{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:12:04Z","timestamp":1790709124275,"version":"4.1.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T00:00:00Z","timestamp":1502409600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T00:00:00Z","timestamp":1502409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca<jats:sup>2+<\/jats:sup> dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na<jats:sup>+<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub>), a key player in SAN automaticity, is still unknown. Here we show that <jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub> and the L-type Ca<jats:sup>2+<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub>) share Ca<jats:sub>V<\/jats:sub>1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that <jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub> is activated in the diastolic depolarization range, and displays Na<jats:sup>+<\/jats:sup> permeability and minimal inactivation and sensitivity to <jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub> activators and blockers. Both Ca<jats:sub>V<\/jats:sub>1.3-mediated <jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub> and <jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub> were abolished in Ca<jats:sub>V<\/jats:sub>1.3-deficient (Ca<jats:sub>V<\/jats:sub>1.3<jats:sup>\u2212\/\u2212<\/jats:sup>) SAN cells but the Ca<jats:sub>V<\/jats:sub>1.2-mediated <jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub> current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive Ca<jats:sub>V<\/jats:sub>1.2 channels (Ca<jats:sub>V<\/jats:sub>1.2<jats:sup>DHP\u2212\/\u2212<\/jats:sup>), <jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub> and Ca<jats:sub>V<\/jats:sub>1.3-mediated <jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub> displayed overlapping sensitivity and concentration\u2013response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that Ca<jats:sub>V<\/jats:sub>1.3 rather than Ca<jats:sub>V<\/jats:sub>1.2 underlies <jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub>, a considerable fraction of <jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub> was resistant to nifedipine inhibition in Ca<jats:sub>V<\/jats:sub>1.2<jats:sup>DHP\u2212\/\u2212<\/jats:sup> SAN cells. These findings identify Ca<jats:sub>V<\/jats:sub>1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive <jats:italic>I<\/jats:italic><jats:sub>st<\/jats:sub> Na<jats:sup>+<\/jats:sup> current in the SAN.<\/jats:p>","DOI":"10.1038\/s41598-017-08191-8","type":"journal-article","created":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T07:49:19Z","timestamp":1502092159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8412-6481","authenticated-orcid":false,"given":"Futoshi","family":"Toyoda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Mesirca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Dubel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Guang","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Striessnig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo E.","family":"Mangoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Matsuura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,11]]},"reference":[{"key":"8191_CR1","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1152\/physrev.00018.2007","volume":"88","author":"ME Mangoni","year":"2008","unstructured":"Mangoni, M. 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