{"doi":"10.1161/circresaha.120.318643","title":"Targeting the Microtubule EB1-CLASP2 Complex Modulates Na <sub>V</sub> 1.5 at Intercalated Discs","abstract":"Rationale: Loss-of-function of the cardiac sodium channel Na V 1.5 causes conduction slowing and arrhythmias. Na V 1.5 is differentially distributed within subcellular domains of cardiomyocytes, with sodium current ( I Na ) being enriched at the intercalated discs (ID). Various pathophysiological conditions associated with lethal arrhythmias display ID-specific I Na reduction, but the mechanisms underlying microdomain-specific targeting of Na V 1.5 remain largely unknown. Objective: To investigate the role of the microtubule plus-end tracking proteins EB1 (end-binding protein 1) and CLASP2 (cytoplasmic linker associated protein 2) in mediating Na V 1.5 trafficking and subcellular distribution in cardiomyocytes. Methods and Results: EB1 overexpression in human-induced pluripotent stem cell-derived cardiomyocytes resulted in enhanced whole-cell I Na , increased action potential upstroke velocity ( V max ), and enhanced Na V 1.5 localization at the plasma membrane as detected by multicolor stochastic optical reconstruction microscopy. Fluorescence recovery after photobleaching experiments in HEK293A cells demonstrated that EB1 overexpression promoted Na V 1.5 forward trafficking. Knockout of MAPRE1 in human induced pluripotent stem cell-derived cardiomyocytes led to reduced whole-cell I Na , decreased V max , and action potential duration (APD) prolongation. Similarly, acute knockout of the MAPRE1 homolog in zebrafish ( mapre1b ) resulted in decreased ventricular conduction velocity and V max as well as increased APD. Stochastic optical reconstruction microscopy imaging and macropatch I Na measurements showed that subacute treatment (2–3 hours) with SB216763 (SB2), a GSK3β (glycogen synthase kinase 3β) inhibitor known to modulate CLASP2-EB1 interaction, reduced GSK3β localization and increased Na V 1.5 and I Na preferentially at the ID region of wild-type murine ventricular cardiomyocytes. By contrast, SB2 did not affect whole cell I Na or Na V 1.5 localization in cardiomyocytes from Clasp2 -deficient mice, uncovering the crucial role of CLASP2 in SB2-mediated modulation of Na V 1.5 at the ID. Conclusions: Our findings demonstrate the modulatory effect of the microtubule plus-end tracking protein EB1 on Na V 1.5 trafficking and function, and identify the EB1-CLASP2 complex as a target for preferential modulation of I Na within the ID region of cardiomyocytes.","journal":"Circulation Research","year":2021,"id":164607,"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":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"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":492744,"name":"Mariam Jouni","orcid":"0000-0002-6576-1922","position":1,"is_corresponding":false},{"id":408516,"name":"David Y. Chiang","orcid":"0000-0002-5883-6383","position":2,"is_corresponding":false},{"id":490414,"name":"Marta Pérez-Hernández","orcid":"0000-0001-6119-103X","position":3,"is_corresponding":false},{"id":686590,"name":"Svitlana Podliesna","orcid":"0000-0003-0774-9674","position":4,"is_corresponding":false},{"id":187815,"name":"Nuo Yu","orcid":null,"position":5,"is_corresponding":false},{"id":686591,"name":"Simona Casini","orcid":"0000-0002-2672-2779","position":6,"is_corresponding":false},{"id":352595,"name":"F Potet","orcid":"0000-0003-4233-5653","position":7,"is_corresponding":false},{"id":686592,"name":"Christiaan C. Veerman","orcid":"0000-0003-4570-5234","position":8,"is_corresponding":false},{"id":686593,"name":"Mischa Klerk","orcid":"0000-0002-3725-9943","position":9,"is_corresponding":false},{"id":686594,"name":"Elisabeth M. Lodder","orcid":"0000-0001-6017-3796","position":10,"is_corresponding":false},{"id":412267,"name":"Isabella Mengarelli","orcid":"0000-0002-7862-8733","position":11,"is_corresponding":false},{"id":686595,"name":"Kaomei Guan","orcid":"0000-0002-0753-3083","position":12,"is_corresponding":false},{"id":465132,"name":"Carlos G. Vanoye","orcid":"0000-0002-4935-1122","position":13,"is_corresponding":false},{"id":279107,"name":"Eli Rothenberg","orcid":"0000-0002-1382-1380","position":14,"is_corresponding":false},{"id":400373,"name":"Flavien Charpentier","orcid":"0000-0002-5057-0998","position":15,"is_corresponding":false},{"id":282699,"name":"Richard Redon","orcid":"0000-0001-7751-2280","position":16,"is_corresponding":false},{"id":321394,"name":"Alfred L. George","orcid":"0000-0002-3993-966X","position":17,"is_corresponding":false},{"id":334986,"name":"Arie O. Verkerk","orcid":"0000-0003-2140-834X","position":18,"is_corresponding":false},{"id":55729,"name":"Connie R. Bezzina","orcid":"0000-0002-0633-3514","position":19,"is_corresponding":false},{"id":56931,"name":"Calum A. MacRae","orcid":"0000-0001-5181-2664","position":20,"is_corresponding":false},{"id":245967,"name":"Paul W. Burridge","orcid":"0000-0001-9616-0006","position":21,"is_corresponding":false},{"id":350416,"name":"Mario Delmar","orcid":"0000-0002-2085-5589","position":22,"is_corresponding":false},{"id":187816,"name":"Niels Galjart","orcid":"0000-0003-1964-3607","position":23,"is_corresponding":false},{"id":686596,"name":"Vincent Portero","orcid":"0000-0002-7221-859X","position":24,"is_corresponding":false},{"id":686597,"name":"Carol Ann Remme","orcid":"0000-0003-0095-0084","position":25,"is_corresponding":false},{"id":686589,"name":"Gerard A. Marchal","orcid":"0000-0002-7353-0235","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":null,"created_at":"2026-07-18T23:45:32.226038Z","pmid":"34092082","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":[]}