{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:44:08Z","timestamp":1792514648469,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2015,8,18]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>\n                      Voltage-gated Na\n                      <jats:sup>+<\/jats:sup>\n                      channels (Na\n                      <jats:sub>v<\/jats:sub>\n                      ) are essential for myocyte membrane excitability and cardiac function. Na\n                      <jats:sub>v<\/jats:sub>\n                      current (\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      ) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      (\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      ) persists because of incomplete\/failed inactivation of a subpopulation of channels. Notably,\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      is directly linked with both congenital and acquired disease states. The multifunctional Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      in vivo remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      To determine the in vivo role of Ser571, 2\n                      <jats:italic>Scn5a<\/jats:italic>\n                      knock-in mouse models were generated expressing either: (1) Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      but not other channel properties previously linked to CaMKII. Ser571-mediated increases in\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      promote abnormal repolarization and intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>\n                      Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      . Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 specifically tunes\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      without altering critical physiological components of the current.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.114.015218","type":"journal-article","created":{"date-parts":[[2015,7,17]],"date-time":"2015-07-17T23:15:55Z","timestamp":1437174955000},"page":"567-577","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":117,"title":["Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo"],"prefix":"10.1161","volume":"132","author":[{"given":"Patric","family":"Glynn","sequence":"first","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Musa","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangqiong","family":"Wu","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathya D.","family":"Unudurthi","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Little","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Qian","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Wright","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw B.","family":"Radwanski","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandor","family":"Gyorke","sequence":"additional","affiliation":[{"name":"From Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology &amp; Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Mohler","sequence":"additional","affiliation":[{"name":"From Dorothy M. 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