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.