{"doi":"10.1101/2022.12.26.521675","title":"SUMOylation of the Cardiac Sodium Channel Na <sub>V</sub> 1.5 Modifies Inward Current and Cardiac Excitability","abstract":"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 by us and others. 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) 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 treatment of SCN5A +/- mice decreased I Na , prolonged QRS duration, and produced heart block and ventricular arrhythmias. 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":314039,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":500199,"name":"Alexander M. Greiner","orcid":null,"position":1,"is_corresponding":false},{"id":444462,"name":"Julia S. Jacobs","orcid":null,"position":2,"is_corresponding":false},{"id":444461,"name":"Young‐Rae Kim","orcid":null,"position":3,"is_corresponding":false},{"id":261892,"name":"William Kutschke","orcid":"0000-0002-9358-795X","position":4,"is_corresponding":false},{"id":499320,"name":"Daniel S. Matasic","orcid":"0000-0001-7010-6298","position":5,"is_corresponding":false},{"id":226328,"name":"Ajit Vikram","orcid":"0000-0003-3724-3842","position":6,"is_corresponding":false},{"id":443374,"name":"Ravinder Reddy Gaddam","orcid":"0000-0003-1062-5082","position":7,"is_corresponding":false},{"id":499322,"name":"Haider Mehdi","orcid":"0000-0001-7591-8180","position":8,"is_corresponding":false},{"id":443378,"name":"Kaikobad Irani","orcid":"0000-0001-9194-7387","position":9,"is_corresponding":false},{"id":32972,"name":"Barry London","orcid":"0000-0003-1506-3947","position":10,"is_corresponding":false},{"id":499321,"name":"Jin‐Young Yoon","orcid":"0000-0002-5707-3636","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T00:33:48.490749Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}