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During the evolution of life, most living cells have maintained a similar ionic composition of their cytoplasms, including low calcium, low sodium, high potassium, and neutral pH (Mulkidjanian et al., 2012). Neurology 79, 1168–1173. Copyright © 2017 Clausen, Hilbers and Poulsen. Na, K-ATPase results from the association of different molecular isoforms of an α- and a β-subunit. Alternatively spliced transcript variants encoding different isoforms have … (2005). Primary sequence and functional expression of a novel ouabain-resistant Na,K-ATPase. Science 331, 768–772. J. Obstet. Physiol. N-glycan-dependent quality control of the Na,K-ATPase β(2) subunit. Immunocytochemical localization of Na-K-ATPase α- and γ-subunits in rat kidney. (1994). Impact of reactive oxygen species on spermatozoa: a balancing act between beneficial and detrimental effects. doi: 10.1074/jbc.M112.425785, Azizan, E. A., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M. V., Lieb, A., et al. Amikura R, Kashikawa M, Nakamura A, Kobayashi S. 2001. 92, 793–802. Life Sci. Sci. doi: 10.1007/s003950200024, McLean, W. J., Smith, K. A., Glowatzki, E., and Pyott, S. J. Natl. Biol Reprod, 75:308-317. The same strategy of apical alpha1 sorting is utilized in the eye where retinal pigment epithelium supplies the fluid of the subretinal space with the high sodium concentration needed to maintain the dark current that keeps photoreceptor cells depolarized in the absence of light (Miller et al., 1978; Sparrow et al., 2010). Villegas J, Araya P, Bustos-Obregon E, Burzio LO. The various subunit isoforms are optimized for the specific requirements and challenges that different cell types face for maintaining ionic homeostasis: the subunit variation allows for fine-tuning of the basic kinetic properties of the pump as elucidated in many studies, but much remains to be learned about how the variation determines interactions with other cellular partners and thereby regulates e.g., the activity, localization and stability of the pump. Ostermeier GC, Dix DJ, Miller D, Khatri P, Krawetz SA. It is also still enigmatic why the different mutations in the alpha3 gene cause such varied diseases, and since alpha4 is essential for sperm function, mutations in its gene are highly likely to affect the male bearers' fertility. Intracellular sorting and polarized cell surface delivery of (Na+,K+)ATPase, an endogenous component of MDCK cell basolateral plasma membranes. Mol Hum Reprod, 6:163-169. Sci. (2016). doi: 10.1095/biolreprod.110.087064, Jones, D. H., Li, T. Y., Arystarkhova, E., Barr, K. J., Wetzel, R. K., Peng, J., et al. If greater evolutionary pressure has optimized alpha4 to increase the probability that spermatozoa reach and fertilize an egg in the female oviduct, there could be specific parameters that make this pump more suitable for the task than the other isoforms. Roles of the Na,K-ATPase alpha4 isoform and the Na+/H+ exchanger in sperm motility. Glia 62, 608–622. Proteomic comparison of detergent-extracted sperm proteins from bulls with different fertility indexes. The functional role of the beta-subunit in the maturation and intracellular transport of Na,K-ATPase. Peng, L.; Martin-Vasallo, P.; Sweadner, K.J. doi: 10.1038/nature07939, Shrivastava, A. N., Redeker, V., Fritz, N., Pieri, L., Almeida, L. G., Spolidoro, M., et al. Identification of Na(+)-K(+)-ATPase β-subunit in alveolar epithelial cells. Na,K-ATPase from mice lacking the γ subunit (FXYD2) exhibits altered Na+ affinity and decreased thermal stability. 131, 427–451. Mapping the isoform differences on homology models of each alpha (Figure 3) shows that the variation is generally found at the surface of the protein, while the ion binding interior of the membrane domain and the linkers to the cytoplasmic domains are highly conserved. Acad. doi: 10.1006/cbir.1997.0137, Mobasheri, A., Pestov, N. B., Papanicolaou, S., Kajee, R., Cozar-Castellano, I., Avila, J., et al. J. Trans. Digoxin: the good and the bad. Mammals express seven FXYD proteins, most of which appear to lower the substrate affinities or Vmax of the pump, though they may also serve functions in addition to modulating Na,K-ATPase function (Geering, 2005). The alpha2 isoform is predominantly expressed in muscle (heart and skeletal) and brain (in astrocytes and glia cells). J. 30. (1989). Subunit isoform selectivity in assembly of Na,K-ATPase α-β heterodimers. Sci. 247, F158–F167. Daniel L, Etkovitz N, Weiss SR, Rubinstein S, Ickowicz D, Breitbart H. 2010. Tissue-specific expression of the Na,K-ATPase beta3 subunit. Nat. Soc. (2011). Genet. It also functions as a signal transducer/integrator to regulate the MAPK pathway, reactive oxygen species (ROS), as well as intracellular calcium. doi: 10.1016/j.toxicon.2010.09.011, Roubergue, A., Philibert, B., Gautier, A., Kuster, A., Markowicz, K., et al. (2016). When the Na,K-ATPase opens toward the cytoplasm, TM1 is believed to slide up (as in the related calcium pump SERCA, Winther et al., 2013) and allow three sodium ions to access the high-affinity binding sites in the middle of the membrane, where negative charges on aspartate and glutamate residues compensate for the charges of the positively charged ions (Figure 2). Ubiquitination and its influence in boar sperm physiology and cryopreservation. Blanco G, Sanchez G, Melton RJ, Tourtellotte WG, Mercer RW. Role of ADF/cofilin. The α4 isoform of the Na,K-ATPase is expressed in the germ cells of the testes. Interestingly it has been demonstrated that as spermatozoa capacitate in the female genital tract, the catalytic activity of alpha4 is up-regulated due to an increased availability of pumps in the membrane (Jimenez et al., 2012), suggesting that alpha4 supports the hyperpolarization and decreased intracellular sodium concentration characteristic of capacitated spermatozoa. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Jimenez T, McDermott JP, Sanchez G, Blanco G. 2011a. Excellent response to a ketogenic diet in a patient with alternating hemiplegia of childhood. 264, 4613–4618. Recently the α4 isoform of Na/K-ATPase (ATP1A4) has received considerable attention, due to its testis-specific expression in post-meiotic germ cells and mature sperm, in addition to its regulation of sperm motility and capacitation. Cell. Free-radical production after post-thaw incubation of ram spermatozoa is related to decreased in vivo fertility. Am J Physiol Cell Physiol, 284:C155s0-60. Nat. In vitro studies have shown that the E1 state of the enzyme favors the cysteine to be glutathionylated more than the E2 state (Garcia et al., 2015). Furthermore, ATP1A4 was the predominant isoform responsible for total Na/K-ATPase activity in capacitated sperm. Cell. (2009). Cell 3, 555–563. doi: 10.1073/pnas.1421182112, Paciorkowski, A. R., McDaniel, S. S., Jansen, L. A., Tully, H., Tuttle, E., Ghoneim, D. H., et al. Plant cells have no endogenous Na,K-ATPase, since they use a proton gradient to energize their membranes, so Na,K-ATPase inhibitors are not toxic to them. For AHC and RDP, ATP1A3 mutations have been found in most but not all of the sequenced patients, so it remains to be determined if mutations in other genes can give similar symptoms. doi: 10.2188/jea.15.180, Sweadner, K. J., Herrera, V. L., Amato, S., Moellmann, A., Gibbons, D. K., and Repke, K. R. (1994). (2015). Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. A few of the mutations in ATP1A2 and ATP1A3 target the same positions (Figure 4), but it is clear from the structural mapping that the ATP1A3 mutations often target the ion binding sites, while that is not the case for ATP1A2, possibly suggesting that impaired ion binding in alpha2 would be incompatible with life or that they cause other symptoms than FHM. Mol Reprod Dev, 61:406-413. Cell, 123:889-901. Furthermore, much energy is stored in the ionic gradients across the plasma membrane, and the steep sodium and potassium gradients in animal cells are used to facilitate secondary transport of molecules (sugars, neurotransmitters, amino acids, metabolites) and other ions (H+, Ca2+, Cl−). This is the non-catalytic component of the active enzyme, which catalyses the hydrolysis of ATP coupled with the exchange of Na + and K + ions across the plasma membrane. doi: 10.1073/pnas.222539999, Horisberger, J. D., and Kharoubi-Hess, S. (2002). Amyloid-beta as well as alpha-synuclein assemblies were found to interact with alpha3, and mapping of the interaction domain located a specific extracellular loop in the pump as the target in both cases (Ohnishi et al., 2015; Shrivastava et al., 2015). doi: 10.1042/bj3040635. U.S.A. 109, E821–E830. We have shown earlier that in renal clear‐cell carcinoma, although near normal levels of α‐subunit were present, reduced levels of β‐subunit in tumor tissues correlated with significantly reduced Na,K‐ATPase activity. Nonetheless, specific inactivation of its gene in cardiomyocytes results in a phenotype that appears healthy until approximately 10 months of age, and reduced contractility and enlarged hearts are only found after an additional 3–4 months (Barwe et al., 2009). 40, 167–174. Clin. Isolation and proteomic analysis of mouse sperm detergent-resistant membrane fractions: evidence for dissociation of lipid rafts during capacitation. 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. Association between mRNA abundance of functional sperm function proteins and fertility of Holstein bulls. J Cell Physiol, 218:537-548. Immunofluorescence reveals ubiquitination of retained distal cytoplasmic droplets on ejaculated porcine spermatozoa. FEBS Lett. Reproduction, 139:835-845. Parent S, Lefièvre L, Brindle Y, Sullivan R. 1999. Managing Bull Fertility in Beef Cattle Herds. De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis. The α1- and α2-isoforms of Na-K-ATPase play different roles in skeletal muscle contractility. B., Salazar, C., Stanojevic, V., Clifford, R. J., Kaplan, J. H., et al. Mol. Biochim. Biochim. (2014). doi: 10.1080/15438600490424514, Walaas, S. I., Czernik, A. J., Olstad, O. K., Sletten, K., and Walaas, O. Identification of a pool of non-pumping Na/K-ATPase. Three sodium pump structures and a homology model are positioned in accordance with the catalytic cycle shown below as both cartoon and reaction scheme. 3, 189–196. Sodium kinetics of Na,K-ATPase α isoforms in intact transfected HeLa cells. Carlier MF, Ressad F, Pantaloni D. 1999. Bichim Biophys Acta, 1784 (1):106-15. When studied in a cellular system, alpha4 is less affected by changes in voltage, extracellular sodium and temperature than alpha1 (Clausen et al., 2016). 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Functional characterization of a testes-specific α-subunit isoform of the sodium/potassium adenosinetriphosphatase. Physiol. Isoforms of Na,K-ATPase alpha and beta subunits in the rat cerebellum and in granule cell cultures. 1992 Aug 25; 267 (24):16895–16903. (2015). 2008. Liang M, Tian J, Liu L, Pierre S, Liu J, Shapiro J, Xie ZJ. 2013. Specifically, the protein pumps sodium ions (Na +) out of cells and potassium ions (K +) into cells. Presynaptic Ca2+ buffers control the strength of a fast post-tetanic hyperpolarization mediated by the α3 Na(+)/K(+)-ATPase. Acta 23, 394–401. The transport of ions against their concentration gradients requires that the transmembrane ion binding site acts like a space shuttle airlock with gates on either side of which at least one is always locked to avoid the energetically favored flow of ions in the opposite direction. Thus, theβ -subunit is a key determinant of Na,K-ATPase subcellular localization as well as function. Stallion sperm transcriptome comprises functionally coherent coding and regulatory RNAs as revealed by microarray analysis and RNA-seq. The physiological significance of this activity and whether it requires the other Na-K-ATPase subunits is unknown. Pharmacol. RDP is characterized by a triggering, stressful event causing sudden (hours to days) onset of irreversible rostrocaudal gradient of dystonia with parkinsonism. 280, 19003–19011. Sodium, potassium-ATPase signalling mechanism inducing capacitation in bull sperm. Blanco G, Mercer RW. Nat. 287, 26115–26125. In: Proceedings of the Annual Mtg. Our data of Atp1a1 isoforms raise the question of whether the expression of the β subunit isoforms in the mouse brain is also heterogeneous. Impact Factor 3.367 | CiteScore 4.3More on impact ›, Hidden secrets and lessons from the crystal structures of integral membrane proteins: channels, pumps and receptors 8:371. doi: 10.3389/fphys.2017.00371. Biophys. 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Comp Physiol. doi: 10.1016/0092-8674(86)90888-3, Capuani, C., Melone, M., Tottene, A., Bragina, L., Crivellaro, G., and Santello, M. (2016). J. Neurosci. Many organs use the sodium and potassium gradients for their specialized functions. Res. Chem. Acad. Gynecol. 2007. doi: 10.1101/mcs.a001008, Sparrow, J. R., Hicks, D., and Hamel, C. P. (2010). Alpha3 is also highly expressed in the human heart; interestingly with gender-specific differences: the relative expression of alpha3 to alpha1 is several-fold higher in men than in women as judged from RNA levels (Gaborit et al., 2010). View specifications, prices, citations, reviews, and more. (2015). Multiple proteins present in purified porcine sperm apical plasma membranes interact with the zona pellucida of the oocyte. Regul. 6:22047. doi: 10.1038/srep22047, Bottger, P., Tracz, Z., Heuck, A., Nissen, P., Romero-Ramos, M., and Lykke-Hartmann, K. (2011). 109, 1852–1862. Cell Tissue Res, 368(1):187-200. Beneficial renal and pancreatic phenotypes in a mouse deficient in FXYD2 regulatory subunit of Na,K-ATPase. J. Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model. doi: 10.1038/nature12578, Kanemasa, H., Fukai, R., Sakai, Y., Torio, M., Miyake, N., and Lee, S. (2016). The amino acids altered by disease-causing mutations in the three alpha subunit genes are shown as spheres and color-coded as indicated for each subunit. 1998. A ketonic diet has also been reported to stall disease progression (Roubergue et al., 2015). Genet. Control of actin dynamics in cell motility. Trends Cardiovasc. (2015). doi: 10.1016/j.bpj.2015.09.015, Stindl, J., Tauber, P., Sterner, C., Tegtmeier, I., Warth, R., and Bandulik, S. (2015). Using fresh bull sperm, we determined that ATP1A4 resided in specialized microdomains (raft and non-raft) of the sperm plasma membrane and activated specific signaling (caveolin-1, EGFR, Src, ERK1/2) molecules during sperm capacitation. J. Biol. (2016). (2010). Apical polarity of Na,K-ATPase in retinal pigment epithelium is linked to a reversal of the ankyrin-fodrin submembrane cytoskeleton. 2006. Proteomic analysis of raft and non-raft fractions revealed a significant interaction between ATP1A4 and plakoglobin, a member of the β-catenin family of proteins involved in cell adhesion, in the equatorial segment of capacitated sperm, suggesting a potential role in sperm-oolemma fusion. (2015). The coupling of ATP1A1 mutations to hypertension does not immediately make as much sense as for the potassium channel and calcium regulators. The onset is typically caused by physical or emotional stress in early adulthood, and in addition to the motor effects, most patients have psychiatric symptoms (Brashear et al., 2012). J. Mol. Quantitation of [3H]ouabain binding and turnover of Na-K-ATPase along the rabbit nephron. (2013). Sutovsky P, Aarabi M, Miranda-Vizuete A, Oko R. 2015. An alternative, and not necessarily conflicting, hypothesis is that since pumps in the membrane of spermatozoa experience dramatic changes in e.g., extracellular sodium levels and membrane potential as the cell passes from testis to oviduct, it could be advantageous with a pump that, like alpha4, responds less to environmental alterations (Clausen et al., 2016). *Correspondence: Hanne Poulsen,, Front. BJU Int. Biol Reprod, 84:153-161. Na,K‐ATPase comprises three subunits (α, β, and FXYD). 2005. Loss of function of the Na + /K + ATPase due to mutations in Na + /K + ATPase genes, anoxic conditions, depletion of ATP or inhibition of the Na + /K + ATPase function using cardiac glycosides such as digitalis, causes a depolarization of … Increased expression of the Na,K-ATPase alpha4 isoform enhances sperm motility in transgenic mice. Rajamanickam GD, Kastelic JP, Thundathil JC. Psychiatric disorders in rapid-onset dystonia-parkinsonism. Jimenez T, Sanchez G, Wertheimer E, Blanco G. 2010. Spermatozoal RNA profiles of normal fertile men. Ghosh, S., Freitag, A. C., Martin-Vasallo, P., and Coca-Prados, M. (1990). The Na,K-ATPase was first described 60 years ago by Jens Christian Skou (Skou, 1957), but novel insight into the pump's atomic structure, cellular regulation and pathophysiological roles continues to emerge, and many aspects await future studies. doi: 10.1016/j.acthis.2014.08.010. Na+, K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions. Stanley, C. M., Gagnon, D. G., Bernal, A., Meyer, D. J., Rosenthal, J. J., and Artigas, P. (2015). Molecular cloning and characterization of porcine Na(+)/K(+)-ATPase isoforms α1, α2, α3 and the ATP1A3 promoter. Rep. 28, 953–969. doi: 10.4331/wjbc.v5.i2.240. doi: 10.1021/bi00610a037, Gaborit, N., Varro, A., Le Bouter, S., Szuts, V., Escande, D., Nattel, S., et al. Dev. A., Velotta, J. 283, 282–293. EMBO Mol. 45, 440–444, 444e1–2. The alpha1 subunit is essentially omnipresent at the tissue and cellular levels. (1993). below). 33, 1047–1057. 47, 552–560. 1994. Am. Mol Rprod Dev, 62:348-356. O'Flaherty C, de Lamirande E, Gagnon C. 2006. In addition, the subunits differ in how they are trafficked to and localized in the membrane, which posttranslational modifications they are subject to, and importantly what cellular partners they interact with. The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane Gene 292, 151–166. Furthermore, they are subject to a more profound evolutionary pressure than other cells, because only a single spermatozoon from a batch of hundreds of millions has a chance of fertilizing an egg, and only mutations that make better spermatozoa count in this race. (2007). Ubiquitin-based sperm assay for the diagnosis of male factor infertility. 21, 4207–4214. Jimenez T, Sanchez G, McDermott JP, Nguyen AN, Kumar TR, Blanco G. 2011b. Doi: 10.1186/1752-0509-2-19. A conserved aspartate in the P-domain is phosphorylated and dephosphorylated during the cycle, and the movements of the cytoplasmic domains cause the connected TM helices to bind and release the pump's substrates in response. Mol. Sci. doi: 10.1074/jbc.M115.687913, Mobasheri, A., Errington, R. J., Golding, S., Hall, A. C., and Urban, J. P. (1997). (2016). 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Overall, results demonstrated that ATP1A4 had unique roles in controlling several aspects of sperm physiology, acting through well-established enzyme activity and signaling functions. (2003). Migraine- and dystonia-related disease-mutations of Na+/K+-ATPases: relevance of behavioral studies in mice to disease symptoms and neurological manifestations in humans. J. Physiol. Role of caveolae in signal-transducing function of cardiac Na+/K+-ATPase. Physiol., 06 June 2017 Florida Cooperative, Extension, Service, Institute of Food and Agricultural Sciences, University of Florida. Expression and cellular localization of Na,K-ATPase isoforms in the rat ventral prostate. The exact function of the beta-3 subunit is not known: Pathways Back to the Basics: A Real World Strategy for Improving the Quality and Consistency of Beef. 127, 835–845. doi: 10.1016/j.tcm.2010.06.002, Rindler, T. N., Lasko, V. M., Nieman, M. L., Okada, M., Lorenz, J. N., and Lingrel, J. 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The alpha subunit has three cytoplasmic domains, the nucleotide binding (N), the phosphorylation (P) and the actuator (A) domains, which function as the kinase, the substrate and the phosphatase, respectively, in the catalytic cycle, when ATP is hydrolyzed (Figure 2). Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Science 337, 1634–1637. Pharmacologically, the same is evident—pump inhibitors like cardiotonic steroids are toxic, but not nearly as toxic as a huge molecule produced in Palythoa corals, palytoxin, which binds the sodium pump and turns it into a channel by causing the inner and outer gates to open simultaneously. Calcium clearance mechanisms of mouse sperm. 73, 101–115. Cardiol. 77, 88–93. 1998. Am. It has been believed that inhibition of the Na,K-ATPase in cardiomyocytes raises cytoplasmic sodium levels, thereby inhibiting the sodium-calcium exchanger and raising cytoplasmic calcium levels, which is imagined to have a direct effect on the heart's contractility, but there is also evidence to suggest that digitalis strengthens the parasympathetic nervous system by vagal activation and slows heart rate (Ziff and Kotecha, 2016). doi: 10.1126/science.1198785, Cholet, N., Pellerin, L., Magistretti, P. J., and Hamel, E. (2002). The sodium potassium ATPase (Na + /K + ATPase) is essential for the maintenance of a low intracellular Na + and a high intracellular K + concentration. 42, 427–443. An increase in the intracellular sodium concentration due to lower levels of Na,K-ATPase will likely decrease calcium export by the Na+/Ca2+-exchanger, which may be the main extrusion pathway in cardiomyocytes. The dependence on extracellular stimuli can, however, be circumvented if the downstream signals are directly induced by mutations in the systems that normally control membrane potential and calcium levels, including a potassium channel (KCNJ5, Choi et al., 2011), a calcium channel (CACNA1D, Azizan et al., 2013), and a calcium pump (ATP2B3, Beuschlein et al., 2013). Int. doi: 10.1046/j.1464-410X.2003.04460.x, Morth, J. P., Pedersen, B. P., Toustrup-Jensen, M. S., Sorensen, T. L., Petersen, J., Andersen, J. P., et al. Fertility-associated antigen on bull sperm indicates fertility potential. doi: 10.1074/jbc.275.3.1976, de Carvalho Aguiar, P., Sweadner, K. J., Penniston, J. T., Zaremba, J., Liu, L., Caton, M., et al. Cardiotonic steroids bind the Na,K-ATPase from the extracellular side in the suggested ion exchange pathway as revealed by the crystal structure of a high-affinity binding complex between the cardiotonic steroid digoxin and Na,K-ATPase purified from pig kidney (Laursen et al., 2015, Figure 1). Dev. Potassium is not (or for the TM9 deletions, only to a minor extend) transported, and physiological potassium levels have negligible effect (Azizan et al., 2013). Na+-K+-ATPase, a new class of plasma membrane receptors. Since the ionic gradients are of vital importance for any organ, disturbance of the Na,K-ATPase activity has been implicated in many pathophysiological conditions, including cancer (Durlacher et al., 2015), diabetes (Vague et al., 2004), and heart failure (Schwinger et al., 2003), and the pump has been suggested as a potential chemotherapy target (Alevizopoulos et al., 2014), though evidence is still lacking for its efficacy (Durlacher et al., 2015). This entry represents the sodium/potassium-transporting ATPase subunit beta.

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