Calcium cycling in the heart is integrally regulated by cardiac sarcoplasmic reticulum (SR) in which Ca2+ is released through a calcium channel (the ryanodine receptor type 2: RyR2) and is restored from cytosol through SR calcium ATPase 2a (SERCA2a). A major protein controlling Ca2+ re-uptake is SERCA2a that is located in the longitudinal region of the SR membrane. The activity of SERCA2a protein is mainly regulated by its inhibitory proteins: phospholamban (PLN), a 52-amino acid phosphoprotein and sarcolipin (SLN), a 31-amino acid transmembrane protein. The regulatory mechanism of PLN on SERCA2a has been extensively investigated. The physiological relevance of SLN in the heart, however, remains under investigation. Phosphorylation of PLN by protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CAMKII) releases its inhibitory effect on SERCA2a through direct molecular interaction and augments the systolic and diastolic parameters. A growing body of evidence has indicated that SERCA2a pump activity is a major determinant of cardiac muscle contractility and relaxation (Frank et al., 2003; Periasamy and Janssen, 2008; Kranias and Hajjar, 2012). In addition to pump function, impaired Ca2+ cycling may be involved in tissue viability, because Ca2+ is also an integral signaling molecule for numerous other cellular processes including survival and cell death. Recent studies have demonstrated that enhancement of the SR function by disrupting the interaction between SERCA2a and PLN or by simply increasing the expression of SERCA2a improves cardiac function and structure in animal models of heart failure. In addition to PLN and SLN, other regulators of SR Ca2+-transport were identified. One such regulator is SUMO (small ubiquitin-like modifier)-1 that causes SUMOylation on SERCA2a protein, which improves protein stability and activity. Another regulator is sarcalumenin, which is located in the SR lumen and interacts with SERCA2a to stabilize SERCA2a protein. In this chapter, I will review the advances in knowledge concerning Ca2+ re-uptake into the SR (Fig. 12.1).
Figure 12.1 A fine-tuning regulatory system of SERCA2a Ca2+ uptake function. Ca2+ is released through RyR2 and is restored from cytosol through SERCA2a. The upper- or lower-half part of the figure illustrates an increase or a decrease in SERCA2 pump activity, respectively. The left- or right-half part of the figure shows the SERCA2 pump regulation in the ventricle or in the atrium, respectively. The activity of SERCA2a protein is mainly regulated by PLN in the ventricle and SLN in the atrium. When the monomer form of PLN and SLN physically interacts with SERCA2a, SERCA2a pump activity is strongly inhibited. PLN also forms a pentamer, the inhibitory effect of which on SERCA2a is weaker than that of the monomeric form. Phosphorylation of PLN by PKA and CAMKII releases its inhibitory effect on SERCA2a, whereas SLN lacks such a phosphorylation site. In addition to PLN and SLN, SUMO (small ubiquitin-like modifier)-1 causes SUMOylation that improves the protein stability and activity of SERCA2a. SAR is located in the SR lumen and interacts with SERCA2a to stabilize SERCA2a protein. When PP-1 dephosphorylates PLN, PLN-interacts with SERCA2a to inhibit its function. I-1 activated by PKA or PKCa inhibits PP-1 activity and then increases the phosphorylated PLN. SR: sarcoplasmic reticulum; SERCA2a: SR calcium ATPase 2a; RyR2: the ryanodine receptor type 2; PLN: phospholamban; P-PLN: phosphorylated phospholamban; SLN; sarcolipin; SRL: sarcalumenin; PKA: protein kinase A; CAMKII: Ca2+/ calmodulin-dependent protein kinase II; SUMO-1: small ubiquitin-like modifier-1; PP-1: protein phosphatase-1; I-1: phosphatase inhibitor-1; PKCa: protein kinase Ca.