SUMOylation of the cardiac sodium channel Na V 1.5 modifies inward current and cardiac excitability.

Autor:	Yoon JY; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa., Greiner AM; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Jacobs JS; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Kim YR; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Rasmussen TP; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Kutschke WJ; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Matasic DS; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa., Vikram A; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa., Gaddam RR; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa., Mehdi H; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa., Irani K; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa; Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, and Heart and Vascular Center, University of Iowa, Iowa City, Iowa. Electronic address: kaikobad-irani@uiowa.edu., London B; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa. Electronic address: barry-london@uiowa.edu.
Jazyk:	angličtina
Zdroj:	Heart rhythm [Heart Rhythm] 2023 Nov; Vol. 20 (11), pp. 1548-1557. Date of Electronic Publication: 2023 Aug 03.
DOI:	10.1016/j.hrthm.2023.07.067
Abstrakt:	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 posttranslational 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: The purpose of this study was 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, whereas 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 pharmacologic manipulation. (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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