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.
In addition to its calcium-transporting functions,
SERCA1 generates heat in
brown adipose tissue and in
skeletal muscles.[2][3] Along with the heat it naturally produces due to its inefficiency in pumping Ca2+ ions, when it binds to a regulator called
sarcolipin it stops pumping and functions solely as an ATP hydrolase. This mechanism of thermogenesis is widespread in mammals and in
endothermic fishes.[4][5]
Regulation
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
β-adrenergic stimulation reduces the association between SERCA and PLB by the phosphorylation of PLB by
PKA.[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 with
GSK3β. Phosphorylation of
SERCA2a 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 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.
For experimental purposes, SERCA can be inhibited by
thapsigargin and induced by
istaroxime.
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]
Paralogs
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.
^Kaasik, Allen; Minajeva, Ave; Paju, Kalju; Eimre, Margus; Seppet, Enn K. (1997). "Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles". Molecular and Cellular Biochemistry. 176 (1/2): 119–126.
doi:
10.1023/A:1006887231150.
PMID9406153.
S2CID8199751.