Gene Symbol: Atp2b4
Description: ATPase, Ca++ transporting, plasma membrane 4
Alias: Pmca4, plasma membrane calcium-transporting ATPase 4
Species: mouse
Products:     Atp2b4

Top Publications

  1. Aravindan R, Fomin V, Naik U, Modelski M, Naik M, Galileo D, et al. CASK interacts with PMCA4b and JAM-A on the mouse sperm flagellum to regulate Ca2+ homeostasis and motility. J Cell Physiol. 2012;227:3138-50 pubmed publisher
    ..The decreased motility is likely due to the collateral net deficit in ATP observed in nulls. Our data indicate that Ca(2+) homeostasis in sperm is maintained by the relative ratios of CASK-PMCA4b and CASK-JAM-A interactions. ..
  2. Patel R, Al Dossary A, Stabley D, Barone C, Galileo D, Strehler E, et al. Plasma membrane Ca2+-ATPase 4 in murine epididymis: secretion of splice variants in the luminal fluid and a role in sperm maturation. Biol Reprod. 2013;89:6 pubmed publisher
    Plasma membrane Ca(2+)-ATPase isoform 4 (PMCA4) is the primary Ca(2+) efflux pump in murine sperm, where it regulates motility. In Pmca4 null sperm, motility loss results in infertility...
  3. Schuh K, Quaschning T, Knauer S, Hu K, Kocak S, Roethlein N, et al. Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump. J Biol Chem. 2003;278:41246-52 pubmed
    ..Therefore, the PMCA represents a novel regulator of vascular tone. ..
  4. Schuh K, Cartwright E, Jankevics E, Bundschu K, Liebermann J, Williams J, et al. Plasma membrane Ca2+ ATPase 4 is required for sperm motility and male fertility. J Biol Chem. 2004;279:28220-6 pubmed
    ..diacetate succinimidyl ester reduced sperm motility in wild-type animals, thus mimicking the effects of PMCA4 deficiency on sperm motility and supporting the hypothesis of a pivotal role of the PMCA4 on the regulation of ..
  5. Okunade G, Miller M, Pyne G, Sutliff R, O Connor K, Neumann J, et al. Targeted ablation of plasma membrane Ca2+-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. 2004;279:33742-50 pubmed
    ..membrane Ca2+-ATPase (PMCA) 1 and PMCA4 was assessed in mice carrying null mutations in their genes (Atp2b1 and Atp2b4)...
  6. Kim H, Prasad V, Hyung S, Lee Z, Lee S, Bhargava A, et al. Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival. J Cell Biol. 2012;199:1145-58 pubmed publisher
    ..b>PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion...
  7. Antalffy G, Mauer A, Pászty K, Hegedüs L, Padányi R, Enyedi A, et al. Plasma membrane calcium pump (PMCA) isoform 4 is targeted to the apical membrane by the w-splice insert from PMCA2. Cell Calcium. 2012;51:171-8 pubmed publisher
    ..We now show that inserting the w-insert into the corresponding location of the PMCA4 isoform confers apical targeting to this normally basolateral pump...
  8. Krizaj D, DeMarco S, Johnson J, Strehler E, Copenhagen D. Cell-specific expression of plasma membrane calcium ATPase isoforms in retinal neurons. J Comp Neurol. 2002;451:1-21 pubmed
    ..b>PMCA4 was found to be selectively expressed in both synaptic layers...
  9. Hunter K, Watson M, Rochelle J, Ontiveros S, Munroe D, Seldin M, et al. Single-strand conformational polymorphism (SSCP) mapping of the mouse genome: integration of the SSCP, microsatellite, and gene maps of mouse chromosome 1. Genomics. 1993;18:510-9 pubmed
    ..1, resulting in a high-density map of the chromosome, containing over 100 loci, all typed on a single interspecific backcross. ..

More Information


  1. Al Dossary A, Strehler E, Martin DeLeon P. Expression and secretion of plasma membrane Ca2+-ATPase 4a (PMCA4a) during murine estrus: association with oviductal exosomes and uptake in sperm. PLoS ONE. 2013;8:e80181 pubmed publisher
    b>PMCA4, a membrane protein, is the major Ca(2+) efflux pump in murine sperm where its deletion leads to a severe loss of hyperactivated motility and to male infertility...
  2. Dorval V, Mandemakers W, Jolivette F, Coudert L, Mazroui R, De Strooper B, et al. Gene and MicroRNA transcriptome analysis of Parkinson's related LRRK2 mouse models. PLoS ONE. 2014;9:e85510 pubmed publisher
    ..Our data thus set the stage for future investigations regarding LRRK2 function in PD development. ..
  3. Liu L, Ishida Y, Okunade G, Shull G, Paul R. Role of plasma membrane Ca2+-ATPase in contraction-relaxation processes of the bladder: evidence from PMCA gene-ablated mice. Am J Physiol Cell Physiol. 2006;290:C1239-47 pubmed
    ..SERCA)2, and Na(+)/Ca(2+) exchanger (NCX) in bladder smooth muscle contractility in Pmca-ablated mice: Pmca4-null mutant (Pmca4(-/-)) and heterozygous Pmca1 and homozygous Pmca4 double gene-targeted (Pmca1(+/-)Pmca4(-/-)) ..
  4. Withers S, Cartwright E, Neyses L. Sperm phenotype of mice carrying a gene deletion for the plasma membrane calcium/calmodulin dependent ATPase 4. Mol Cell Endocrinol. 2006;250:93-7 pubmed
    ..our group has identified a number of specialized functions of the PMCAs, notably a prominent regulatory role of PMCA4 (splice variant b) for neuronal NO synthase as well as for the Ras pathway...
  5. Liu L, Ishida Y, Okunade G, Pyne Geithman G, Shull G, Paul R. Distinct roles of PMCA isoforms in Ca2+ homeostasis of bladder smooth muscle: evidence from PMCA gene-ablated mice. Am J Physiol Cell Physiol. 2007;292:C423-31 pubmed
    ..Among the four PMCA isoforms only PMCA1 and PMCA4 are expressed in smooth muscle...
  6. Ang S, Uebersohn A, Spencer C, Huang Y, Lee J, Ge K, et al. KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation. Development. 2016;143:810-21 pubmed publisher
    ..Our findings indicate that KMT2D is essential for regulating cardiac gene expression during heart development primarily via H3K4 di-methylation. ..
  7. Mohamed T, Abou Leisa R, Stafford N, Maqsood A, Zi M, Prehar S, et al. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy. Nat Commun. 2016;7:11074 pubmed publisher
    ..response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4)...
  8. Garcia M, Strehler E. Plasma membrane calcium ATPases as critical regulators of calcium homeostasis during neuronal cell function. Front Biosci. 1999;4:D869-82 pubmed
    ..Particular emphasis is placed on the role of the PMCAs in vestibular and auditory functions, localized calcium signaling in photoreceptor synaptic terminals and calcium-mediated cell death. ..
  9. Baggott R, Alfranca A, López Maderuelo D, Mohamed T, Escolano A, Oller J, et al. Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. Arterioscler Thromb Vasc Biol. 2014;34:2310-20 pubmed publisher
    ..Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and ..
  10. Baggaley E, McLarnon S, Demeter I, Varga G, Bruce J. Differential regulation of the apical plasma membrane Ca(2+) -ATPase by protein kinase A in parotid acinar cells. J Biol Chem. 2007;282:37678-93 pubmed
    ..that PMCA1 was distributed throughout the plasma membrane, PMCA2 was localized to the basolateral membrane, and PMCA4 was localized to the apical membrane of parotid acinar cells...
  11. Yang Y, Lee J, Jo H, Park S, Chang I, Muallem S, et al. Homer2 protein regulates plasma membrane Ca²?-ATPase-mediated Ca²? signaling in mouse parotid gland acinar cells. J Biol Chem. 2014;289:24971-9 pubmed publisher
    ..Homer2 deletion markedly increased expression of plasma membrane Ca(2+)-ATPase (PMCA) pumps, in particular PMCA4, at the apical pole. Accordingly, Homer2 deficiency increased Ca(2+) extrusion by acinar cells...
  12. Brini M, Cali T, Ottolini D, Carafoli E. The plasma membrane calcium pump in health and disease. FEBS J. 2013;280:5385-97 pubmed publisher
    ..A cerebellar X-linked human ataxia has recently been found to be caused by a mutation in the calmodulin-binding domain of PMCA3. ..
  13. Mohamed T, Oceandy D, Zi M, Prehar S, Alatwi N, Wang Y, et al. Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain. J Biol Chem. 2011;286:41520-9 pubmed publisher
    ..Although there is growing evidence that the plasma membrane Ca(2+)/calmodulin-dependent ATPase 4 (PMCA4) is a regulator of neuronal nitric-oxide synthase, the physiological consequence of this regulation is unclear...
  14. Kurusamy S, López Maderuelo D, Little R, Cadagan D, Savage A, Ihugba J, et al. Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion. J Mol Cell Cardiol. 2017;109:38-47 pubmed publisher
    ..Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway...
  15. Zacharias D, Kappen C. Developmental expression of the four plasma membrane calcium ATPase (Pmca) genes in the mouse. Biochim Biophys Acta. 1999;1428:397-405 pubmed
    ..The differential and restricted expression of Pmca genes supports the notion that they play unique functional roles in mammalian development. ..
  16. Mohamed T, Oceandy D, Prehar S, Alatwi N, Hegab Z, Baudoin F, et al. Specific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium. J Biol Chem. 2009;284:12091-8 pubmed publisher
    ..In conclusion, these results showed that the nNOS-PMCA4b complex regulates contractility via cAMP and phosphorylation of both PLB and cTnI. ..
  17. van Loon E, Little R, Prehar S, Bindels R, Cartwright E, Hoenderop J. Calcium Extrusion Pump PMCA4: A New Player in Renal Calcium Handling?. PLoS ONE. 2016;11:e0153483 pubmed publisher
    ..However, in recent studies TRPV5-expressing tubules were shown to highly express PMCA4. Therefore, PMCA4 may have a predominant role in renal Ca2+ handling...
  18. Olli K, Li K, Galileo D, Martin DeLeon P. Plasma membrane calcium ATPase 4 (PMCA4) co-ordinates calcium and nitric oxide signaling in regulating murine sperm functional activity. J Cell Physiol. 2018;233:11-22 pubmed publisher
    ..asthenospermia) and resulting infertility arise from deletion of the Plasma Membrane Ca2+ -ATPase 4 (Pmca4) gene which encodes the highly conserved Ca2+ efflux pump, PMCA4...
  19. Bond H, Dilworth M, Baker B, Cowley E, Requena Jimenez A, Boyd R, et al. Increased maternofetal calcium flux in parathyroid hormone-related protein-null mice. J Physiol. 2008;586:2015-25 pubmed publisher
    ..In situ perfusion of mouse placenta is a robust methodology for allowing detailed dissection of placental transfer mechanisms in genetically modified mice. ..
  20. Engelhardt C, Bundschu K, Messerschmitt M, Renne T, Walter U, Reinhard M, et al. Expression and subcellular localization of Spred proteins in mouse and human tissues. Histochem Cell Biol. 2004;122:527-38 pubmed
    ..Furthermore, it becomes most likely that Spred-2 is involved in the regulation of secretory pathways. ..
  21. Chen J, McLean P, Neel B, Okunade G, Shull G, Wortis H. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nat Immunol. 2004;5:651-7 pubmed
    ..Moreover, CD22 regulation of efflux and the calcium response required the tyrosine phosphatase SHP-1. Thus, SHP-1 and PMCA provide a mechanism by which CD22, a tissue-specific negative regulator, can affect calcium responses. ..
  22. Afroze T, Yang L, Wang C, Gros R, Kalair W, Hoque A, et al. Calcineurin-independent regulation of plasma membrane Ca2+ ATPase-4 in the vascular smooth muscle cell cycle. Am J Physiol Cell Physiol. 2003;285:C88-95 pubmed
    Calcineurin mediates repression of plasma membrane Ca2+-ATPase-4 (PMCA4) expression in neurons, whereas c-Myb is known to repress PMCA1 expression in vascular smooth muscle cells (VSMC)...
  23. Shull G. Gene knockout studies of Ca2+-transporting ATPases. Eur J Biochem. 2000;267:5284-90 pubmed
    ..These studies are yielding important insights regarding the physiological functions of individual Ca2+-transporting ATPases in vivo. ..
  24. Tye C, Sharma R, Smith C, Bartlett J. Altered ion-responsive gene expression in Mmp20 null mice. J Dent Res. 2010;89:1421-6 pubmed publisher
    ..These pH changes were greatly attenuated in Mmp20(-/-) mice. Expression of 4 ion-regulatory genes (Atp2b4, Slc4a2, Car6, Cftr) was significantly decreased in enamel organs from Mmp20(-/-) mice...
  25. Wu X, Chang B, Blair N, Sargent M, York A, Robbins J, et al. Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents. J Clin Invest. 2009;119:976-85 pubmed publisher
    ..Furthermore, Pmca4 gene-targeted mice showed increased cardiac hypertrophy and heart failure events after TAC...
  26. El Yazbi A, Cho W, Schulz R, Daniel E. Calcium extrusion by plasma membrane calcium pump is impaired in caveolin-1 knockout mouse small intestine. Eur J Pharmacol. 2008;591:80-7 pubmed publisher
    Plasma membrane calcium ATPase (PMCA) is an important calcium extrusion mechanism in smooth muscle cells. PMCA4 is the predominant isoform operating in conditions of high intracellular calcium during contraction...
  27. Ueda K, Valdivia C, Medeiros Domingo A, Tester D, Vatta M, Farrugia G, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci U S A. 2008;105:9355-60 pubmed publisher
    ..These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene. ..
  28. Afroze T, Yang G, Khoshbin A, Tanwir M, Tabish T, Momen A, et al. Calcium efflux activity of plasma membrane Ca2+ ATPase-4 (PMCA4) mediates cell cycle progression in vascular smooth muscle cells. J Biol Chem. 2014;289:7221-31 pubmed publisher
    We explored the role played by plasma membrane calcium ATPase-4 (PMCA4) and its alternative splice variants in the cell cycle of vascular smooth muscle cells (VSMC). A novel variant (PMCA4e) was discovered...
  29. Williams J, Armesilla A, Mohamed T, Hagarty C, McIntyre F, Schomburg S, et al. The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex. J Biol Chem. 2006;281:23341-8 pubmed
    ..PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production...
  30. Reuter H, Henderson S, Han T, Mottino G, Frank J, Ross R, et al. Cardiac excitation-contraction coupling in the absence of Na(+) - Ca2+ exchange. Cell Calcium. 2003;34:19-26 pubmed
    ..Expression of the sarcolemmal Ca(2+) pump was not upregulated. The sarcolemmal Ca(2+) pump, however, was able to compensate surprisingly well for the absence of Na(+) - Ca(2+) exchange under basal conditions. ..
  31. Lessard S, Gatof E, Beaudoin M, Schupp P, Sher F, Ali A, et al. An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility. J Clin Invest. 2017;127:3065-3074 pubmed publisher
    ..quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (rbc)...
  32. Alexander R, Beggs M, Zamani R, Marcussen N, Frische S, Dimke H. Ultrastructural and immunohistochemical localization of plasma membrane Ca2+-ATPase 4 in Ca2+-transporting epithelia. Am J Physiol Renal Physiol. 2015;309:F604-16 pubmed publisher
    ..The Pmca4 isoform is enriched in distal nephron isolates and decreased in mice lacking the epithelial transient receptor ..