Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity.
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.
Yuan
Qunying
Q
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
Fan
Guo-Chang
GC
Dong
Min
M
Altschafl
Beth
B
Diwan
Abhinav
A
Ren
Xiaoping
X
Hahn
Harvey H
HH
Zhao
Wen
W
Waggoner
Jason R
JR
Jones
Larry R
LR
Jones
W Keith
WK
Bers
Donald M
DM
Dorn
Gerald W
GW
Wang
Hong-Sheng
HS
Valdivia
Héctor H
HH
Chu
Guoxiang
G
Kranias
Evangelia G
EG
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*
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