SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability

Yoon, J.-Y.; Greiner, A.; Jacobs, J. S.; Kim, Y.-R.; Rasmussen, T. P.; Kutschke, W.; Matasic, D. S.; Vikram, A.; Gaddam, R. R.; Mehdi, H.; Irani, K.; London, B.

doi:10.1101/2022.12.26.521675

bioRxiv · 10.1101/2022.12.26.521675

SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability

Yoon, J.-Y.·Greiner, A.·Jacobs, J. S.·Kim, Y.-R.·Rasmussen, T. P.·Kutschke, W.·Matasic, D. S.·Vikram, A.·Gaddam, R. R.·Mehdi, H.·Irani, K.·London, B.

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Abstract

BackgroundDecreased peak sodium current (INa) and increased late sodium current (INa,L), through the cardiac sodium channel NaV1.5 encoded by SCN5A, cause arrhythmias. Many NaV1.5 post-translational modifications have been reported by us and others. A recent report concluded that acute hypoxia increases INa,L by increasing a Small Ubiquitin-like MOdifier (SUMOylation) at K442-NaV1.5. ObjectiveTo determine whether and by what mechanisms SUMOylation alters INa, INa,L and cardiac electrophysiology. MethodsSUMOylation of NaV1.5 was detected by immunoprecipitation and immunoblotting. INa was measured by patch clamp with/without SUMO1 overexpression in HEK293 cells expressing wild type (WT) or K442R-NaV1.5 and in neonatal rat cardiac myocytes (NRCMs). SUMOylation effects were studied in vivo by electrocardiograms and ambulatory telemetry using Scn5a heterozygous knockout (SCN5A+/-) mice and the de-SUMOylating protein SENP2 (AAV9-SENP2) or the SUMOylation inhibitor anacardic acid. NaV1.5 trafficking was detected by immunofluorescence. ResultsNaV1.5 was SUMOylated in HEK293 cells, NRCMs and human heart tissue. HyperSUMOylation at NaV1.5-K442 increased INa in NRCMs and in HEK cells overexpressing WT but not K442R-Nav1.5. SUMOylation did not alter other channel properties including INa,L. AAV9-SENP2 or anacardic acid treatment of SCN5A+/- mice decreased INa, prolonged QRS duration, and produced heart block and ventricular arrhythmias. SUMO1 overexpression enhanced membrane localization of NaV1.5. ConclusionSUMOylation of K442-Nav1.5 increases peak INa without changing INa,L, at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in INa,L. Nav1.5 SUMOylation may modify arrhythmic risk in disease states and represents a potential target for pharmacological manipulation.

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Yoon, J.-Y., Greiner, A., Jacobs, J. S., Kim, Y.-R., Rasmussen, T. P., Kutschke, W., Matasic, D. S., Vikram, A., Gaddam, R. R., Mehdi, H., Irani, K., London, B.. 2022-12-26. SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability. https://doi.org/10.1101/2022.12.26.521675

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