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

作者：Kucerova Dana^*; Baba Hideo A; Boknik Peter; Fabritz Larissa; Heinick Alexander; Mat' us Marek; Mueller Frank U; Neumann Joachim; Schmitz Wilhelm; Kirchhefer Uwe

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2012, 302(10): H2008-H2017.

DOI：10.1152/ajpheart.00457.2011

• contractility
• calcium signaling
• sarcoplasmic reticulum
• overexpression
• heart failure

Kucerova D, Baba HA, Boknik P, Fabritz L, Heinick A, Mat%26apos;us M, Muller FU, Neumann J, Schmitz W, Kirchhefer U. Modulation of SR Ca2+ release by the triadin-to-calsequestrin ratio in ventricular myocytes. Am J Physiol Heart Circ Physiol 302: H2008-H2017, 2012. First published March 16, 2012; doi: 10.1152/ajpheart.00457.2011.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 (TG(CSQ)) 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 (TG(CxT)) could be beneficial for impaired intracellular Ca2+ signaling and contractile function. Indeed, the depressed intracellular Ca2+ 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 Ca2+ regulatory proteins. For example, the protein level of the L-type Ca2+ channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo) plasmic reticulum Ca2+-ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared with TGCSQ, whereas JUN expression and [H-3]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 Ca2+ load was higher in both TG(CxT) and TG(CSQ) 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 TG(CxT) compared with TG(CSQ). Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca2+ 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 beta-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca2+ signaling.

• 出版日期2012-5