Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2009; 106(18):7636-41. DOI: 10.1073/pnas.0902919106
Source: PubMed


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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Available from: Clara Franzini-Armstrong, Feb 03, 2015
    • "Cytoplasmic actins together with a specific tropomodulin isoform play an important role in their organisation[27], together with the protein Bin1, which is required for shaping T-tubules[28]and the protein junctophilin-2, which defines the distance between the plasma membrane and the membrane of the SR[29]. Within the SR, proteins such as triadin and to a lesser extent junctin[30,31]were shown to be important for the organisation of diads in mice and recently mutations in triadin were shown to be a possible cause of sudden cardiac death in humans[32]. "
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    • "In contrast, the frequency and extent of JMCs are largely preserved in Casq2-null cardiomyocytes, although SR cisternae are significantly enlarged in these cells [21]. In Trdnnull mice, the number and the size of dyadic junctions are reduced in cardiomyocytes [22], while triad alteration is subtler in skeletal muscles [23]. Specifically, triad orientation is modified and calsequestrin is occasionally mis-localized in triadin-deficient skeletal muscle cells [23]. "
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    • "Thereby, lowering the SR Ca 2+ concentration during a spark would make the RyRs insensitive for Ca 2+ on the cytosolic side of the channels, which causes their deactivation. Based on observations in SR vesicles, RyRs in lipid bilayers and cells overexpressing calsequestrin, deactivation has been suggested to occur via a retrograde signal mediated by allosteric interactions between calsequestrin (acting as the Ca 2+ sensor) and junctin and/or triadin and the RyR [2] [8] [49] [50]. This mode of spark termination could be stabilized by a reinforcing mechanism that has been proposed recently based on model predictions. "
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