SERCA

Function

SERCA is a P-type ATPase. It resides in the sarcoplasmic reticulum (SR) within myocytes. It is a Ca2+ ATPase that transfers Ca2+ from the cytosol of the cell to the lumen of the SR. This uses energy from ATP hydrolysis during muscle relaxation.

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. Along with the heat it naturally produces due to its inefficiency in pumping 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.

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. 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.

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 and in rodent myocardium by thyroid hormones. This mechanism may contribute to the proarrhythmogenic effect of thyrotoxicosis.

Paralogs

There are 3 major paralogs, 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.

References

References

1. Marín-García, José. (2014-01-01). "Chapter 23 - Gene- and Cell-Based Therapy for Cardiovascular Disease". Academic Press.
2. (2005). "The thermogenic activity of rat brown adipose tissue and rabbit white muscle Ca²⁺-ATPase". IUBMB Life.
3. (June 2007). "Thermogenic activity of Ca²⁺-ATPase from skeletal muscle heavy sarcoplasmic reticulum: the role of ryanodine Ca²⁺ channel". Biochim. Biophys. Acta.
4. (2020-03-02). "Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis". Philosophical Transactions of the Royal Society B: Biological Sciences.
5. (2020-03-02). "The evolution of mechanisms involved in vertebrate endothermy". Philosophical Transactions of the Royal Society B: Biological Sciences.
6. MacLennan, David H.. (July 2003). "Phospholamban: a crucial regulator of cardiac contractility". Nature Reviews Molecular Cell Biology.
7. (2023-06-08). "SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases". Nature Communications.
8. (November 2005). "Thyroid hormones differentially regulate the distribution of rabbit skeletal muscle Ca(2+)-ATPase (SERCA) isoforms in light and heavy sarcoplasmic reticulum.". Molecular Membrane Biology.
9. (1 October 1997). "Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts.". The Journal of Clinical Investigation.
10. (1997). "Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles". Molecular and Cellular Biochemistry.
11. (15 August 2022). "Minor perturbations of thyroid homeostasis and major cardiovascular endpoints—Physiological mechanisms and clinical evidence". Frontiers in Cardiovascular Medicine.