SERCA resides in the sarcoplasmic reticulum (SR) within myocytes. It is a Ca2+ ATPase that transfers Ca2+ from the cytosol of the cell to the lumen of the SR at the expense of ATP hydrolysis during muscle relaxation.
There are 3 major domains on the cytoplasmic face of SERCA: the phosphorylation and nucleotide-binding domains, which form the catalytic site, and the actuator domain, which is involved in the transmission of major conformational changes.
The rate at which SERCA moves Ca2+ across the SR membrane can be controlled by the regulatory protein phospholamban (PLB/PLN). SERCA is not as active when PLB is bound to it. Increased ?-adrenergic stimulation reduces the association between SERCA and PLB by the phosphorylation of PLB by PKA. When PLB is associated with SERCA, the rate of Ca2+ movement is reduced; upon dissociation of PLB, Ca2+ movement increases.
Another protein, calsequestrin, binds calcium within the SR and helps to reduce the concentration of free calcium within the SR, which assists SERCA so that it does not have to pump against such a high concentration gradient. The SR has a much higher concentration of Ca2+ (10,000x) inside when compared to the cytoplasmic Ca2+ concentration. SERCA2 can be regulated by microRNAs, for instance miR-25 suppresses SERCA2 in heart failure.
There are 3 major paralogs, SERCA1-3, which are expressed at various levels in different cell types.
There are additional post-translational isoforms of both SERCA2 and SERCA3, which serve to introduce the possibility of cell-type-specific Ca2+-reuptake responses as well as increasing the overall complexity of the Ca2+ signaling mechanism.