Alternative titles; symbols
HGNC Approved Gene Symbol: ATP2B4
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:203,626,832-203,744,081 (from NCBI)
The Ca(2+)-ATPases are a family of plasma membrane pumps encoded by at least 4 genes: ATP2B1 (108731) on chromosome 12q21; ATP2B2 (108733) on 3q26; ATP2B3 (300014) on Xq28; and ATP2B4.
By PCR, Brandt et al. (1992) detected expression of the PMCA4a variant in all tissues examined. They identified a second variant, PMCA4b, that was primarily expressed in skeletal muscle, small intestine, heart, spinal cord, and brain. Brandt et al. (1992) isolated the full-length PMCA4b cDNA from a fetal brain cDNA library. The deduced 473-amino acid protein lacks a large portion of the C terminus found in PMCA4a.
By RT-PCR, Santiago-Garcia et al. (1996) found variable expression of the PMCA and SERCA (see 108730) genes during human fetal heart development. PMCA4 and PMCA1 were expressed in 8-, 12-, and 20-week fetal heart and in adult heart. Two PMCA4 splice variants were detected in heart tissue, whereas only 1 was detected in placenta.
Okunade et al. (2004) examined Pmca1 and Pmca4 expression in mouse tissues. Pmca1 was expressed in all tissues examined, and Pmca4 was expressed in all tissues examined except liver. Pmca1 predominated in brain, intestine, kidney, lung, and stomach, whereas Pmca4 predominated in aorta, portal vein, bladder, diaphragm, seminal vesicles, and testis. Immunostaining localized Pmca4 to the principal piece of the sperm tail, the location of Catsper (606389), the major Ca(2+) channel required for sperm motility.
Olson et al. (1991) mapped the PMCA4 gene to chromosome 1q25-q32 by Southern analysis of human-rodent somatic cell hybrids, in situ hybridization of human metaphase spreads, and genetic linkage analysis in the CEPH pedigrees. No evidence was obtained for multiple copies of the gene at this locus; however, a cross-hybridizing sequence was detected on Xq13-qter at low stringency.
Associations Pending Confirmation
For discussion of a possible association between variation in the ATP2B4 gene and resistance to severe malaria, see 611162.
Chen et al. (2004) expressed mouse Cd22 (107266) in mouse and chicken B-cell lines devoid of Cd22 and examined B cells from mice deficient in Cd22 or Pmca4. They identified an activation-dependent interaction between phosphorylated Cd22 and Pmca4 and found that Cd22 together with Shp1 (PTPN6; 176883) provided negative control of B-cell activation by enhancing Pmca4-mediated calcium efflux after B-cell receptor stimulation.
Okunade et al. (2004) found that loss of both copies of the mouse Pmca4 gene resulted in no overt phenotype. Loss of Pmca4 impaired phasic contractions and caused apoptosis in portal vein smooth muscle in vitro, but this phenotype was dependent on the mouse strain employed. On a Black Swiss background, the phenotype was not expressed unless the mice also carried a null mutation in 1 copy of the Pmca1 gene. Pmca4 -/- male mice were infertile but had normal spermatogenesis and mating behavior. Pmca4 -/- sperm that had not undergone capacitation exhibited normal motility but did not achieve hyperactivated motility needed to traverse the female genital tract. Ultrastructure of the motility apparatus of mutant sperm tails showed mitochondrial condensation, indicating Ca(2+) overload. Okunade et al. (2004) concluded that PMCA4 expression in the principal piece of sperm tail is essential for hyperactivated motility and male fertility.
Brandt, P., Neve, R. L., Kammesheidt, A., Rhoads, R. E., Vanaman, T. C. 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. J. Biol. Chem. 267: 4376-4385, 1992. [PubMed: 1531651]
Chen, J., McLean, P. A., Neel, B. G., Okunade, G., Shull, G. E., Wortis, H. H. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nature Immun. 5: 651-657, 2004. [PubMed: 15133509] [Full Text: https://doi.org/10.1038/ni1072]
Okunade, G. W., Miller, M. L., Pyne, G. J., Sutliff, R. L., O'Connor, K. T., Neumann, J. C., Andringa, A., Miller, D. A., Prasad, V., Doetschman, T., Paul, R. J., Shull, G. E. Targeted ablation of plasma membrane Ca(2+)-ATPase (PMCA) 1 and 4 indicates a major housekeeping function for PMCA1 and a critical role in hyperactivated sperm motility and male fertility for PMCA4. J. Biol. Chem. 279: 33742-33750, 2004. [PubMed: 15178683] [Full Text: https://doi.org/10.1074/jbc.M404628200]
Olson, S., Wang, M. G., Carafoli, E., Strehler, E. E., McBride, O. W. Localization of two genes encoding plasma membrane Ca(2+)-transporting ATPases to human chromosomes 1q25-32 and 12q21-23. Genomics 9: 629-641, 1991. [PubMed: 1674727] [Full Text: https://doi.org/10.1016/0888-7543(91)90356-j]
Santiago-Garcia, J., Mas-Oliva, J., Saavedra, D., Zarain-Herzberg, A. Analysis of mRNA expression and cloning of a novel plasma membrane Ca(2+)-ATPase splice variant in human heart. Molec. Cell. Biochem. 155: 173-182, 1996. [PubMed: 8700162] [Full Text: https://doi.org/10.1007/BF00229314]