Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias

Nagesh Chopra, Tao Yang, Parisa Asghari, Edwin D. Moore, Sabine Huke, Brandy Akin, Robert A. Cattolica, Claudio F. Perez, Thinn Hlaing, Barbara E C Knollmann-Ritschel, Larry R. Jones, Isaac N Pessah, Paul D. Allen, Clara Franzini-Armstrong, Björn C. Knollmann

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Heart muscle excitation-contraction (E-C) coupling is governed by Ca 2+ release units (CRUs) whereby Ca 2+ influx via L-type Ca 2+ channels (Cav1.2) triggers Ca 2+ release from juxtaposed Ca 2+ release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn -/-). The structure and protein composition of the cardiac CRU is significantly altered in Trdn -/- hearts. jSR proteins (RyR2, Casq2, junctin, and juncto- philin 1 and 2) are significantly reduced in Trdn -/-hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn -/-myocytes. CRU function is impaired in Trdn -/- myocytes, with reduced SR Ca 2+ release and impaired negative feedback of SR Ca 2+ release on Cav1.2 Ca 2+ currents (I Ca). Uninhibited Ca 2+ influx via I Ca likely contributes to Ca 2+ overload and results in spontaneous SR Ca 2+ releases upon β-adrenergic receptor stimulation with isoproterenol in Trdn -/- myocytes, and ventricular arrhythmias in Trdn -/- mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.

Original languageEnglish (US)
Pages (from-to)7636-7641
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number18
DOIs
StatePublished - May 5 2009

Fingerprint

Excitation Contraction Coupling
Cardiac Arrhythmias
Sarcoplasmic Reticulum
Ryanodine Receptor Calcium Release Channel
Genes
Muscle Cells
Proteins
Calsequestrin
Muscle Contraction
triadin
Isoproterenol
Adrenergic Receptors
Myocardium
Electron Microscopy

Keywords

  • Calsequestrin
  • Cardiac muscle
  • Cav1.2
  • RyR2
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • General

Cite this

Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias. / Chopra, Nagesh; Yang, Tao; Asghari, Parisa; Moore, Edwin D.; Huke, Sabine; Akin, Brandy; Cattolica, Robert A.; Perez, Claudio F.; Hlaing, Thinn; Knollmann-Ritschel, Barbara E C; Jones, Larry R.; Pessah, Isaac N; Allen, Paul D.; Franzini-Armstrong, Clara; Knollmann, Björn C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 18, 05.05.2009, p. 7636-7641.

Research output: Contribution to journalArticle

Chopra, N, Yang, T, Asghari, P, Moore, ED, Huke, S, Akin, B, Cattolica, RA, Perez, CF, Hlaing, T, Knollmann-Ritschel, BEC, Jones, LR, Pessah, IN, Allen, PD, Franzini-Armstrong, C & Knollmann, BC 2009, 'Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 18, pp. 7636-7641. https://doi.org/10.1073/pnas.0902919106
Chopra, Nagesh ; Yang, Tao ; Asghari, Parisa ; Moore, Edwin D. ; Huke, Sabine ; Akin, Brandy ; Cattolica, Robert A. ; Perez, Claudio F. ; Hlaing, Thinn ; Knollmann-Ritschel, Barbara E C ; Jones, Larry R. ; Pessah, Isaac N ; Allen, Paul D. ; Franzini-Armstrong, Clara ; Knollmann, Björn C. / Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 18. pp. 7636-7641.
@article{7af6f399e9fb4b4da6cea269de10cd99,
title = "Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias",
abstract = "Heart muscle excitation-contraction (E-C) coupling is governed by Ca 2+ release units (CRUs) whereby Ca 2+ influx via L-type Ca 2+ channels (Cav1.2) triggers Ca 2+ release from juxtaposed Ca 2+ release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn -/-). The structure and protein composition of the cardiac CRU is significantly altered in Trdn -/- hearts. jSR proteins (RyR2, Casq2, junctin, and juncto- philin 1 and 2) are significantly reduced in Trdn -/-hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50{\%} reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn -/-myocytes. CRU function is impaired in Trdn -/- myocytes, with reduced SR Ca 2+ release and impaired negative feedback of SR Ca 2+ release on Cav1.2 Ca 2+ currents (I Ca). Uninhibited Ca 2+ influx via I Ca likely contributes to Ca 2+ overload and results in spontaneous SR Ca 2+ releases upon β-adrenergic receptor stimulation with isoproterenol in Trdn -/- myocytes, and ventricular arrhythmias in Trdn -/- mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.",
keywords = "Calsequestrin, Cardiac muscle, Cav1.2, RyR2, Sarcoplasmic reticulum",
author = "Nagesh Chopra and Tao Yang and Parisa Asghari and Moore, {Edwin D.} and Sabine Huke and Brandy Akin and Cattolica, {Robert A.} and Perez, {Claudio F.} and Thinn Hlaing and Knollmann-Ritschel, {Barbara E C} and Jones, {Larry R.} and Pessah, {Isaac N} and Allen, {Paul D.} and Clara Franzini-Armstrong and Knollmann, {Bj{\"o}rn C.}",
year = "2009",
month = "5",
day = "5",
doi = "10.1073/pnas.0902919106",
language = "English (US)",
volume = "106",
pages = "7636--7641",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias

AU - Chopra, Nagesh

AU - Yang, Tao

AU - Asghari, Parisa

AU - Moore, Edwin D.

AU - Huke, Sabine

AU - Akin, Brandy

AU - Cattolica, Robert A.

AU - Perez, Claudio F.

AU - Hlaing, Thinn

AU - Knollmann-Ritschel, Barbara E C

AU - Jones, Larry R.

AU - Pessah, Isaac N

AU - Allen, Paul D.

AU - Franzini-Armstrong, Clara

AU - Knollmann, Björn C.

PY - 2009/5/5

Y1 - 2009/5/5

N2 - Heart muscle excitation-contraction (E-C) coupling is governed by Ca 2+ release units (CRUs) whereby Ca 2+ influx via L-type Ca 2+ channels (Cav1.2) triggers Ca 2+ release from juxtaposed Ca 2+ release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn -/-). The structure and protein composition of the cardiac CRU is significantly altered in Trdn -/- hearts. jSR proteins (RyR2, Casq2, junctin, and juncto- philin 1 and 2) are significantly reduced in Trdn -/-hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn -/-myocytes. CRU function is impaired in Trdn -/- myocytes, with reduced SR Ca 2+ release and impaired negative feedback of SR Ca 2+ release on Cav1.2 Ca 2+ currents (I Ca). Uninhibited Ca 2+ influx via I Ca likely contributes to Ca 2+ overload and results in spontaneous SR Ca 2+ releases upon β-adrenergic receptor stimulation with isoproterenol in Trdn -/- myocytes, and ventricular arrhythmias in Trdn -/- mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.

AB - Heart muscle excitation-contraction (E-C) coupling is governed by Ca 2+ release units (CRUs) whereby Ca 2+ influx via L-type Ca 2+ channels (Cav1.2) triggers Ca 2+ release from juxtaposed Ca 2+ release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn -/-). The structure and protein composition of the cardiac CRU is significantly altered in Trdn -/- hearts. jSR proteins (RyR2, Casq2, junctin, and juncto- philin 1 and 2) are significantly reduced in Trdn -/-hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn -/-myocytes. CRU function is impaired in Trdn -/- myocytes, with reduced SR Ca 2+ release and impaired negative feedback of SR Ca 2+ release on Cav1.2 Ca 2+ currents (I Ca). Uninhibited Ca 2+ influx via I Ca likely contributes to Ca 2+ overload and results in spontaneous SR Ca 2+ releases upon β-adrenergic receptor stimulation with isoproterenol in Trdn -/- myocytes, and ventricular arrhythmias in Trdn -/- mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.

KW - Calsequestrin

KW - Cardiac muscle

KW - Cav1.2

KW - RyR2

KW - Sarcoplasmic reticulum

UR - http://www.scopus.com/inward/record.url?scp=66149129989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149129989&partnerID=8YFLogxK

U2 - 10.1073/pnas.0902919106

DO - 10.1073/pnas.0902919106

M3 - Article

VL - 106

SP - 7636

EP - 7641

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -