SERCA

SERCA, or sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.

Function

SERCA is a P-type ATPase.[1] It resides in the sarcoplasmic reticulum (SR) within myocytes.[1] It is a Ca2+ ATPase that transfers Ca2+ from the cytosol of the cell to the lumen of the SR.[1] This uses energy from ATP hydrolysis during muscle relaxation.[1]

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.

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[7] and in rodent myocardium[8][9] by thyroid hormones. This mechanism may contribute to the proarrhythmogenic effect of thyrotoxicosis.[10]

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.

References
  1. Marín-García, José (2014-01-01), Marín-García, José (ed.), "Chapter 23 - Gene- and Cell-Based Therapy for Cardiovascular Disease", Post-Genomic Cardiology (Second Edition), Boston: Academic Press, pp. 783–833, doi:10.1016/b978-0-12-404599-6.00023-8, ISBN 978-0-12-404599-6, retrieved 2020-12-28
  2. de Meis L; Oliveira GM; Arruda AP; Santos R; Costa RM; Benchimol M (2005). "The thermogenic activity of rat brown adipose tissue and rabbit white muscle Ca2+-ATPase". IUBMB Life. 57 (4–5): 337–45. doi:10.1080/15216540500092534. PMID 16036618.
  3. Arruda AP; Nigro M; Oliveira GM; de Meis L (June 2007). "Thermogenic activity of Ca2+-ATPase from skeletal muscle heavy sarcoplasmic reticulum: the role of ryanodine Ca2+ channel". Biochim. Biophys. Acta. 1768 (6): 1498–505. doi:10.1016/j.bbamem.2007.03.016. PMID 17466935.
  4. Bal, Naresh C.; Periasamy, Muthu (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. 375 (1793): 20190135. doi:10.1098/rstb.2019.0135. PMC 7017432. PMID 31928193.
  5. Legendre, Lucas J.; Davesne, Donald (2020-03-02). "The evolution of mechanisms involved in vertebrate endothermy". Philosophical Transactions of the Royal Society B: Biological Sciences. 375 (1793): 20190136. doi:10.1098/rstb.2019.0136. PMC 7017440. PMID 31928191.
  6. MacLennan, David H.; Kranias, Evangelia G. (July 2003). "Phospholamban: a crucial regulator of cardiac contractility". Nature Reviews Molecular Cell Biology. 4 (7): 566–577. doi:10.1038/nrm1151. PMID 12838339. S2CID 3050392.
  7. Arruda, AP; Oliveira, GM; Carvalho, DP; De Meis, L (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. 22 (6): 529–37. doi:10.1080/09687860500412257. PMID 16373324. S2CID 29949157.
  8. Chang, KC; Figueredo, VM; Schreur, JH; Kariya, K; Weiner, MW; Simpson, PC; Camacho, SA (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. 100 (7): 1742–9. doi:10.1172/JCI119699. PMC 508357. PMID 9312172.
  9. 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. PMID 9406153. S2CID 8199751.
  10. Müller, Patrick; Leow, Melvin Khee-Shing; Dietrich, Johannes W. (15 August 2022). "Minor perturbations of thyroid homeostasis and major cardiovascular endpoints—Physiological mechanisms and clinical evidence". Frontiers in Cardiovascular Medicine. 9: 942971. doi:10.3389/fcvm.2022.942971. PMC 9420854. PMID 36046184.
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