Modulation of SR Ca2+ release by the triadin-to-calsequestrin ratio in ventricular myocytes

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 302; no. 10; p. H2008
• Main Authors: Kučerová, Dana, Baba, Hideo A, Bokník, Peter, Fabritz, Larissa, Heinick, Alexander, Mát'uš, Marek, Müller, Frank U, Neumann, Joachim, Schmitz, Wilhelm, Kirchhefer, Uwe
• Format: Journal Article
• Language: English
• Published: United States 15-05-2012
• Subjects: Animals; Calcium - metabolism; Calcium Signaling - physiology; Calsequestrin - genetics; Calsequestrin - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Disease Models, Animal; Fibrosis; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Ventricles - cytology; Heart Ventricles - metabolism; Heart Ventricles - pathology; Mice; Mice, Transgenic; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardial Contraction - physiology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00457.2011

Calsequestrin (CSQ) is a Ca(2+) storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca(2+) signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TG(CSQ)) was associated with heart failure, attenuation of SR Ca(2+) release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TG(CxT)) could be beneficial for impaired intracellular Ca(2+) signaling and contractile function. Indeed, the depressed intracellular Ca(2+) concentration ([Ca](i)) peak amplitude in TG(CSQ) was normalized by co-overexpression in TG(CxT) myocytes. This effect was associated with changes in the expression of cardiac Ca(2+) regulatory proteins. For example, the protein level of the L-type Ca(2+) channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared with TG(CSQ), whereas JUN expression and [(3)H]ryanodine binding were lower in both TG(CxT) and TG(CSQ) compared with wild-type hearts. As a result of these expressional changes, the SR Ca(2+) load was higher in both TG(CxT) and TG(CSQ) myocytes. In contrast to the improved cellular Ca(2+), 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 TG(CxT) compared with TG(CSQ). Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca(2+) release compared with TG(CSQ) 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 Ca(2+) signaling.