Multimeric Protein Complexes in Regulation of Cardiomyocyte Calcium Cycling and Survival

Abstract

Depressed sarcoplasmic reticulum (SR) Ca-cycling, leading to decreased function is a clinical hallmark of human and experimental heart failure. Thus, efforts have concentrated on elucidating the mechanisms contributing to aberrant SR Ca-homeostasis to uncover new therapeutic targets. Studies indicate that both SERCA and phospholamban (PLN) may represent attractive targets. However, the initial simple view of the PLN/SERCA regulatory complex has been modified by our identification of new proteins associated with regulation of SR Ca-transport and overall Ca-homeostasis in the cardiomyocyte. One of them is HAX-1, the anti-apoptotic protein, which interacts with PLN and alters the PLN inhibitory function. Acute or chronic overexpression of HAX-1 promoted PLN inhibition on the Ca-ATPase and decreased cardiomyocyte calcium kinetics and contractile parameters. Accordingly, ablation of HAX-1 significantly enhanced SERCA activity and calcium kinetics. Furthermore, the HAX-1/PLN interaction appeared to also regulate cardiomyocyte survival. The other regulatory protein is the SR intraluminal histidine-rich Ca-binding protein (HRC), which interacts with SERCA and regulates the enzyme's maximal Ca-transport velocity. Thus, HAX-1 and HRC may represent potential therapeutic targets in correcting the depressed SR Ca-cycling in heart failure. Furthermore, PLN activity is regulated by two phosphoproteins, the inhibitor-1 of protein phosphatase 1 and the small heat shock protein 20, which affect overall Ca-cycling and contractility. Interestingly, recent studies indicate that this multimeric SERCA/PLN-ensemble is involved in heart failure and arrhythmias, as well as apoptosis and cell death. Thus, targeted approaches to correct abnormalities at the SERCA/PLN complex may hold therapeutic promise in heart failure. In addition, we have identified human variants in these calcium-cycling genes that affect their “activity”, reflecting aberrant Ca-handling and increased cell death. Therefore, these mutations may be used as prognostic or diagnostic markers for heart failure and arrhythmia development.