Structure-Function Relationship of the SERCA Pump and Its Regulation by Phospholamban and Sarcolipin

Calcium is a universal second messenger involved in diverse cellular processes, including excitation-contraction coupling in muscle. The contraction and relaxation of cardiac muscle cells are regulated by the cyclic movement of calcium primarily between the extracellular space, the cytoplasm and the sarcoplasmic reticulum (SR). The rapid removal of calcium from the cytosol is primarily facilitated by the sarco(endo)plasmic reticulum calcium ATPase (SERCA) which pumps calcium back into the SR lumen and thereby controls the amount of calcium in the SR. The most studied member of the P-type ATPase family, SERCA has multiple tissue- and cell-specific isoforms and is primarily regulated by two peptides in muscle, phospholamban and sarcolipin. The multifaceted regulation of SERCA via these peptides is exemplified in the biological fine-tuning of their independent oligomerization and regulation. In this chapter, we overview the structure-function relationship of SERCA and its peptide modulators, detailing the regulation of the complexes and summarizing their physiological and disease relevance.