title: Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias.
abstract: Mutations in SCN2B, encoding voltage-gated sodium channel β2-subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo.
  
  
  
  To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current densities in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional reentry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild-type ventricles, as were levels of Nav1.5 protein, suggesting that similar to the previous work in neurons, the major function of β2-subunits in the ventricle is to chaperone voltage-gated sodium channel α-subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared with wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than wild-type littermates.
  
  
  
  Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Bao
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: B Cicero
authors.initials: BC
authors.lastname: Willis
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Chad R
authors.initials: CR
authors.lastname: Frasier
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Luis F
authors.initials: LF
authors.lastname: Lopez-Santiago
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Xianming
authors.initials: X
authors.lastname: Lin
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Ramos-Mondragón
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: David S
authors.initials: DS
authors.lastname: Auerbach
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Chunling
authors.initials: C
authors.lastname: Chen
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Zhenxun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Justus
authors.initials: J
authors.lastname: Anumonwo
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
authors.forename: José
authors.initials: J
authors.lastname: Jalife
authors.affiliation: From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.). lisom@umich.edu.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Isom
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology; D015153:Blotting, Western; D002478:Cells, Cultured; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000503:physiopathology*; D051379:Mice; D009000:Monocytes; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000503:physiopathology; D062548:Voltage-Gated Sodium Channel beta-2 Subunit / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; C540272:SCN2B protein, mouse; D062548:Voltage-Gated Sodium Channel beta-2 Subunit
keywords: action potentials; atrial fibrillation; fibrosis; potassium channels; sodium channels