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Gene Review

Atp2a1  -  ATPase, Ca++ transporting, cardiac muscle,...

Mus musculus

Synonyms: Calcium pump 1, Calcium-transporting ATPase sarcoplasmic reticulum type, fast twitch skeletal muscle isoform, Endoplasmic reticulum class 1/2 Ca(2+) ATPase, SERCA1, SR Ca(2+)-ATPase 1, ...
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Disease relevance of Atp2a1


High impact information on Atp2a1

  • S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide [6].
  • Nitric oxide (NO) physiologically stimulates the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) to decrease intracellular Ca(2+) concentration and relax cardiac, skeletal and vascular smooth muscle [6].
  • Purified SERCA was S-glutathiolated by ONOO(-) and the increase in Ca(2+)-uptake activity of SERCA reconstituted in phospholipid vesicles required the presence of glutathione [6].
  • Mutation of the SERCA-reactive Cys674 to serine abolished these effects [6].
  • Here, we show that NO-derived peroxynitrite (ONOO(-)) directly increases SERCA activity by S-glutathiolation and that this modification of SERCA is blocked by irreversible oxidation of the relevant cysteine thiols during atherosclerosis [6].

Chemical compound and disease context of Atp2a1

  • The absence of SERCA1 in type II fibers, and the absence of compensatory increases in other Ca(2+) handling proteins, coupled with the marked increase in contractile function required of the diaphragm muscle to support postnatal respiration, can account for respiratory failure in term SERCA1-null mice [1].

Biological context of Atp2a1


Anatomical context of Atp2a1

  • PLB via modulation of SERCA can play a major role in regulation of both phasic and tonic smooth muscle contractility [11].
  • Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) [12].
  • These findings indicate that ectopic expression of phospholamban in fast-twitch skeletal muscle is associated with inhibition of SERCA1 activity and decreased relaxation rates of this muscle [13].
  • To determine the effect of phospholamban expression on SERCA1 activity, microsomes were isolated from transfected and nontransfected C2C12 cell myotubes, and the initial rates of 45Ca(2+)-uptake were determined over a wide range of Ca2+ concentrations (0.1-10 microM) [14].
  • Differentiation of C2C12 myoblasts to myotubes was associated with induction of SERCA1 expression, assessed by Western blotting analysis using Ca(2+)-ATPase isoform specific antibodies [14].

Associations of Atp2a1 with chemical compounds


Regulatory relationships of Atp2a1


Other interactions of Atp2a1

  • The role of sarcolipin (SLN) in cardiac physiology was critically evaluated by generating a transgenic (TG) mouse model in which the SLN to sarco(endoplasmic)reticulum (SR) Ca(2+) ATPase (SERCA) ratio was increased in the ventricle [20].
  • This effect of IRS-1 may be mediated via an interaction with the sarco-endoplasmic reticulum calcium ATPase (SERCA) [16].
  • Triadin 1 overexpression was accompanied by time-dependent changes in the protein expression of the ryanodine receptor, junctin, and cardiac/slow-twitch muscle SR Ca(2+)-ATPase isoform [21].
  • The SERCA 2a-inhibitor cyclopiazonic acid did not affect myosin ATPase-activity in this system [22].
  • We evaluated the importance and role of phospholamban, a protein which inhibits the sarcoplasmic reticulum (SR) calcium ATPase (SERCA), in regulating the contractility of the phasic mouse portal vein [23].

Analytical, diagnostic and therapeutic context of Atp2a1

  • RESULTS: Quantitative immunoblotting revealed an increase of 1.8-fold in total SERCA level, while SERCA2 was decreased to 50% of wild types [24].
  • Co-immunoprecipitation of IRS-1 and SERCA in CHO-T cells and beta-cells confirms that these proteins do indeed interact directly [16].
  • Tissue distribution of the alternatively spliced mRNAs was studied by RT-PCR: SERCA 3b was the only isoform expressed in endothelial cells from aorta and heart and also was the major isoform in lung and kidney whereas SERCA 3a and 3b were coexpressed in trachea, intestine, thymus, spleen, and fetal liver [25].
  • Recent studies have shown that decreased expression and activity of SERCA are associated with end-stage heart failure in humans and in experimental animal models of heart failure [4].
  • A gene therapy type of approach delivering increased amounts of SERCA or phospholamban mutants leading to increased SERCA activity should therefore be considered in the future [5].


  1. Targeted disruption of the ATP2A1 gene encoding the sarco(endo)plasmic reticulum Ca2+ ATPase isoform 1 (SERCA1) impairs diaphragm function and is lethal in neonatal mice. Pan, Y., Zvaritch, E., Tupling, A.R., Rice, W.J., de Leon, S., Rudnicki, M., McKerlie, C., Banwell, B.L., MacLennan, D.H. J. Biol. Chem. (2003) [Pubmed]
  2. Altered force-frequency response in non-failing hearts with decreased SERCA pump-level. Huke, S., Liu, L.H., Biniakiewicz, D., Abraham, W.T., Periasamy, M. Cardiovasc. Res. (2003) [Pubmed]
  3. The effect of isoproterenol on phospholamban-deficient mouse hearts with altered thyroid conditions. Brittsan, A.G., Kiss, E., Edes, I., Grupp, I.L., Grupp, G., Kranias, E.G. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  4. Transgenic mouse models for cardiac dysfunction by a specific gene manipulation. Babu, G.J., Periasamy, M. Methods Mol. Med. (2005) [Pubmed]
  5. Calcium regulatory proteins and their alteration by transgenic approaches. Dillmann, W.H. Am. J. Cardiol. (1999) [Pubmed]
  6. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Adachi, T., Weisbrod, R.M., Pimentel, D.R., Ying, J., Sharov, V.S., Schöneich, C., Cohen, R.A. Nat. Med. (2004) [Pubmed]
  7. The gene encoding sarcoplasmic reticulum calcium ATPase-1 (Atp2a1) maps to distal mouse chromosome 7. Schleef, M., Simon-Chazottes, D., Lengeling, A., Klocke, R., Jockusch, H., Yarden, Y., Guénet, J. Mamm. Genome (1996) [Pubmed]
  8. Phenotypes of SERCA and PMCA knockout mice. Prasad, V., Okunade, G.W., Miller, M.L., Shull, G.E. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  9. Targeted ablation of the phospholamban gene is associated with a marked decrease in sensitivity in aortic smooth muscle. Lalli, J., Harrer, J.M., Luo, W., Kranias, E.G., Paul, R.J. Circ. Res. (1997) [Pubmed]
  10. Sarco(endo)plasmic reticulum Ca2+ ATPase isoforms and their role in muscle physiology and pathology. Loukianov, E., Ji, Y., Baker, D.L., Reed, T., Babu, J., Loukianova, T., Greene, A., Shull, G., Periasamy, M. Ann. N. Y. Acad. Sci. (1998) [Pubmed]
  11. The sarcoplasmic reticulum and smooth muscle function: evidence from transgenic mice. Paul, R.J., Shull, G.E., Kranias, E.G. Novartis Found. Symp. (2002) [Pubmed]
  12. Phospholamban is present in endothelial cells and modulates endothelium-dependent relaxation. Evidence from phospholamban gene-ablated mice. Sutliff, R.L., Hoying, J.B., Kadambi, V.J., Kranias, E.G., Paul, R.J. Circ. Res. (1999) [Pubmed]
  13. Ectopic expression of phospholamban in fast-twitch skeletal muscle alters sarcoplasmic reticulum Ca2+ transport and muscle relaxation. Slack, J.P., Grupp, I.L., Ferguson, D.G., Rosenthal, N., Kranias, E.G. J. Biol. Chem. (1997) [Pubmed]
  14. Expression of phospholamban in C2C12 cells and regulation of endogenous SERCA1 activity. Harrer, J.M., Ponniah, S., Ferguson, D.G., Kranias, E.G. Mol. Cell. Biochem. (1995) [Pubmed]
  15. Maximal inhibition of SERCA2 Ca(2+) affinity by phospholamban in transgenic hearts overexpressing a non-phosphorylatable form of phospholamban. Brittsan, A.G., Carr, A.N., Schmidt, A.G., Kranias, E.G. J. Biol. Chem. (2000) [Pubmed]
  16. Insulin receptor substrate 1 regulation of sarco-endoplasmic reticulum calcium ATPase 3 in insulin-secreting beta-cells. Borge, P.D., Wolf, B.A. J. Biol. Chem. (2003) [Pubmed]
  17. Sarcolipin retention in the endoplasmic reticulum depends on its C-terminal RSYQY sequence and its interaction with sarco(endo)plasmic Ca(2+)-ATPases. Gramolini, A.O., Kislinger, T., Asahi, M., Li, W., Emili, A., MacLennan, D.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. SERCA overexpression reduces hydroxyl radical injury in murine myocardium. Hiranandani, N., Bupha-Intr, T., Janssen, P.M. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  19. The amino-terminal 200 amino acids of the plasma membrane Na+,K+-ATPase alpha subunit confer ouabain sensitivity on the sarcoplasmic reticulum Ca(2+)-ATPase. Ishii, T., Takeyasu, K. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  20. Targeted overexpression of sarcolipin in the mouse heart decreases sarcoplasmic reticulum calcium transport and cardiac contractility. Babu, G.J., Bhupathy, P., Petrashevskaya, N.N., Wang, H., Raman, S., Wheeler, D., Jagatheesan, G., Wieczorek, D., Schwartz, A., Janssen, P.M., Ziolo, M.T., Periasamy, M. J. Biol. Chem. (2006) [Pubmed]
  21. Altered function in atrium of transgenic mice overexpressing triadin 1. Kirchhefer, U., Baba, H.A., Kobayashi, Y.M., Jones, L.R., Schmitz, W., Neumann, J. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  22. The enhanced contractility in phospholamban deficient mouse hearts is not associated with alterations in (Ca2+)-sensitivity or myosin ATPase-activity of the contractile proteins. Schwinger, R.H., Brixius, K., Savvidou-Zaroti, P., Bölck, B., Zobel, C., Frank, K., Kranias, E.G., Hoischen, S., Erdmann, E. Basic Res. Cardiol. (2000) [Pubmed]
  23. Regulation of the spontaneous contractile activity of the portal vein by the sarcoplasmic reticulum: evidence from the phospholamban gene-ablated mouse. Sutliff, R.L., Conforti, L., Weber, C.S., Kranias, E.G., Paul, R.J. Vascul. Pharmacol. (2004) [Pubmed]
  24. Combined phospholamban ablation and SERCA1a overexpression result in a new hyperdynamic cardiac state. Zhao, W., Frank, K.F., Chu, G., Gerst, M.J., Schmidt, A.G., Ji, Y., Periasamy, M., Kranias, E.G. Cardiovasc. Res. (2003) [Pubmed]
  25. Characterization of the 3' end of the mouse SERCA 3 gene and tissue distribution of mRNA spliced variants. Ozog, A., Pouzet, B., Bobe, R., Lompré, A.M. FEBS Lett. (1998) [Pubmed]
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