{"doi":"10.14814/phy2.15121","title":"Phosphorylation of Lamin A/C at serine 22 modulates Na <sub>v</sub> 1.5 function","abstract":"Variants in the LMNA gene, which encodes for Lamin A/C, are associated with cardiac conduction disease (CCD). We previously reported that Lamin A/C variants p.R545H and p.A287Lfs*193, which were identified in CCD patients, decreased peak INa in HEK-293 cells expressing Nav1.5. Decreased peak INa in the cardiac conduction system could account for patients’ atrioventricular block. We found that serine 22 (Ser 22) phosphorylation of Lamin A/C was decreased in the p.R545H variant and hypothesized that lamin phosphorylation modulated Nav1.5 activity. To test this hypothesis, we assessed Nav1.5 function in HEK-293 cells co-transfected with LMNA variants or treated with the small molecule LBL1 (lamin-binding ligand 1). LBL1 decreased Ser 22 phosphorylation by 65% but did not affect Nav1.5 function. To test the complete loss of phosphorylation, we generated a version of LMNA with serine 22 converted to alanine 22 (S22A-LMNA); and a version of mutant R545H-LMNA that mimics phosphorylation via serine 22 to aspartic acid 22 substitution (S22D-R545H-LMNA). We found that S22A-LMNA inhibited Lamin-mediated activation of peak INa by 63% and shifted voltage-dependency of steady-state inactivation of Nav1.5. Conversely, S22D-R545H-LMNA abolished the effects of mutant R545H-LMNA on voltage-dependency but not peak INa. We conclude that Lamin A/C Ser 22 phosphorylation can modulate Nav1.5 function and contributes to the mechanism by which R545H-LMNA alters Nav1.5 function. The differential impact of complete versus partial loss of Ser 22 phosphorylation suggests a threshold of phosphorylation that is required for full Nav1.5 modulation. This is the first study to link Lamin A/C phosphorylation to Nav1.5 function.","journal":"Physiological Reports","year":2021,"id":195902,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":552168,"name":"Tomohiko Ai","orcid":"0000-0003-0376-0227","position":1,"is_corresponding":false},{"id":767840,"name":"Bo Chao","orcid":"0000-0002-4186-8354","position":2,"is_corresponding":false},{"id":255386,"name":"Xiangshu Xiao","orcid":"0000-0001-9520-1371","position":3,"is_corresponding":false},{"id":767841,"name":"Matteo Vatta","orcid":"0000-0003-0962-8163","position":4,"is_corresponding":false},{"id":338681,"name":"Beth A. Habecker","orcid":"0000-0002-4658-8730","position":5,"is_corresponding":false},{"id":400788,"name":"Michael A. Olaopa","orcid":null,"position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:50:11.609550Z","pmid":"34806324","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":[]}