Endoplasmic reticulum calcium ATPase (SERCA)

Endoplasmic reticulum calcium ATPase (SERCA) is a membrane-bound P-type ATPase that uses ATP hydrolysis to pump calcium ions from the cytosol into the lumen of the endoplasmic or sarcoplasmic reticulum, thereby regulating intracellular calcium concentration[3][5][6]. SERCA is encoded by three main genes in humans (ATP2A1, ATP2A2, ATP2A3), generating multiple isoforms with tissue-specific distribution[4]. The enzyme is structurally characterized by 10 (or 11 for some isoforms) transmembrane helices and three cytoplasmic domains (actuator, nucleotide-binding, and phosphorylation)[4][5]. In muscle cells, SERCA is essential for muscle relaxation by sequestering calcium after contraction, and in non-muscle cells, it is critical for maintaining low cytosolic Ca²⁺ to support proper signaling and metabolic activity[6][7]. SERCA is tightly regulated by proteins such as phospholamban and sarcolipin, as well as by post-translational modifications and microRNAs[3][7][8]. Pathological alterations in SERCA expression or function contribute to heart failure, arrhythmias, and other diseases, making it an established and intensively studied therapeutic target[1][2][6].

Other names

Sarco/endoplasmic reticulum calcium ATPaseSarcoplasmic/endoplasmic reticulum calcium ATPaseSR Ca²⁺-ATPaseCalcium pumpATP2A1, ATP2A2, ATP2A3 (gene names for major human isoforms)

Inhibitors (e.g., thapsigargin, CPA): block Ca²⁺ transport by stabilizing specific conformational states, leading to cytosolic Ca²⁺ overload and apoptosis in sensitive cells; Activators (e.g., istaroxime): enhance calcium reuptake into the reticulum, improving muscle relaxation and cardiac function; Indirect modulation: targeting regulator proteins, such as phospholamban, that affect SERCA activity