{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:54:13Z","timestamp":1787018053286,"version":"build-2736575974"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Voltage-gated Na\n                      <jats:sup>+<\/jats:sup>\n                      channel (\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      ) function is critical for normal cardiac excitability. However, the Na\n                      <jats:sup>+<\/jats:sup>\n                      channel late component (\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      ) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. CaMKII (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/calmodulin-dependent kinase II) enhances\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII\/Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      To define phosphatase pathways that regulate\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      A mouse model lacking a key regulatory subunit (B56\u03b1) of the PP (protein phosphatase) 2A holoenzyme displayed aberrant action potentials after adrenergic stimulation. Unbiased computational modeling of B56\u03b1 KO (knockout) mouse myocyte action potentials revealed an unexpected role of PP2A in\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      regulation that was confirmed by direct\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      recordings from B56\u03b1 KO myocytes. Further, B56\u03b1 KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sub>Na,L<\/jats:sub>\n                      , and reduced CaMKII-dependent phosphorylation of Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5. At the molecular level, PP2A\/B56\u03b1 complex was found to localize and coimmunoprecipitate with the primary cardiac Na\n                      <jats:sub>v<\/jats:sub>\n                      channel, Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      PP2A regulates Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 late current and requires PP2A-B56\u03b1. Our study supports B56\u03b1 as a novel target for the treatment of arrhythmia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.118.314350","type":"journal-article","created":{"date-parts":[[2019,1,3]],"date-time":"2019-01-03T05:00:25Z","timestamp":1546491625000},"page":"737-746","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Protein Phosphatase 2A Regulates Cardiac Na\n                    <sup>+<\/sup>\n                    Channels"],"prefix":"10.1161","volume":"124","author":[{"given":"Mona","family":"El Refaey","sequence":"first","affiliation":[{"name":"From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. 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