{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:50:50Z","timestamp":1791571850943,"version":"4.3.4"},"reference-count":66,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"41","funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1R01HL163576"],"award-info":[{"award-number":["1R01HL163576"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01 HL164319"],"award-info":[{"award-number":["P01 HL164319"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K99 HL177343"],"award-info":[{"award-number":["K99 HL177343"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:p>\n                    Despite their emerging prominence, ion channelopathies have remained challenging to correct, as ion channel dysfunction linked to disease is multifaceted, involving changes in activity and\/or localization. Yet, current corrective strategies typically focus on restoring only one aspect leading to incomplete efficacy. Here, focusing on the voltage-gated sodium channel, Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5, whose dysfunction is linked to life-threatening cardiac arrhythmias, we develop a genetically encoded bifunctional actuator as a proof-of-concept molecular strategy to reverse pathophysiological changes in channel function. Specifically, we engineer a high affinity nanobody targeting Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 with two moieties: (i) a peptide that restores proper inactivation and (ii) a linkage-specific deubiquitinase that promotes surface-membrane localization. Functional validation in heterologous systems and in human and mouse cardiomyocytes demonstrated restoration of Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 trafficking and\/or gating. In all, this approach shows promise for reversing molecular deficits observed with Na\n                    <jats:sub>V<\/jats:sub>\n                    channelopathies and provides a framework to engineer multifunctional modulators targeting ion channelopathies.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb2110","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:06:59Z","timestamp":1791569219000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1837-9093","authenticated-orcid":true,"given":"Lucile","family":"Fossier","sequence":"first","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4098-5580","authenticated-orcid":true,"given":"Marc","family":"Yehya","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3959-5094","authenticated-orcid":true,"given":"Richard Z.","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1467-401X","authenticated-orcid":true,"given":"Sri Karthika","family":"Shanmugam","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4590-2724","authenticated-orcid":true,"given":"Ryan","family":"Mahling","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5809-548X","authenticated-orcid":true,"given":"Timothy","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4800-9855","authenticated-orcid":true,"given":"Audrey","family":"Kochiss","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2065-3802","authenticated-orcid":true,"given":"Allen L.","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1205-5204","authenticated-orcid":true,"given":"Sandra B.","family":"Gabelli","sequence":"additional","affiliation":[{"name":"Discovery Chemistry, Merck Research Laboratory, Merck and Co. Inc., West Point, PA 19486, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9382-1574","authenticated-orcid":true,"given":"Gordana","family":"Vunjak-Novakovic","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA."},{"name":"Department of Medicine, Columbia University, New York, NY 10032, USA."},{"name":"College of Dental Medicine, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2340-8899","authenticated-orcid":true,"given":"Henry M.","family":"Colecraft","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."},{"name":"Department of Pharmacology and Molecular Therapeutics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5645-0815","authenticated-orcid":true,"given":"Manu","family":"Ben-Johny","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.281204"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.01.020"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3849"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-00418-4"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2014.01.004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00022.2023"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(97)00430-6"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021014-071838"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25505"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-020-02429-7"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00121"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00272-8"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010818-021757"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201511492"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90359-3"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001573-200201000-00007"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.09.069"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00721.2017"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa082"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.256461"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104471200"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2018.03.006"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.12.1206"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2015.05.006"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-021-00900-9"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccep.2014.07.003"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00413"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00071.2017"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.120.000048"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2016.10.021"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00060-6"},{"key":"e_1_3_2_33_2","doi-asserted-by":"crossref","unstructured":"R. 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Makita, E. Behr, W. Shimizu, M. Horie, A. Sunami, L. Crotti, E. Schulze-Bahr, S. Fukuhara, N. Mochizuki, T. Makiyama, H. Itoh, M. Christiansen, P. McKeown, K. Miyamoto, S. Kamakura, H. Tsutsui, P. J. Schwartz, A. L. George Jr., D. M. Roden, The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J. Clin. Invest. 118, 2219\u20132229 (2008).","journal-title":"J. Clin. 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K. Shanmugam S. A. Kanner X. Zou E. Amarh P. Choudhury R. Soni R. S. Kass H. M. Colecraft Decoding polyubiquitin regulation of KV7. 1 functional expression with engineered linkage-selective deubiquitinases. bioRxiv 2024.09.17.613539 [Preprint] (2024) https:\/\/doi.org\/10.1101\/2024.09.17.613539.","DOI":"10.1038\/s41467-025-60893-0"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.04.035"},{"key":"e_1_3_2_64_2","first-page":"21.3.1","article-title":"Chemically defined culture and cardiomyocyte differentiation of human pluripotent stem cells","volume":"87","author":"Burridge P. W.","year":"2015","unstructured":"P. W. Burridge, A. Holmstrom, J. C. Wu, Chemically defined culture and cardiomyocyte differentiation of human pluripotent stem cells. Curr. Protoc. Hum. Genet. 87, 21.3.1\u201321.3.15 (2015).","journal-title":"Curr. Protoc. Hum. 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