Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity

Qunying Yuan, Guo Chang Fan, Min Dong, Beth Altschafl, Abhinav Diwan, Xiaoping Ren, Harvey H. Hahn, Wen Zhao, Jason R. Waggoner, Larry Jones, W. Keith Jones, Donald M. Bers, Gerald W. Dorn, Hong Sheng Wang, Héctor H. Valdivia, Guoxiang Chu, Evangelia G. Kranias

Research output: Contribution to journalArticle

68 Citations (Scopus)

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. METHODS AND 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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)300-309
Number of pages10
JournalCirculation
Volume115
Issue number3
DOIs
StatePublished - Jan 2007

Fingerprint

Sarcoplasmic Reticulum
Calcium
Cardiac Arrhythmias
Heart Block
Calcium Signaling
Ventricular Premature Complexes
Atrioventricular Block
Isoproterenol
Calsequestrin
Ryanodine Receptor Calcium Release Channel
Ventricular Tachycardia
Embryonic Stem Cells
Cardiac Myocytes
Muscle Cells
Genes
Homeostasis
Maintenance
Mutation

Keywords

  • Arrhythmia
  • Calcium
  • Proteins
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity. / Yuan, Qunying; Fan, Guo Chang; Dong, Min; Altschafl, Beth; Diwan, Abhinav; Ren, Xiaoping; Hahn, Harvey H.; Zhao, Wen; Waggoner, Jason R.; Jones, Larry; Jones, W. Keith; Bers, Donald M.; Dorn, Gerald W.; Wang, Hong Sheng; Valdivia, Héctor H.; Chu, Guoxiang; Kranias, Evangelia G.

In: Circulation, Vol. 115, No. 3, 01.2007, p. 300-309.

Research output: Contribution to journalArticle

Yuan, Q, Fan, GC, Dong, M, Altschafl, B, Diwan, A, Ren, X, Hahn, HH, Zhao, W, Waggoner, JR, Jones, L, Jones, WK, Bers, DM, Dorn, GW, Wang, HS, Valdivia, HH, Chu, G & Kranias, EG 2007, 'Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity', Circulation, vol. 115, no. 3, pp. 300-309. https://doi.org/10.1161/CIRCULATIONAHA.106.654699
Yuan, Qunying ; Fan, Guo Chang ; Dong, Min ; Altschafl, Beth ; Diwan, Abhinav ; Ren, Xiaoping ; Hahn, Harvey H. ; Zhao, Wen ; Waggoner, Jason R. ; Jones, Larry ; Jones, W. Keith ; Bers, Donald M. ; Dorn, Gerald W. ; Wang, Hong Sheng ; Valdivia, Héctor H. ; Chu, Guoxiang ; Kranias, Evangelia G. / Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity. In: Circulation. 2007 ; Vol. 115, No. 3. pp. 300-309.
@article{6ce291b9610d4e7fbe7a2f8f7e05be8c,
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. METHODS AND 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. CONCLUSION: 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.",
keywords = "Arrhythmia, Calcium, Proteins, Sarcoplasmic reticulum",
author = "Qunying Yuan and Fan, {Guo Chang} and Min Dong and Beth Altschafl and Abhinav Diwan and Xiaoping Ren and Hahn, {Harvey H.} and Wen Zhao and Waggoner, {Jason R.} and Larry Jones and Jones, {W. Keith} and Bers, {Donald M.} and Dorn, {Gerald W.} and Wang, {Hong Sheng} and Valdivia, {H{\'e}ctor H.} and Guoxiang Chu and Kranias, {Evangelia G.}",
year = "2007",
month = "1",
doi = "10.1161/CIRCULATIONAHA.106.654699",
language = "English",
volume = "115",
pages = "300--309",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity

AU - Yuan, Qunying

AU - Fan, Guo Chang

AU - Dong, Min

AU - Altschafl, Beth

AU - Diwan, Abhinav

AU - Ren, Xiaoping

AU - Hahn, Harvey H.

AU - Zhao, Wen

AU - Waggoner, Jason R.

AU - Jones, Larry

AU - Jones, W. Keith

AU - Bers, Donald M.

AU - Dorn, Gerald W.

AU - Wang, Hong Sheng

AU - Valdivia, Héctor H.

AU - Chu, Guoxiang

AU - Kranias, Evangelia G.

PY - 2007/1

Y1 - 2007/1

N2 - 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. METHODS AND 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. CONCLUSION: 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.

AB - 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. METHODS AND 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. CONCLUSION: 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.

KW - Arrhythmia

KW - Calcium

KW - Proteins

KW - Sarcoplasmic reticulum

UR - http://www.scopus.com/inward/record.url?scp=33846460794&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846460794&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.106.654699

DO - 10.1161/CIRCULATIONAHA.106.654699

M3 - Article

VL - 115

SP - 300

EP - 309

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 3

ER -