Alternative titles; symbols
HGNC Approved Gene Symbol: ATP1B1
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38) : 1:169,106,690-169,132,719 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.2 | [Blood pressure regulation QTL] | 145500 | Multifactorial | 2 |
The Na+/K+ ATPase is a plasma membrane pump with numerous physiologic functions. It maintains ionic homeostasis that is critical for cell survival, differentiation, and apoptosis. The Na+/K+ ATPase holoenzyme consists of a catalytic alpha subunit (see 182310), a beta subunit, and a modulatory gamma subunit (FXYD2; 601814). Beta subunits, such as ATP1B1, are responsible for formation and structural integrity of the Na+/K+ ATPase holoenzyme (summary by Li et al., 2011).
From HeLa cells, Kawakami et al. (1986) isolated a cDNA clone that covered the entire coding region of the beta subunit of Na,K-ATPase. Remarkably, 61% homology to the amino acid sequence of the Torpedo (electric ray) counterpart was demonstrated.
Pseudogenes
Lane et al. (1989) isolated clones for a processed pseudogene designated ATP1BL1. Whether this is the same as the ATP1BL1 gene mapped to chromosome 4 by Yang-Feng et al. (1988) was not certain.
Lane et al. (1989) found that the ATP1B gene spans about 26.7 kb of genomic DNA and includes 24 kb of intron sequence. The complete message is encoded by 6 exons ranging in size from 81 to 1,427 bp.
Yang-Feng et al. (1988) assigned the ATP1B gene to 1q by Southern analysis of DNA from rodent/human somatic cell hybrids.
In the course of construction of a physical map of human 1q23-q25, Oakey et al. (1992) mapped ATP1B near the middle of this segment. The corresponding gene in the mouse is located on chromosome 1 (Kent et al., 1987). By linkage studies in interspecific backcrosses of Mus spretus and Mus musculus domesticus, Seldin (1989) also demonstrated that the homologous gene is located on mouse chromosome 1.
Crystal Structure
Morth et al. (2007) presented the x-ray crystal structure at 3.5-angstrom resolution of the pig renal sodium/potassium ATPase (Na+,K(+)-ATPase) with 2 rubidium ions bound (as potassium congeners) in an occluded state in the transmembrane part of the alpha subunit (see ATP1A1, 182310). Several of the residues forming the cavity for rubidium/potassium occlusion in the Na+,K(+)-ATPase are homologous to those binding calcium in the calcium-ion ATPase of sarcoendoplasmic reticulum (SERCA1; 108730). The beta and gamma (ATP1G1; 601814) subunits specific to the Na+,K(+)-ATPase are associated with transmembrane helices alpha-M7/alpha-M10, and alpha-M9, respectively. The gamma subunit corresponds to a fragment of the V-type ATPase c subunit. The carboxy terminus of the alpha subunit is contained within a pocket between transmembrane helices and seems to be a novel regulatory element controlling sodium affinity, possibly influenced by the membrane potential.
Crystal structures of the potassium-bound form of the Na+/K(+)-ATPase pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain (e.g., Morth et al., 2007). Poulsen et al. (2010) showed that this element is a key regulator of a theretofore unrecognized ion pathway. Models of P-type ATPases operated with a single ion conduit through the pump, but the data of Poulsen et al. (2010) suggested an additional pathway in the Na+/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least 8 mutations in the region that cause severe neurologic diseases. This novel model for ion transport by the Na+/K(+)-ATPase was established by electrophysiologic studies of C-terminal mutations in familial hemiplegic migraine (602481) and was further substantiated by molecular dynamics simulations. Poulsen et al. (2010) considered a similar ion regulation likely to apply to the H+/K(+)-ATPase and the Ca(2+)-ATPase.
Using yeast 2-hybrid analysis, Zatyka et al. (2008) found that the C-terminal domain of WFS1 (606201) bound the C-terminal domain of ATP1B1. The interaction was confirmed by reciprocal coimmunoprecipitation analysis of proteins expressed in transfected COS-7 cells and endogenous proteins in human and mouse cell lines. Fibroblasts from Wolfram syndrome (222300) patients with 2 different WFS1 mutations showed reduced ATP1B1 levels. Conversely, knockdown of Atp1b1 expression in a mouse insulinoma cell line led to reduced Wfs1 expression. Zatyka et al. (2008) concluded that interaction with WFS1 may be important for ATP1B1 maturation in the endoplasmic reticulum and that loss of this interaction may contribute to the pathology seen in Wolfram syndrome.
The estrogen 17-beta-estradiol (E2) enhances the activity of the Na+/K+ ATPase in various tissues and cells. Li et al. (2011) found that NDRG2 (605272) had a role in E2-dependent upregulation of Na+/K+ ATPase in human cell lines. Chromatin immunoprecipitation, EMSA, and mutation analysis showed that E2 upregulated NDRG2 expression via binding of liganded estrogen receptor (ER)-beta (ESRB2; 601663), but not ER-alpha (ESR1; 133430), to an estrogen receptor element in the NDRG2 promoter. Immunoprecipitation analysis and inhibitor studies indicated that upregulated NDRG2 stabilized the Na+/K+ ATPase by directly binding to ATP1B1, protecting it from ubiquitination and proteasome-mediated degradation. Knockdown of either ESRB2 or NDRG2 attenuated the effects of E2 on Na+/K+ ATPase stability and function.
Using various methods, Lanciotti et al. (2012) found that MLC1 (605908), TRPV4 (605427), HEPACAM (611642), syntrophin (see 601017), caveolin-1 (CAV1; 601047), Kir4.1 (KCNJ10; 602208), and AQP4 (600308) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit, and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress.
Chang et al. (2007) reported genomewide linkage and candidate gene-based association studies that demonstrated a replicated linkage peak for blood pressure regulation on human chromosome 1q23-q32, homologous to mouse and rat quantitative trait loci (QTLs) for blood pressure. The region contained at least 3 genes associated with blood pressure level in multiple samples: ATP1B1, RGS5 (603276), and SELE (131210). Individual variants in these 3 genes accounted for 2- to 5-mm Hg differences in mean systolic blood pressure, and the cumulative effect reached 8 to 10 mm Hg. Because the associated alleles in these genes are relatively common (frequency more than 5%), these 3 genes are important contributors to elevated blood pressure in the population at large. Chang et al. (2007) viewed the probable relationship between each of these genes and blood pressure regulation.
Chang, Y.-P. C., Liu, X., Kim, J. D. O., Ikeda, M. A., Layton, M. R., Weder, A. B., Cooper, R. S., Kardia, S. L. R., Rao, D. C., Hunt, S. C., Luke, A., Boerwinkle, E., Chakravarti, A. Multiple genes for essential-hypertension susceptibility on chromosome 1q. Am. J. Hum. Genet. 80: 253-264, 2007. [PubMed: 17236131] [Full Text: https://doi.org/10.1086/510918]
Kawakami, K., Nojima, H., Ohta, T., Nagano, K. Molecular cloning and sequence analysis of human Na,K-ATPase beta-subunit. Nucleic Acids Res. 14: 2833-2844, 1986. [PubMed: 3008098] [Full Text: https://doi.org/10.1093/nar/14.7.2833]
Kent, R. B., Fallows, D. A., Geissler, E., Glaser, T., Emanuel, J. R., Lalley, P. A., Levenson, R., Housman, D. E. Genes encoding alpha and beta subunits of Na,K-ATPase are located on three different chromosomes in the mouse. Proc. Nat. Acad. Sci. 84: 5369-5373, 1987. [PubMed: 2885848] [Full Text: https://doi.org/10.1073/pnas.84.15.5369]
Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E. Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations. Hum. Molec. Genet. 21: 2166-2180, 2012. [PubMed: 22328087] [Full Text: https://doi.org/10.1093/hmg/dds032]
Lane, L. K., Shull, M. M., Whitmer, K. R., Lingrel, J. B. Characterization of two genes for the human Na,K-ATPase beta subunit. Genomics 5: 445-453, 1989. [PubMed: 2559024] [Full Text: https://doi.org/10.1016/0888-7543(89)90008-6]
Li, Y., Yang, J., Li, S., Zhang, J., Zheng, J., Hou, W., Zhao, H., Guo, Y., Liu, X., Dou, K., Situ, Z., Yao, L. N-myc downstream-regulated gene 2, a novel estrogen-targeted gene, is involved in the regulation of Na+/K(+)-ATPase. J. Biol. Chem. 286: 32289-32299, 2011. [PubMed: 21771789] [Full Text: https://doi.org/10.1074/jbc.M111.247825]
Morth, J. P., Pedersen, B. P., Toustrup-Jensen, M. S., Sorensen, T. L.-M., Petersen, J., Andersen, J. P., Vilsen, B., Nissen, P. Crystal structure of the sodium-potassium pump. Nature 450: 1043-1049, 2007. [PubMed: 18075585] [Full Text: https://doi.org/10.1038/nature06419]
Oakey, R. J., Watson, M. L., Seldin, M. F. Construction of a physical map on mouse and human chromosome 1: comparison of 13 Mb of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620, 1992. [PubMed: 1301170] [Full Text: https://doi.org/10.1093/hmg/1.8.613]
Poulsen, H., Khandelia, H., Morth, J. P., Bublitz, M., Mouritsen, O. G., Egebjerg, J., Nissen, P. Neurological disease mutations compromise a C-terminal ion pathway in the Na+/K+-ATPase. Nature 467: 99-102, 2010. [PubMed: 20720542] [Full Text: https://doi.org/10.1038/nature09309]
Seldin, M. F. Personal Communication. Durham, N. C. 3/13/1989.
Yang-Feng, T. L., Schneider, J. W., Lindgren, V., Shull, M. M., Benz, E. J., Jr., Lingrel, J. B., Francke, U. Chromosomal localization of human Na+,K+-ATPase alpha- and beta-subunit genes. Genomics 2: 128-138, 1988. [PubMed: 2842249] [Full Text: https://doi.org/10.1016/0888-7543(88)90094-8]
Zatyka, M., Ricketts, C., Xavier, G. S., Minton, J., Fenton, S., Hofmann-Thiel, S., Rutter, G. A., Barrett, T. G. Sodium-potassium ATPase beta-1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress. Hum. Molec. Genet. 17: 190-200, 2008. [PubMed: 17947299] [Full Text: https://doi.org/10.1093/hmg/ddm296]