SERCA

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SERCA, or sarcoplasmic/endoplasmic reticulum Ca 2+-ATPase , or SR Ca 2+-ATPase , is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.

Contents

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.

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.

Related Research Articles

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<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

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<span class="mw-page-title-main">Calsequestrin</span> Calcium-binding protein

Calsequestrin is a calcium-binding protein that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also helps the sarcoplasmic reticulum store an extraordinarily high amount of calcium ions. Each molecule of calsequestrin can bind 18 to 50 Ca2+ ions. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface. Two forms of calsequestrin have been identified. The cardiac form Calsequestrin-2 (CASQ2) is present in cardiac and slow skeletal muscle and the fast skeletal form Calsequestrin-1(CASQ1) is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation. When calcium binds there is a structural change whereby the alpha-helical content of the protein increases from 3 to 11%. Both forms of calsequestrin are phosphorylated by casein kinase 2, but the cardiac form is phosphorylated more rapidly and to a higher degree. Calsequestrin is also secreted in the gut where it deprives bacteria of calcium ions..

<span class="mw-page-title-main">Calcium ATPase</span> Class of enzymes

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Plasma membrane Ca<sup>2+</sup> ATPase Transport protein

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The Bowditch effect, also known as the Treppe phenomenon or Treppe effect or Staircase Phenomenon, is an autoregulation method by which myocardial tension increases with an increase in heart rate. It was first observed by Henry Pickering Bowditch in 1871.

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<span class="mw-page-title-main">P-type ATPase</span>

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<span class="mw-page-title-main">ATP2A1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Sarcolipin</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Istaroxime</span> Chemical compound

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

References

  1. 1 2 3 4 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. ↑ Gonnot, Fabrice; Boulogne, Laura; Brun, Camille; Dia, Maya; Gouriou, Yves; Bidaux, Gabriel; Chouabe, Christophe; Crola Da Silva, Claire; Ducreux, Sylvie; Pillot, Bruno; Kaczmarczyk, Andrea; Leon, Christelle; Chanon, Stephanie; Perret, Coralie; Sciandra, Franck (2023-06-08). "SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases". Nature Communications. 14 (1): 3346. doi:10.1038/s41467-023-39027-x. ISSN   2041-1723. PMC   10250397 . PMID   37291092.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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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