{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T11:02:57Z","timestamp":1782471777286,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2015,6,7]],"date-time":"2015-06-07T00:00:00Z","timestamp":1433635200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Basic Research Program of China","award":["2013CB531100"],"award-info":[{"award-number":["2013CB531100"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81221001"],"award-info":[{"award-number":["81221001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Major International Joint Research Program Fund of China","award":["81120108004"],"award-info":[{"award-number":["81120108004"]}]},{"name":"General Program of National Natural Science Foundation of China","award":["81170224"],"award-info":[{"award-number":["81170224"]}]},{"name":"General Program of National Natural Science Foundation of China","award":["81270313"],"award-info":[{"award-number":["81270313"]}]},{"name":"General Program of National Natural Science Foundation of China","award":["31271214"],"award-info":[{"award-number":["31271214"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2015,9]]},"abstract":"Abstract<\/jats:title>The voltage\u2010gated Na+<\/jats:sup> channel Nav<\/jats:sub>1.5 is essential for action potential (AP<\/jats:styled-content>) formation and electrophysiological homoeostasis in the heart. The ubiquitin\u2013proteasome system (UPS<\/jats:styled-content>) is a major degradative system for intracellular proteins including ion channels. The ubiquitin protein ligase E3 component N\u2010recognin (UBR<\/jats:styled-content>) family is a part of the UPS<\/jats:styled-content>; however, their roles in regulating cardiac Nav<\/jats:sub>1.5 channels remain elusive. Here, we found that all of the UBR<\/jats:styled-content> members were expressed in cardiomyocytes. Individual knockdown of UBR<\/jats:styled-content>3 or UBR<\/jats:styled-content>6, but not of other UBR<\/jats:styled-content> members, significantly increased Nav<\/jats:sub>1.5 protein levels in neonatal rat ventricular myocytes, and this effect was verified in HEK<\/jats:styled-content>293T cells expressing Nav<\/jats:sub>1.5 channels. The UBR<\/jats:styled-content>3\/6\u2010dependent regulation of Nav<\/jats:sub>1.5 channels was not transcriptionally mediated, and pharmacological inhibition of protein biosynthesis failed to counteract the increase in Nav<\/jats:sub>1.5 protein caused by UBR<\/jats:styled-content>3\/6 reduction, suggesting a degradative modulation of UBR<\/jats:styled-content>3\/6 on Nav<\/jats:sub>1.5. Furthermore, the effects of UBR<\/jats:styled-content>3\/6 knockdown on Nav<\/jats:sub>1.5 proteins were abolished under the inhibition of proteasome activity, and UBR<\/jats:styled-content>3\/6 knockdown reduced Nav<\/jats:sub>1.5 ubiquitylation. The double UBR<\/jats:styled-content>3\u2013UBR<\/jats:styled-content>6 knockdown resulted in comparable increases in Nav<\/jats:sub>1.5 proteins to that observed for single knockdown of either UBR<\/jats:styled-content>3 or UBR<\/jats:styled-content>6. Electrophysiological recordings showed that UBR<\/jats:styled-content>3\/6 reduction\u2010mediated increase in Nav<\/jats:sub>1.5 protein enhanced the opening of Nav<\/jats:sub>1.5 channels and thereby the amplitude of the AP<\/jats:styled-content>. Thus, our findings indicate that UBR<\/jats:styled-content>3\/6 regulate cardiomyocyte Nav<\/jats:sub>1.5 channel protein levels via<\/jats:italic> the ubiquitin\u2013proteasome pathway. It is likely that UBR<\/jats:styled-content>3\/6 have the potential to be a therapeutic target for cardiac arrhythmias.<\/jats:p>","DOI":"10.1111\/jcmm.12588","type":"journal-article","created":{"date-parts":[[2015,6,11]],"date-time":"2015-06-11T03:02:16Z","timestamp":1433991736000},"page":"2143-2152","source":"Crossref","is-referenced-by-count":14,"title":["Cardiac Nav<\/sub>1.5 is modulated by ubiquitin protein ligase E3 component n\u2010recognin UBR<\/scp>3 and 6"],"prefix":"10.1111","volume":"19","author":[{"given":"Chunxia","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Arrhythmias of the Ministry of Education of China East Hospital Tongji University School of Medicine Shanghai China"},{"name":"Department of Cardiology Shanghai East Hospital Tongji University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of 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