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 language | English (US) |
|---|---|
| Pages (from-to) | 7636-7641 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 106 |
| Issue number | 18 |
| DOIs | |
| State | Published - May 5 2009 |
Fingerprint
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 journal › Article
}
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
C2 - 19383796
AN - SCOPUS:66149129989
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 -