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 junctophilin 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 beta-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.
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Authors | 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 |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 106
Issue 18
Pg. 7636-41
(May 05 2009)
ISSN: 1091-6490 [Electronic] United States |
PMID | 19383796
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- CACNA1C protein, mouse
- Calcium Channels, L-Type
- Carrier Proteins
- Intracellular Signaling Peptides and Proteins
- Muscle Proteins
- Trdn protein, mouse
- Calcium
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Topics |
- Animals
- Arrhythmias, Cardiac
(genetics, pathology, physiopathology)
- Calcium
(metabolism)
- Calcium Channels, L-Type
(metabolism)
- Carrier Proteins
(genetics, physiology)
- Heart
(physiology, physiopathology)
- Intracellular Signaling Peptides and Proteins
- Mice
- Mice, Mutant Strains
- Muscle Proteins
(genetics, physiology)
- Myocardial Contraction
(genetics)
- Myocardium
(metabolism, ultrastructure)
- Sarcoplasmic Reticulum
(metabolism, ultrastructure)
- Sequence Deletion
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