{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T15:22:45Z","timestamp":1781623365157,"version":"3.54.5"},"reference-count":39,"publisher":"Walter de Gruyter GmbH","issue":"11-12","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM121375"],"award-info":[{"award-number":["GM121375"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE2993\/18-1"],"award-info":[{"award-number":["HE2993\/18-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Heme (Fe<jats:sup>2+<\/jats:sup>-protoporphyrin IX) is a well-known protein prosthetic group; however, heme and hemin (Fe<jats:sup>3+<\/jats:sup>-protoporphyrin IX) are also increasingly viewed as signaling molecules. Among the signaling targets are numerous ion channels, with intracellular-facing heme-binding sites modulated by heme and hemin in the sub-\u00b5<jats:sc>M<\/jats:sc> range. Much less is known about extracellular hemin, which is expected to be more abundant, in particular after hemolytic insults. Here we show that the human cardiac voltage-gated sodium channel hNa<jats:sub>V<\/jats:sub>1.5 is potently inhibited by extracellular hemin (<jats:italic>IC<\/jats:italic>\n                  <jats:sub>50<\/jats:sub>\u00a0\u2248\u00a080\u00a0n<jats:sc>M<\/jats:sc>), while heme, dimethylhemin, and protoporphyrin IX are ineffective. Hemin is selective for hNa<jats:sub>V<\/jats:sub>1.5 channels: hNa<jats:sub>V<\/jats:sub>1.2, hNa<jats:sub>V<\/jats:sub>1.4, hNa<jats:sub>V<\/jats:sub>1.7, and hNa<jats:sub>V<\/jats:sub>1.8 are insensitive to 1\u00a0\u00b5<jats:sc>M<\/jats:sc> hemin. Using domain chimeras of hNa<jats:sub>V<\/jats:sub>1.5 and rat rNa<jats:sub>V<\/jats:sub>1.2, domain II was identified as the critical determinant. Mutation N803G in the domain II S3\/S4 linker largely diminished the impact of hemin on the cardiac channel. This profile is reminiscent of\u00a0the interaction of some peptide voltage-sensor toxins with Na<jats:sub>V<\/jats:sub> channels. In line with a mechanism of select gating modifiers, the impact of hemin on Na<jats:sub>V<\/jats:sub>1.5 channels is reversely use dependent, compatible with an interaction of hemin and the voltage sensor of domain II. Extracellular hemin thus has potential to modulate the cardiac function.<\/jats:p>","DOI":"10.1515\/hsz-2022-0194","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T01:55:42Z","timestamp":1661824542000},"page":"1067-1081","source":"Crossref","is-referenced-by-count":6,"title":["Extracellular hemin is a reverse use-dependent gating modifier of cardiac voltage-gated Na<sup>+<\/sup> channels"],"prefix":"10.1515","volume":"403","author":[{"given":"Guido","family":"Gessner","sequence":"first","affiliation":[{"name":"Department of Biophysics, Center for Molecular Biomedicine , Friedrich Schiller University Jena and Jena University Hospital , Hans-Kn\u00f6ll-Stra\u00dfe 2, D-07745 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdi","family":"Jamili","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Center for Molecular Biomedicine , Friedrich Schiller University Jena and Jena University Hospital , Hans-Kn\u00f6ll-Stra\u00dfe 2, D-07745 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Tomczyk","sequence":"additional","affiliation":[{"name":"Kekul\u00e9-Institute for Organic Chemistry and Biochemistry, University of Bonn , Gerhard-Domagk-Stra\u00dfe 1, D-53121 Bonn , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Menche","sequence":"additional","affiliation":[{"name":"Kekul\u00e9-Institute for Organic Chemistry and Biochemistry, University of Bonn , Gerhard-Domagk-Stra\u00dfe 1, D-53121 Bonn , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Sch\u00f6nherr","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Center for Molecular Biomedicine , Friedrich Schiller University Jena and Jena University Hospital , Hans-Kn\u00f6ll-Stra\u00dfe 2, D-07745 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinori","family":"Hoshi","sequence":"additional","affiliation":[{"name":"Department of Physiology , University of Pennsylvania , Philadelphia , PA 19104-6085 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4144-0251","authenticated-orcid":false,"given":"Stefan H.","family":"Heinemann","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Center for Molecular Biomedicine , Friedrich Schiller University Jena and Jena University Hospital , Hans-Kn\u00f6ll-Stra\u00dfe 2, D-07745 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"2023033110082028936_j_hsz-2022-0194_ref_001","doi-asserted-by":"crossref","unstructured":"Burton, M.J., Kapetanaki, S.M., Chernova, T., Jamieson, A.G., Dorlet, P., Santolini, J., Moody, P.C., Mitcheson, J.S., Davies, N.W., Schmid, R., et al.. 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