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Gene Review

Atp2a2  -  ATPase, Ca++ transporting, cardiac muscle,...

Mus musculus

Synonyms: 9530097L16Rik, Calcium pump 2, Calcium-transporting ATPase sarcoplasmic reticulum type, slow twitch skeletal muscle isoform, D5Wsu150e, Endoplasmic reticulum class 1/2 Ca(2+) ATPase, ...
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Disease relevance of Atp2a2


High impact information on Atp2a2

  • Plasticity and adaptation of Ca2+ signaling and Ca2+-dependent exocytosis in SERCA2(+/-) mice [6].
  • The [Ca2+]i transient evoked by maximal agonist stimulation was shorter in cells from SERCA2(+/-) mice, due to an up-regulation of specific plasma membrane Ca2+ pump isoforms [6].
  • Altered Ca(2+) response was instead due to accelerated removal of Ca(2+) from the cytoplasm into intracellular compartments, which occurred in association with Hif-1alpha-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic/endoplasmic reticulum calcium ATPase 2) [7].
  • Consequently, the relative ratio of phospholamban to SERCA2 mRNA was 4.2-fold lower in the atrium than in the ventricle [8].
  • However, the relative mRNA level of Ca(2+)-ATPase (ratio of sarcoplasmic reticulum Ca(2+)-ATPase [SERCA2] to alpha-MHC) in the ventricle was 80% of that in the atrium [8].

Biological context of Atp2a2

  • The genetic mechanism of tumorigenesis did not involve loss of heterozygosity, as tumor cells analyzed by laser capture microdissection contained the wild-type Atp2a2 allele [9].
  • In summary, gene manipulation of PMCA indicates that PMCA, in addition to SERCA2 and NCX, plays a significant role in both excitation-contraction coupling and the Ca(2+) extrusion-relaxation relationship, i.e., Ca(2+) homeostasis, of bladder smooth muscle [10].
  • These results indicate that enhanced expression of the PFK, FAS and SERCA2 proteins may be important for FGF-1-stimulated cell proliferation [11].
  • These results indicate that reduced expression and increased phosphorylation of phospholamban provides compensation for decreased SERCA2 protein levels in heterozygous heart [12].
  • However, the resulting deficit is partially compensated by alterations in phospholamban/SERCA2 interactions and by up-regulation of the Na(+)-Ca(2+) exchanger [12].

Anatomical context of Atp2a2

  • Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility [9].
  • Atp2a2+/- mice overexpressed keratins associated with keratinocyte hyperactivation in normal forestomachs as early as 2 months of age [9].
  • These findings show that SERCA2 haploinsufficiency predisposes mice to tumor development via a novel mode of cancer susceptibility involving a global change in the tumorigenic potential of keratinized epithelium in Atp2a2+/- mice [9].
  • Here we show that aged heterozygous mutant (Atp2a2(+/-)) mice develop squamous cell tumors of the forestomach, esophagus, oral mucosa, tongue, and skin [1].
  • As the genes for myosin heavy chains (MHC alpha and MHC beta) and the cardiac sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2) are known to be regulated by T3, their cardiac expression was analyzed [13].

Associations of Atp2a2 with chemical compounds

  • We measured the contributions of Ca(2+) clearance components by inhibiting SERCA2 (with 10 microM cyclopiazonic acid) and/or NCX (by replacing NaCl with N-methyl-D-glucamine/HCl plus 10 microM KB-R7943) [10].
  • These results demonstrate that a decrease in SERCA2 levels can directly modify intracellular Ca(2+) homeostasis and myocyte contractility [12].
  • These findings are important and point out that the expression of NCX-1 is regulated antithetically to that of SERCA2 during heart development and in response to alterations in thyroid hormone levels [14].
  • Our results furthermore indicated that the myogenic RNA processing could be reversed for both types of Ca2+ pumps since the expression of the PMCA1 and SERCA2 muscle-specific messengers was rapidly down-regulated by cycloheximide treatment [15].
  • Decreased activity or levels of the calcium adenosine triphosphatase of the sarco(endo)plasmic reticulum (SERCA2) particularly have been known to cause a delay in calcium transients [16].

Physical interactions of Atp2a2


Regulatory relationships of Atp2a2


Other interactions of Atp2a2


Analytical, diagnostic and therapeutic context of Atp2a2

  • Inhibition of SERCA2 and NCX as well as gene targeting all prolonged the relaxation half-time [10].
  • Western blot analyses showed that SERCA2 protein levels were reduced in skin and other affected tissues of heterozygous mice [1].
  • By immunoblotting with monoclonal antibodies, we observed that these SR vesicles contained a normal amount of the cardiac isoform of the Ca2+ pump (SERCA 2) but only a trace level of PLB [25].
  • Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/- mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure [5].
  • In preliminary results, we found that SERCA2 transgenic rats submitted to ascending aortic constriction did not show the delayed relaxation of papillary muscle as was found in wild-type rats submitted to aortic constriction [16].


  1. Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump. Liu, L.H., Boivin, G.P., Prasad, V., Periasamy, M., Shull, G.E. J. Biol. Chem. (2001) [Pubmed]
  2. Cardiac protective effect of astragalus on viral myocarditis mice: comparison with perindopril. Chen, X.J., Bian, Z.P., Lu, S., Xu, J.D., Gu, C.R., Yang, D., Zhang, J.N. Am. J. Chin. Med. (2006) [Pubmed]
  3. The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Trost, S.U., Swanson, E., Gloss, B., Wang-Iverson, D.B., Zhang, H., Volodarsky, T., Grover, G.J., Baxter, J.D., Chiellini, G., Scanlan, T.S., Dillmann, W.H. Endocrinology (2000) [Pubmed]
  4. A SERCA2 pump with an increased Ca2+ affinity can lead to severe cardiac hypertrophy, stress intolerance and reduced life span. Vangheluwe, P., Tjwa, M., Van Den Bergh, A., Louch, W.E., Beullens, M., Dode, L., Carmeliet, P., Kranias, E., Herijgers, P., Sipido, K.R., Raeymaekers, L., Wuytack, F. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  5. Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity. Schultz, J.e.l. .J., Glascock, B.J., Witt, S.A., Nieman, M.L., Nattamai, K.J., Liu, L.H., Lorenz, J.N., Shull, G.E., Kimball, T.R., Periasamy, M. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  6. Plasticity and adaptation of Ca2+ signaling and Ca2+-dependent exocytosis in SERCA2(+/-) mice. Zhao, X.S., Shin, D.M., Liu, L.H., Shull, G.E., Muallem, S. EMBO J. (2001) [Pubmed]
  7. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Neumann, A.K., Yang, J., Biju, M.P., Joseph, S.K., Johnson, R.S., Haase, V.H., Freedman, B.D., Turka, L.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Differential phospholamban gene expression in murine cardiac compartments. Molecular and physiological analyses. Koss, K.L., Ponniah, S., Jones, W.K., Grupp, I.L., Kranias, E.G. Circ. Res. (1995) [Pubmed]
  9. Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility. Prasad, V., Boivin, G.P., Miller, M.L., Liu, L.H., Erwin, C.R., Warner, B.W., Shull, G.E. Cancer Res. (2005) [Pubmed]
  10. Role of plasma membrane Ca2+-ATPase in contraction-relaxation processes of the bladder: evidence from PMCA gene-ablated mice. Liu, L., Ishida, Y., Okunade, G., Shull, G.E., Paul, R.J. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  11. Fibroblast growth factor-1 induces phosphofructokinase, fatty acid synthase and Ca(2+)-ATPase mRNA expression in NIH 3T3 cells. Hsu, D.K., Donohue, P.J., Alberts, G.F., Winkles, J.A. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  12. Disruption of a single copy of the SERCA2 gene results in altered Ca2+ homeostasis and cardiomyocyte function. Ji, Y., Lalli, M.J., Babu, G.J., Xu, Y., Kirkpatrick, D.L., Liu, L.H., Chiamvimonvat, N., Walsh, R.A., Shull, G.E., Periasamy, M. J. Biol. Chem. (2000) [Pubmed]
  13. Altered cardiac phenotype in transgenic mice carrying the delta337 threonine thyroid hormone receptor beta mutant derived from the S family. Gloss, B., Sayen, M.R., Trost, S.U., Bluhm, W.F., Meyer, M., Swanson, E.A., Usala, S.J., Dillmann, W.H. Endocrinology (1999) [Pubmed]
  14. The expression of SR calcium transport ATPase and the Na(+)/Ca(2+)Exchanger are antithetically regulated during mouse cardiac development and in Hypo/hyperthyroidism. Reed, T.D., Babu, G.J., Ji, Y., Zilberman, A., Ver Heyen, M., Wuytack, F., Periasamy, M. J. Mol. Cell. Cardiol. (2000) [Pubmed]
  15. Alternative processing of the gene transcripts encoding a plasma-membrane and a sarco/endoplasmic reticulum Ca2+ pump during differentiation of BC3H1 muscle cells. De Jaegere, S., Wuytack, F., De Smedt, H., Van den Bosch, L., Casteels, R. Biochim. Biophys. Acta (1993) [Pubmed]
  16. Calcium regulatory proteins and their alteration by transgenic approaches. Dillmann, W.H. Am. J. Cardiol. (1999) [Pubmed]
  17. The relative phospholamban and SERCA2 ratio: a critical determinant of myocardial contractility. Koss, K.L., Grupp, I.L., Kranias, E.G. Basic Res. Cardiol. (1997) [Pubmed]
  18. 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]
  19. Isoform switching of the sarco(endo)plasmic reticulum Ca2+ pump during differentiation of BC3H1 myoblasts. de Smedt, H., Eggermont, J.A., Wuytack, F., Parys, J.B., Van den Bosch, L., Missiaen, L., Verbis, J., Casteels, R. J. Biol. Chem. (1991) [Pubmed]
  20. Regulation of splicing is responsible for the expression of the muscle-specific 2a isoform of the sarco/endoplasmic-reticulum Ca(2+)-ATPase. Van den Bosch, L., Eggermont, J., De Smedt, H., Mertens, L., Wuytack, F., Casteels, R. Biochem. J. (1994) [Pubmed]
  21. 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]
  22. Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice. Lewis, W., Haase, C.P., Raidel, S.M., Russ, R.B., Sutliff, R.L., Hoit, B.D., Samarel, A.M. Lab. Invest. (2001) [Pubmed]
  23. Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. Zarain-Herzberg, A., Rupp, H. Expert opinion on investigational drugs. (2002) [Pubmed]
  24. Ca(2+)-dependent and thapsigargin-inhibited phosphorylation of Na+,K(+)-ATPase catalytic domain following chimeric recombination with Ca(2+)-ATPase. Sumbilla, C., Lu, L., Lewis, D.E., Inesi, G., Ishii, T., Takeyasu, K., Feng, Y., Fambrough, D.M. J. Biol. Chem. (1993) [Pubmed]
  25. Residues 2-25 of phospholamban are insufficient to inhibit Ca2+ transport ATPase of cardiac sarcoplasmic reticulum. Jones, L.R., Field, L.J. J. Biol. Chem. (1993) [Pubmed]
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