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) |
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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 |
Keywords
- Calsequestrin
- Cardiac muscle
- Cav1.2
- RyR2
- Sarcoplasmic reticulum
ASJC Scopus subject areas
- General