NaV1.2/1.6/1.7 in the atria. These results reveal a surprising chamber-specific isoform landscape of cardiac sodium currents which may underlie the right ventricular predominant phenotype of Brugada syndrome and highlight non-NaV1.5 isoforms as potential mediators of chamber-specific cardiac pathologies and as pharmacological targets.

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Clark, C. J., Anderson, C., Dou, A., Dierdorff, J., Galpin, J. D., Gissot, L., Thompson, S., Choi, H., Yoon, J.-Y., Infield, D. T., Leeds, K., Bronk, P., McLendon, J. M., Boudreau, R. L., Choi, B.-R., London, B., Ahern, C. A.. 2025-09-01. Non-canonical Sodium Channel Isoforms Underlie Chamber Specific Cardiac Excitability. https://doi.org/10.1101/2025.08.27.672688

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