Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR 
Ca-transport and Ca-release, is a key and universal characteristic of human and 
experimental heart failure. These SR processes are regulated by multimeric 
protein complexes, including protein kinases and phosphatases as well as their 
anchoring and regulatory subunits that fine-tune Ca-handling in specific SR 
sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and 
its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an 
inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or 
calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory 
effects. Recent studies identified additional regulatory proteins, associated 
with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of 
protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the 
HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal 
histidine-rich calcium binding protein (HRC) has been shown to interact with 
both SERCA2a and triadin. Notably, there is physical and direct interaction 
between these protein players, mediating a fine-cross talk between SR Ca-uptake, 
storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA 
interactome does not only impact cardiomyocyte contractility, but also survival 
and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes 
modulate their activity and interactions with other protein partners, resulting 
in depressed contractility and accelerated remodeling. These genetic variants 
may serve as potential prognostic or diagnostic markers in cardiac 
pathophysiology.