SERCA

SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, is a membrane-bound enzyme of the P-type ATPase family that uses the energy from ATP hydrolysis to pump calcium ions from the cytosol into the lumen of the sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER). By maintaining low cytosolic Ca2+ and high internal stores, SERCA enables muscle relaxation and regulates various Ca2+-dependent signaling pathways.

In humans, there are three SERCA genes: ATP2A1 (SERCA1), ATP2A2 (SERCA2), and ATP2A3 (SERCA3). They encode distinct isoforms with tissue-specific expression patterns: SERCA1a is prominent in fast-twitch skeletal muscle; SERCA2a is the cardiac/slow-twitch isoform; SERCA2b is more ubiquitous with different kinetic properties; and SERCA3 is expressed in several tissues, including secretory cells. The enzyme is a P-type ATPase with ten transmembrane helices and cytosolic A, P, and N domains that coordinate phosphorylation and Ca2+ binding.

Mechanistically, SERCA cycles between E1 and E2 conformations. In E1, two Ca2+ ions bind from the cytosol. ATP binding leads to phosphorylation and formation of E1P, which converts to E2P and transports Ca2+ into the SR/ER lumen. Dephosphorylation returns the enzyme to E2 and then to E1, ready for another cycle. The overall stoichiometry is pumping two Ca2+ ions per ATP hydrolyzed.

Regulation is key to tissue physiology. In cardiac muscle, phospholamban (PLN) inhibits SERCA2a when unphosphorylated; phosphorylation by PKA or CaMKII relieves inhibition, enhancing Ca2+ uptake and relaxation. Other regulatory peptides, such as sarcolipin and myoregulin, modulate SERCA activity in muscle. Thapsigargin is a well-known experimental inhibitor that blocks SERCA by binding to the pump.

Mutations in ATP2A2 (SERCA2) cause Darier disease, a skin disorder, highlighting SERCA’s role in calcium homeostasis beyond muscle.