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Gene Review

ATP2B4  -  ATPase, Ca++ transporting, plasma membrane 4

Homo sapiens

Synonyms: ATP2B2, MXRA1, Matrix-remodeling-associated protein 1, PMCA4, PMCA4b, ...
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Disease relevance of ATP2B4


High impact information on ATP2B4

  • Using this approach, we discovered that the plasma membrane calcium ATPase 4 (PMCA4) is required for TNF-induced cell death in L929 cells [2].
  • Resistance to tumor necrosis factor-induced cell death mediated by PMCA4 deficiency [2].
  • Under basal conditions, PMCA4-deficient (PMCA(mut)) cells have a normal phenotype [2].
  • Transgenic rat lines carrying the human PMCA 4 cDNA under control of the ventricle-specific myosin light chain-2 promoter were established, and expression in the myocardium was ascertained at the mRNA, protein, and functional levels [3].
  • Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice [4].

Biological context of ATP2B4

  • The genes for PMCA isoforms 1 and 4 (ATP2B1 and ATP2B4) have been previously localized to human chromosomes 12q21-->q23 and 1q25-->q32, respectively [5].
  • We cloned and sequenced eight cDNA inserts encoding for the PMCA1 and PMCA4 variants from a fetal human heart cDNA library confirming that these are the two main PMCA genes expressed in cardiac muscle [6].
  • When the human PMCA4 gene spanning this region of variable exon splicing was sequenced, it confirmed the intron-exon boundaries where alternate splicing occurs to produce PMCA4a and PMCA4b [7].
  • As has also been shown for PMCA1a, this insertion produced a shift in the reading frame at the 3'-end of the PMCA4 mRNA that yielded a sequence encoding a Ca(2+)-ATPase lacking a large portion of the C-terminal regulatory domain [7].
  • The PDZ protein-binding COOH-terminal tail of PMCA2b was not responsible for its apical membrane localization, as a chimeric pump made of an NH(2)-terminal portion from PMCA4 and a COOH-terminal tail from PMCA2b was targeted to the basolateral domain [8].

Anatomical context of ATP2B4


Associations of ATP2B4 with chemical compounds

  • Vitamin D3 dependent Ca-binding protein 28k (CaBP28k), a factor involved in Ca2+ influx, and plasma membrane Ca ATPases (PMCA), a factor involved in Ca2+ efflux, were studied in hypertensive 16-week-old SHR and normotensive Wistar-Kyoto rats (WKY). mRNA levels for CaBP28k, PMCA 2 and PMCA 4 were not different in the two strains [12].
  • Partial sequencing of the cross-linked, radioactive peptides has identified a site of the pump located C terminally to the phosphoenzyme-forming aspartic acid, spanning residues 537-544 of the hPMCA4 isoform of the enzyme [13].
  • The PMCA2CI protein was maximally activated by 0.5% ethanol, a concentration 8-10 times lower than that needed to obtain the same effect on the PMCA4 protein or on the pump of erythrocyte membranes, which is a mixture of isoforms 1 and 4 [14].
  • Flow cytometry kinetic studies of MXR efflux showed that MXRG cells effluxed 50% of the drug at a faster rate than MXRA and MXRT cells (t50: 15.3 min vs. 27.8 and 44.5 min, respectively) [15].

Regulatory relationships of ATP2B4


Other interactions of ATP2B4


Analytical, diagnostic and therapeutic context of ATP2B4


  1. Expression of plasma membrane calcium pump isoform mRNAs in breast cancer cell lines. Lee, W.J., Roberts-Thomson, S.J., Holman, N.A., May, F.J., Lehrbach, G.M., Monteith, G.R. Cell. Signal. (2002) [Pubmed]
  2. Resistance to tumor necrosis factor-induced cell death mediated by PMCA4 deficiency. Ono, K., Wang, X., Han, J. Mol. Cell. Biol. (2001) [Pubmed]
  3. Overexpression of the sarcolemmal calcium pump in the myocardium of transgenic rats. Hammes, A., Oberdorf-Maass, S., Rother, T., Nething, K., Gollnick, F., Linz, K.W., Meyer, R., Hu, K., Han, H., Gaudron, P., Ertl, G., Hoffmann, S., Ganten, U., Vetter, R., Schuh, K., Benkwitz, C., Zimmer, H.G., Neyses, L. Circ. Res. (1998) [Pubmed]
  4. The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex. Williams, J.C., Armesilla, A.L., Mohamed, T.M., Hagarty, C.L., McIntyre, F.H., Schomburg, S., Zaki, A.O., Oceandy, D., Cartwright, E.J., Buch, M.H., Emerson, M., Neyses, L. J. Biol. Chem. (2006) [Pubmed]
  5. Localization of two genes encoding plasma membrane Ca2+ ATPases isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes 3p26-->p25 and Xq28, respectively. Wang, M.G., Yi, H., Hilfiker, H., Carafoli, E., Strehler, E.E., McBride, O.W. Cytogenet. Cell Genet. (1994) [Pubmed]
  6. Analysis of mRNA expression and cloning of a novel plasma membrane Ca(2+)-ATPase splice variant in human heart. Santiago-García, J., Mas-Oliva, J., Saavedra, D., Zarain-Herzberg, A. Mol. Cell. Biochem. (1996) [Pubmed]
  7. Analysis of the tissue-specific distribution of mRNAs encoding the plasma membrane calcium-pumping ATPases and characterization of an alternately spliced form of PMCA4 at the cDNA and genomic levels. Brandt, P., Neve, R.L., Kammesheidt, A., Rhoads, R.E., Vanaman, T.C. J. Biol. Chem. (1992) [Pubmed]
  8. Alternative splicing of the first intracellular loop of plasma membrane Ca2+-ATPase isoform 2 alters its membrane targeting. Chicka, M.C., Strehler, E.E. J. Biol. Chem. (2003) [Pubmed]
  9. Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium. Talarico, E.F., Kennedy, B.G., Marfurt, C.F., Loeffler, K.U., Mangini, N.J. Mol. Vis. (2005) [Pubmed]
  10. Inhibitory interaction of the 14-3-3{epsilon} protein with isoform 4 of the plasma membrane Ca(2+)-ATPase pump. Rimessi, A., Coletto, L., Pinton, P., Rizzuto, R., Brini, M., Carafoli, E. J. Biol. Chem. (2005) [Pubmed]
  11. A comparative functional analysis of plasma membrane Ca2+ pump isoforms in intact cells. Brini, M., Coletto, L., Pierobon, N., Kraev, N., Guerini, D., Carafoli, E. J. Biol. Chem. (2003) [Pubmed]
  12. Renal abnormality of calcium handling in spontaneously hypertensive rats. Kamijo, T., Gonzalez, J.M., Jost, L.J., Barrios, R., Suki, W.N. Kidney Int. Suppl. (1996) [Pubmed]
  13. The plasma membrane Ca2+ pump contains a site that interacts with its calmodulin-binding domain. Falchetto, R., Vorherr, T., Brunner, J., Carafoli, E. J. Biol. Chem. (1991) [Pubmed]
  14. The effect of ethanol on the plasma membrane calcium pump is isoform-specific. Cervino, V., Benaim, G., Carafoli, E., Guerini, D. J. Biol. Chem. (1998) [Pubmed]
  15. Flow cytometry-based approach to ABCG2 function suggests that the transporter differentially handles the influx and efflux of drugs. García-Escarp, M., Martínez-Muñoz, V., Sales-Pardo, I., Barquinero, J., Domingo, J.C., Marin, P., Petriz, J. Cytometry. Part A : the journal of the International Society for Analytical Cytology. (2004) [Pubmed]
  16. Plasma membrane calcium-ATPase 2 and 4 in human breast cancer cell lines. Lee, W.J., Roberts-Thomson, S.J., Monteith, G.R. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  17. Caytaxin deficiency disrupts signaling pathways in cerebellar cortex. Xiao, J., Gong, S., Ledoux, M.S. Neuroscience (2007) [Pubmed]
  18. Plasma membrane calcium ATPase (PMCA4): a housekeeper for RT-PCR relative quantification of polytopic membrane proteins. Calcagno, A.M., Chewning, K.J., Wu, C.P., Ambudkar, S.V. BMC Mol. Biol. (2006) [Pubmed]
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