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Modulation of SR Ca^sup 2+^ release by the triadin-to-calsequestrin ratio in ventricular myocytes
Calsequestrin (CSQ) is a Ca2+ storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca2+ signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (...
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Published in: | American journal of physiology. Heart and circulatory physiology 2012-05, Vol.302 (10), p.H2008 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Calsequestrin (CSQ) is a Ca2+ storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca2+ signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TGCSQ) was associated with heart failure, attenuation of SR Ca2+ release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TGCxT) could be beneficial for impaired intracellular Ca2+ signaling and contractile function. Indeed, the depressed intracellular Ca2+ concentration ([Ca]i) peak amplitude in TGCSQ was normalized by co-overexpression in TGCxT myocytes. This effect was associated with changes in the expression of cardiac Ca2+ regulatory proteins. For example, the protein level of the L-type Ca2+ channel Cav1.2 was higher in TGCxT compared with TGCSQ. Sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) expression was reduced in TGCxT compared with TGCSQ, whereas JUN expression and [3H]ryanodine binding were lower in both TGCxT and TGCSQ compared with wild-type hearts. As a result of these expressional changes, the SR Ca2+ load was higher in both TGCxT and TGCSQ myocytes. In contrast to the improved cellular Ca2+, transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TGCxT compared with TGCSQ. Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca2+ release compared with TGCSQ mice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca2+ signaling. [PUBLICATION ABSTRACT] |
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ISSN: | 0363-6135 1522-1539 |