title: Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.
abstract: BACKGROUND
  Voltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) 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 INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown.
  
  
  RESULTS
  To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) 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.
  
  
  CONCLUSIONS
  Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Patric
authors.initials: P
authors.lastname: Glynn
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Xiangqiong
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Sathya D
authors.initials: SD
authors.lastname: Unudurthi
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Sean
authors.initials: S
authors.lastname: Little
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Wright
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Przemyslaw B
authors.initials: PB
authors.lastname: Radwanski
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Sandor
authors.initials: S
authors.lastname: Gyorke
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: 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 & 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, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.). Thomas.Hund@osumc.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000503:physiopathology; D003250:Constriction; D055879:Gene Knock-In Techniques; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000083:Acetanilides; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines; C568321:Scn5a protein, mouse; D026941:Sodium Channel Blockers; D010768:Phosphoserine; D012964:Sodium; D000069458:Ranolazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Na+ current; action potential; arrhythmias, cardiac; calcium-calmodulin-dependent protein kinase type 2; ion channels