SERCA2a Plays a Central Role in Ca2+Uptake
The SR, an extensive intracellular membrane system consisting of a lipid bilayer that surrounds each myofibril, is a fundamental organelle that coordinates the movement of cytosolic Ca2+ during each cycle of cardiac contraction and relaxation.
SERCA2a, a cardiac and slow-twitch skeletal muscle isoform of the SERCA family that is a P-type ATPases, is the primary regulator of the rate of Ca2+ re-uptake during relaxation in the heart. SERCA2a is a 110 kD integral membrane protein with ten transmembrane helices that pumps Ca2+ into the SR lumen at the expense of ATP hydrolysis. The structure of SERCA, especially SERCA1 has been extensively investigated by Toyoshima's group (Toyoshima and Cornelius, 2013). They unveiled the high-resolution structure of SERCA1a, a fast-twitch skeletal muscle isoform of the SERCA family, providing in-depth information to understand the fundamental SERCA function for Ca2+ transport (Toyoshima and Mizutani, 2004). Since SERCA1a has high homology with SERCA 2a and is known to interact similarly with PLN and SLN, the high-resolution structure of SERCA1a should also provide new insights into the SERCA 2a pump function.
Numerous studies have demonstrated that the expression levels and enzymatic activity of SERCA2a are significantly decreased in human and experimental heart failure (Gwathmey et al., 1987; Lehnart et al., 2009). This can be simply confirmed by gene-targeting experiments in which heterozygous SERCA2a gene knockout mice have depressed cardiac function and myocyte contractility (Ji et al., 2000; Periasamy et al., 1999). Although the reduction in the expression levels of SERCA2a protein is critical to maintaining normal cardiac function, compensatory mechanisms could come into play. An inducible model with cardiac-specific deletion of SERCA2a was generated in order to investigate the mechanisms of SERCA2a deficiency (Andersson et al., 2009). Cardiac function was only moderately impaired 4 weeks after SERCA2a deletion in adult mice (Andersson et al., 2009). Heinis et al. also demonstrated that cardiac function was practically normal with SERCA2a protein levels at 32% of control hearts one week after initiating the down- regulation of SERCA2a (Heinis et al., 2013). Therefore, compensatory mechanisms help the heart with the down-regulation of SERCA2a to maintain its function for a limited time before going into a deteriorated state. The increases in the expression and activity of the Na+/Ca2+ exchanger and the plasma membrane Ca2+-ATPase and the decrease in phospholamban protein may collectively compensate for SERCA2a-deficient cardiac function for a limited time.
The endogenous inhibitor PLN tightly regulates the activity of SERCA2a, which will be discussed later. Although SERCA2a is known to be phosphorylated at serine-38 by Ca2/calmodulin- dependent protein kinase, the biophysiological significance of phosphorylated SERCA2a for Ca2+ transport is controversial (Rodriguez et al., 2004; Frank et al., 2003).
Instead of phosphorylation, it is now evident that SERCA2 activity is regulated by post-translational modification such as SUMOylation. SUMOylation is a ubiquitin-like reversible posttranslational modifications where SUMO (small ubiquitin-like modifier) covalently attaches at two lysine residues of SERCA2a. SERCA2a activity is specifically modified by SUMO-1 that binds SERCA2a to improve protein stability and activity (Kho et al., 2011).