title: Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity.
abstract: BACKGROUND
  Abnormal sarcoplasmic reticulum calcium (Ca) cycling is increasingly recognized as an important mechanism for increased ventricular automaticity that leads to lethal ventricular arrhythmias. Previous studies have linked lethal familial arrhythmogenic disorders to mutations in the ryanodine receptor and calsequestrin genes, which interact with junctin and triadin to form a macromolecular Ca-signaling complex. The essential physiological effects of junctin and its potential regulatory roles in sarcoplasmic reticulum Ca cycling and Ca-dependent cardiac functions, such as myocyte contractility and automaticity, are unknown.
  
  
  RESULTS
  The junctin gene was targeted in embryonic stem cells, and a junctin-deficient mouse was generated. Ablation of junctin was associated with enhanced cardiac function in vivo, and junctin-deficient cardiomyocytes exhibited increased contractile and Ca-cycling parameters. Short-term isoproterenol stimulation elicited arrhythmias, including premature ventricular contractions, atrioventricular heart block, and ventricular tachycardia. Long-term isoproterenol infusion also induced premature ventricular contractions and atrioventricular heart block in junctin-null mice. Further examination of the electrical activity revealed a significant increase in the occurrence of delayed afterdepolarizations. Consistently, 25% of the junctin-null mice died by 3 months of age with structurally normal hearts.
  
  
  CONCLUSIONS
  Junctin is an essential regulator of sarcoplasmic reticulum Ca release and contractility in normal hearts. Ablation of junctin is associated with aberrant Ca homeostasis, which leads to fatal arrhythmias. Thus, normal intracellular Ca cycling relies on maintenance of junctin levels and an intricate balance among the components in the sarcoplasmic reticulum quaternary Ca-signaling complex.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
authors.forename: Qunying
authors.initials: Q
authors.lastname: Yuan
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.forename: Beth
authors.initials: B
authors.lastname: Altschafl
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ren
authors.forename: Harvey H
authors.initials: HH
authors.lastname: Hahn
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.forename: Jason R
authors.initials: JR
authors.lastname: Waggoner
authors.forename: Larry R
authors.initials: LR
authors.lastname: Jones
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Chu
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D002316:Cardiotonic Agents; D004562:Electrocardiography; D053595:Embryonic Stem Cells; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007545:Isoproterenol; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018754:Ventricular Dysfunction / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*
chemical_list: D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D008565:Membrane Proteins; D009124:Muscle Proteins; C498841:Asph protein, mouse; D006899:Mixed Function Oxygenases; D007545:Isoproterenol; D002118:Calcium