Journal article
SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability
Heart rhythm, Vol.20(11), pp.1548-1557
10/31/2023
DOI: 10.1016/j.hrthm.2023.07.067
PMCID: PMC12007604
PMID: 37543305
Abstract
Background
Decreased peak sodium current (I Na ) and increased late sodium current (I Na,L ), through the cardiac sodium channel Na V 1.5 encoded by SCN5A , cause arrhythmias. Many Na V 1.5 post-translational modifications have been reported. A recent report concluded that acute hypoxia increases I Na,L by increasing a Small Ubiquitin-like MOdifier (SUMOylation) at K442-Na V 1.5.
Objective
To determine whether and by what mechanisms SUMOylation alters I Na , I Na,L and cardiac electrophysiology.
Methods
SUMOylation of Na V 1.5 was detected by immunoprecipitation and immunoblotting. I Na was measured by patch clamp with/without SUMO1 overexpression in HEK293 cells expressing wild type (WT) or K442R-Na V 1.5 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), AAV9-SUMO1, or the SUMOylation inhibitor anacardic acid. Na V 1.5 trafficking was detected by immunofluorescence.
Results
Na V 1.5 was SUMOylated in HEK293 cells, NRCMs and human heart tissue. HyperSUMOylation at Na V 1.5-K442 increased I Na in NRCMs and in HEK cells overexpressing WT but not K442R-Na v 1.5. SUMOylation did not alter other channel properties including I Na,L . AAV9-SENP2 or anacardic acid decreased I Na , prolonged QRS duration, and produced heart block and arrhythmias in SCN5A +/- mice, while AAV9-SUMO1 increased I Na and shortened QRS duration . SUMO1 overexpression enhanced membrane localization of Na V 1.5.
Conclusion
SUMOylation of K442-Na v 1.5 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. Na v 1.5 SUMOylation may modify arrhythmic risk in disease states and represents a potential target for pharmacological manipulation.
Details
- Title: Subtitle
- SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability
- Creators
- Jin-Young YoonAlexander M Greiner - University of IowaJulia S Jacobs - University of IowaYoung-Rae Kim - University of IowaTyler P Rasmussen - University of IowaWilliam J Kutschke - University of IowaDaniel S Matasic - University of IowaAjit Vikram - University of IowaRavinder R Gaddam - University of IowaHaider Mehdi - University of IowaKaikobad Irani - University of IowaBarry London - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Heart rhythm, Vol.20(11), pp.1548-1557
- DOI
- 10.1016/j.hrthm.2023.07.067
- PMID
- 37543305
- PMCID
- PMC12007604
- NLM abbreviation
- Heart Rhythm
- ISSN
- 1547-5271
- eISSN
- 1556-3871
- Language
- English
- Electronic publication date
- 08/03/2023
- Date published
- 10/31/2023
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984449721802771
Metrics
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