{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:47:34Z","timestamp":1790837254655,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T00:00:00Z","timestamp":1551657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007206","name":"Vanderbilt Institute for Clinical and Translational Research","doi-asserted-by":"publisher","award":["VR52197"],"award-info":[{"award-number":["VR52197"]}],"id":[{"id":"10.13039\/100007206","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Modification of voltage\u2010gated Na<jats:sup>+<\/jats:sup> channel (Na<jats:sub>V<\/jats:sub>) function by intracellular Ca<jats:sup>2+<\/jats:sup> has been a topic of much controversy. Early studies relied on measuring Na<jats:sub>V<\/jats:sub> function in the absence or presence of intracellular Ca<jats:sup>2+<\/jats:sup>, and generated seemingly disparate results. Subsequent investigations revealed the mechanism(s) of Ca<jats:sup>2+<\/jats:sup>\u2010driven Na<jats:sub>V<\/jats:sub> modulation are complex and involve multiple accessory proteins. The Ca<jats:sup>2+<\/jats:sup>\u2010sensing protein calmodulin (CaM) has a central role in tuning Na<jats:sub>V<\/jats:sub> function to [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, but the mechanism has been obscured by other proteins (such as fibroblast growth factors (FGF) or CaM\u2010dependent kinase II (CaMKII)) that can also modify channel function or exert an influence in a Ca<jats:sup>2+<\/jats:sup>\u2010dependent manner. Significant progress has been made in understanding the architecture of full\u2010length ion channels and the structural and biophysical details of Na<jats:sub>V<\/jats:sub>\u2013accessory protein interactions. Interdisciplinary structure\u2013function studies are beginning to resolve the effect each interaction has on Na<jats:sub>V<\/jats:sub> gating. Carefully designed structure\u2010guided or strategically selected disease\u2010associated mutations are able to impair Na<jats:sub>V<\/jats:sub>\u2013accessory protein interactions without altering other properties of channel function. Recently CaM was found to engage part of Na<jats:sub>V<\/jats:sub>1.5 that is required for channel inactivation with high affinity. Careful impairment of this interaction disrupted Na<jats:sub>V<\/jats:sub>1.5's ability to recover from inactivation. Such results support a paradigm of CaM\u2010facilitated recovery from inactivation (CFRI). How Na<jats:sub>V<\/jats:sub>\u2013CaM, CaMKII and FGF\/fibroblast growth factor homologous factor interactions affect the timing or function of CFRI in cardiomyocytes remain open questions that are discussed herein. Moreover whether CFRI dysfunction or premature activation underlie certain Na<jats:sub>V<\/jats:sub> channelopathies are important questions that will require further investigation.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp13429-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1113\/jp277553","type":"journal-article","created":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T20:31:25Z","timestamp":1549053085000},"page":"2835-2846","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Calcium modulation of cardiac sodium channels"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5307-798X","authenticated-orcid":false,"given":"Christopher N.","family":"Johnson","sequence":"first","affiliation":[{"name":"The Ohio State Wexner Medical Centre Dorothy M. 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