SERCA, orsarcoplasmic/endoplasmic reticulumCa²⁺-ATPase, orSRCa²⁺-ATPase, is acalcium ATPase-typeP-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.

SERCA is aP-type ATPase.^[1] It resides in thesarcoplasmic reticulum (SR) withinmyocytes.^[1] It is a Ca²⁺ ATPase that transfers Ca²⁺ from thecytosol of the cell to thelumen of the SR.^[1] This uses energy fromATP hydrolysis during muscle relaxation.^[1]

There are 3 majordomains on the cytoplasmic face of SERCA: thephosphorylation and nucleotide-binding domains, which form thecatalytic site, and the actuator domain, which is involved in the transmission of majorconformational changes.

In addition to its calcium-transporting functions,SERCA1 generates heat inbrown adipose tissue and inskeletal muscles.^[2][3] Along with the heat it naturally produces due to its inefficiency in pumpingCa²⁺
ions, when it binds to a regulator calledsarcolipin it stops pumping and functions solely as an ATP hydrolase. This mechanism of thermogenesis is widespread in mammals and inendothermic fishes.^[4][5]

The rate at which SERCA moves Ca²⁺ across the SR membrane can be controlled by the regulatory proteinphospholamban (PLB/PLN). SERCA is not as active when PLB is bound to it. Increasedβ-adrenergic stimulation reduces the association between SERCA and PLB by the phosphorylation of PLB byPKA.^[6] When PLB is associated with SERCA, the rate of Ca²⁺ movement is reduced; upon dissociation of PLB, Ca²⁺ movement increases.

Activity regulation of SERCA can also involve phosphorylation of SERCA itself by interaction withGSK3β. Phosphorylation ofSERCA2a at S663 was shown to reduce SERCA2a activity.^[7]

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 highconcentration 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.

For experimental purposes, SERCA can be inhibited bythapsigargin and induced byistaroxime.

SERCA function is upregulated in the skeletal muscle of rabbits^[8] and in rodent myocardium^[9][10] by thyroid hormones. This mechanism may contribute to the proarrhythmogenic effect of thyrotoxicosis.^[11]

There are 3 majorparalogs, SERCA1-3, which are expressed at various levels in different cell types.

• ATP2A1 – SERCA1
• ATP2A2 – SERCA2
• ATP2A3 – SERCA3

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.

• Sarcoplasmic+Reticulum+Calcium-Transporting+ATPases at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Transmembrane proteins

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