Abstract 14053: Sumoylation of the Cardiac Sodium Channel Na V 1.5 Does Not Increase Late Sodium Current
Circulation(2021)
Abstract
Introduction: The sodium current (I Na ) controlling cardiac cell excitability is conducted via the Na + channel Na V 1.5 (encoded by SCN5A ). Dysregulation of Na V 1.5 has been implicated in arrhythmia, with increased late Na V 1.5 current (I Na,L ) causing long QT type 3. Many Na V 1.5 post-translational modifications have been reported by us and others, including SUMOylation, the addition of a Small Ubiquitin-like MOdifier (SUMO) at K442-Na V 1.5. Plant et al. (2020) recently reported that hypoxia increases I Na,L by increased Na V 1.5 SUMOylation. Hypothesis: SUMOylation modifies peak but not late Na V 1.5 currents through membrane localization. Methods: SUMOylation of Na V 1.5 by SUMO1 was detected by immunoprecipitation and immunoblot. The effects of SUMOylation on peak I Na and I Na,L were measured using patch clamp in HEK293 cells transfected with wild type (WT) or mutant K442R-Na V 1.5 with/without the β1 subunit and in neonatal rat cardiac myocytes (NRCMs). Tetrodotoxin (TTX) was used to quantitate I Na,L in NRCMs. Na V 1.5 trafficking was detected by immunofluorescence. Results: Na V 1.5 was SUMOylated by SUMO1 in HEK cells, NRCMs, and human heart samples. Overexpressing or directly applying SUMO1 induced hyperSUMOylation of Na V 1.5 at K442 and increased the amplitude of peak I Na in NRCMs and in HEK cells overexpressing WT but not K442R-Na v 1.5. SUMOylation did not affect I Na,L in HEK293 cells expressing Na V 1.5 with/without the β1 subunit or in NRCMs (Fig. 1A, B). SUMO1 enhanced membrane localization of Na V 1.5 in HEK293 cells (Fig. 1C) with minimal changes to steady state activation, inactivation or channel kinetics. Conclusion: SUMOylation of Na v 1.5 at K442 increases peak I Na without changing I Na,L , at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in I Na,L .
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