title: Neuronal Na+Channels Are Integral Components of Pro-arrhythmic Na+/Ca2+Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-adrenergic Stimulation.
abstract: BACKGROUND
  Cardiac arrhythmias are a leading cause of death in the US. Vast majority of these arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with increased levels of circulating catecholamines and involve abnormal impulse formation secondary to aberrant Ca2+and Na+handling. However, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) remains elusive.
  
  
  RESULTS
  We performed functional and structural studies to assess Ca2+and Na+signaling in ventricular myocyte as well as surface electrocardiograms in mouse models of cardiac calsequestrin (CASQ2)-associated CPVT. We demonstrate that a subpopulation of Na+channels (neuronal Na+channels; nNav) that colocalize with RyR2 and Na+/Ca2+exchanger (NCX) are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na+entry via nNavin the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA)-mediated SR Ca2+refill is both an essential and a necessary factor for the arrhythmogenesis. Furthermore, we show that augmentation of Na+entry involves β-AR-mediated activation of CAMKII subsequently leading to nNavaugmentation. Importantly, selective pharmacological inhibition as well as silencing of Nav1.6 inhibit myocyte arrhythmic potential and prevent arrhythmiasin vivo.
  
  
  CONCLUSIONS
  These data suggest that the arrhythmogenic alteration in Na+/Ca2+handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na+influx through nNav. Therefore, selective inhibition of these channels and Nav1.6 in particular can serve as a potential antiarrhythmic therapy.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US ; Division of Pharmacy Practice and Sciences, College of Pharmacy, The Ohio State University, Columbus, OH, US.
authors.forename: Przemysław B
authors.initials: PB
authors.lastname: Radwański
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.affiliation: Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, VA, USA.
authors.forename: Rengasayee
authors.initials: R
authors.lastname: Veeraraghavan
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Lucia
authors.initials: L
authors.lastname: Brunello
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA.
authors.forename: Sathya D
authors.initials: SD
authors.lastname: Unudurthi
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Makara
authors.affiliation: Division of Cardiology and Molecular Cardiology, Maugeri Foundation-University of Pavia, Pavia, Italy.
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Pompeo
authors.initials: P
authors.lastname: Volpe
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Antonis A
authors.initials: AA
authors.lastname: Armoundas
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, TN, USA.
authors.forename: Bjorn C
authors.initials: BC
authors.lastname: Knollmann
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, VA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA ; Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, US.
authors.forename: Sándor
authors.initials: S
authors.lastname: Györke
keywords: Diastolic Ca2+ release; Neuronal Na+ channels; Ventricular arrhythmias; β-adrenergic receptor