Comprehensive Physiology Wiley Online Library

Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump

Full Article on Wiley Online Library



Abstract

Na,K‐ATPase is an ubiquitous enzyme actively transporting Na‐ions out of the cell in exchange for K‐ions, thereby maintaining their concentration gradients across the cell membrane. Since its discovery more than six decades ago the Na‐pump has been studied extensively and its vital physiological role in essentially every cell has been established. This article aims at providing an overview of well‐established biochemical properties with a focus on Na,K‐ATPase isoforms, its transport mechanism and principle conformations, inhibitors, and insights gained from crystal structures. © 2021 American Physiological Society. Compr Physiol 11:1‐21, 2021.

Figure 1. Figure 1. Post‐Albers scheme for pumping cycle of Na,K‐ATPase.
Figure 2. Figure 2. Variety of the chemical structure of the cardiotonic steroids.
Figure 3. Figure 3. Snapshots of phosphoryl transfer reaction of the Na,K‐ATPase, revealed by crystallization with metallic fluorides. ADP:AlFx complex [PDB 3WGU, 136] mimics the Na‐occluded [Na3]E1P‐ADP state, BeFx complex [PDB 4XE5, 102] is shown with the corresponding E2P ground state [PDB 4HYT 152], both stabilized by cardiotonic steroids. [Rb2]E2:MgFx [PDB 3KDP, 181] represents product state of dephosphorylation reaction. Modified, with permission, from Kanai R, et al., 2013 136; Gregersen JL, et al., 2016 102; Laursen M, et al., 2015 152; Morth JP, et al., 2007 181.
Figure 4. Figure 4. Structure of the Na,K‐ATPase. (A) Crystal structure of the porcine Na,K‐ATPase in the Mg‐bound E2P*‐ouabain form [PDB 4HYT, 153, membrane from MemProtMD database 187]. (B) α/β/FXYD interface; (C) TGES motif shielding phosphorylaspartate in the E2P‐conformation. Mg2+ and phosphate are depicted as spheres in green and orange, respectively. Glycosylation of the β subunit, and bound ouabain (Obn) are shown in stick representation. (A) Modified, with permission, from Laursen M, et al., 2013 153; Newport TD, et al., 2019 187.
Figure 5. Figure 5. Comparison of the ion‐binding sites viewed from the cytoplasmic side of the membrane in the (A) [Na3]E1‐AlFx‐ADP [PDB 3WGU, 136] and (B) [K2]E2‐MgFx [PDB 2ZXE, 225] conformation. Residues of the ion‐binding sites are shown in stick representation with K+ colored in purple and Na+ in lime. (A) Modified, with permission, from Kanai R, et al., 2013 136. (B) Modified, with permission, from Shinoda T, et al., 2009 225.
Figure 6. Figure 6. Structures of porcine high affinity Na,K‐ATPase‐CTS complexes. (A) Crystal structure of the ouabain (Obn) complex is shown in black, bufalin (Buf) and digoxin (Dig) bound Na,K‐ATPase complexes are shown in light grey [PDB 4HYT 153, 4RES, 4RET 152]. Structures are aligned on the αM7‐10 segment highlighting the high similarity of the three complexes. (B) Comparison of the ouabain‐bound high affinity E2P (black) and low affinity [K2]E2:MgFx [light grey, PDB 3A3Y 194] conformations aligned against αM7‐10, which are not shown for clarity. Residues Q111 and D122 conferring ouabain sensitivity are shown as sticks, K and Mg ions are depicted as spheres and colored purple and green, respectively. (A) Modified, with permission, from Laursen M, et al., 2015 152; Modified, with permission, from Laursen M, et al., 2013 153. (B) Modified, with permission, from Ogawa H, et al., 2009 194.


Figure 1. Post‐Albers scheme for pumping cycle of Na,K‐ATPase.


Figure 2. Variety of the chemical structure of the cardiotonic steroids.


Figure 3. Snapshots of phosphoryl transfer reaction of the Na,K‐ATPase, revealed by crystallization with metallic fluorides. ADP:AlFx complex [PDB 3WGU, 136] mimics the Na‐occluded [Na3]E1P‐ADP state, BeFx complex [PDB 4XE5, 102] is shown with the corresponding E2P ground state [PDB 4HYT 152], both stabilized by cardiotonic steroids. [Rb2]E2:MgFx [PDB 3KDP, 181] represents product state of dephosphorylation reaction. Modified, with permission, from Kanai R, et al., 2013 136; Gregersen JL, et al., 2016 102; Laursen M, et al., 2015 152; Morth JP, et al., 2007 181.


Figure 4. Structure of the Na,K‐ATPase. (A) Crystal structure of the porcine Na,K‐ATPase in the Mg‐bound E2P*‐ouabain form [PDB 4HYT, 153, membrane from MemProtMD database 187]. (B) α/β/FXYD interface; (C) TGES motif shielding phosphorylaspartate in the E2P‐conformation. Mg2+ and phosphate are depicted as spheres in green and orange, respectively. Glycosylation of the β subunit, and bound ouabain (Obn) are shown in stick representation. (A) Modified, with permission, from Laursen M, et al., 2013 153; Newport TD, et al., 2019 187.


Figure 5. Comparison of the ion‐binding sites viewed from the cytoplasmic side of the membrane in the (A) [Na3]E1‐AlFx‐ADP [PDB 3WGU, 136] and (B) [K2]E2‐MgFx [PDB 2ZXE, 225] conformation. Residues of the ion‐binding sites are shown in stick representation with K+ colored in purple and Na+ in lime. (A) Modified, with permission, from Kanai R, et al., 2013 136. (B) Modified, with permission, from Shinoda T, et al., 2009 225.


Figure 6. Structures of porcine high affinity Na,K‐ATPase‐CTS complexes. (A) Crystal structure of the ouabain (Obn) complex is shown in black, bufalin (Buf) and digoxin (Dig) bound Na,K‐ATPase complexes are shown in light grey [PDB 4HYT 153, 4RES, 4RET 152]. Structures are aligned on the αM7‐10 segment highlighting the high similarity of the three complexes. (B) Comparison of the ouabain‐bound high affinity E2P (black) and low affinity [K2]E2:MgFx [light grey, PDB 3A3Y 194] conformations aligned against αM7‐10, which are not shown for clarity. Residues Q111 and D122 conferring ouabain sensitivity are shown as sticks, K and Mg ions are depicted as spheres and colored purple and green, respectively. (A) Modified, with permission, from Laursen M, et al., 2015 152; Modified, with permission, from Laursen M, et al., 2013 153. (B) Modified, with permission, from Ogawa H, et al., 2009 194.
References
 1.Abe K, Tani K, Fujiyoshi Y. Structural and functional characterization of H+, K+‐ATPase with bound fluorinated phosphate analogs. J Struct Biol 170: 60‐68, 2010. DOI: 10.1016/j.jsb.2009.12.008.
 2.Aguirre Dávila L, Weber K, Bavendiek U, Bauersachs J, Wittes J, Yusuf S, Koch A. Digoxin‐mortality: Randomized vs. observational comparison in the DIG trial. Eur Heart J 40: 3336‐3341, 2019. DOI: 10.1093/eurheartj/ehz395.
 3.Albers RW. Biochemical aspects of active transport. Annu Rev Biochem 36: 727‐756, 1967. DOI: 10.1146/annurev.bi.36.070167.003455.
 4.Apell H‐J. Finding Na,K‐ATPase II ‐ From fluxes to ion movements. Substantia 3: 19‐41, 2019. DOI: 10.13128/Substantia‐207.
 5.Aperia A. New roles for an old enzyme: Na,K‐ATPase emerges as an interesting drug target. J Intern Med 261: 44‐52, 2007. DOI: 10.1111/j.1365‐2796.2006.01745.x.
 6.Artigas P, Gadsby DC. Ion occlusion/deocclusion partial reactions in individual palytoxin‐modified Na/K pumps. Ann N Y Acad Sci 986: 116‐126, 2003. DOI: 10.1111/j.1749‐6632.2003.tb07148.x.
 7.Artigas P, Gadsby DC. Na+/K+‐pump ligands modulate gating of palytoxin‐induced ion channels. Proc Natl Acad Sci U S A 100: 501‐505, 2003. DOI: 10.1073/pnas.0135849100.
 8.Artigas P, Gadsby DC. Large diameter of palytoxin‐induced Na/K pump channels and modulation of palytoxin interaction by Na/K pump ligands. J Gen Physiol 123: 357‐376, 2004. DOI: 10.1085/jgp.200308964.
 9.Arystarkhova E, Haq IU, Luebbert T, Mochel F, Saunders‐Pullman R, Bressman SB, Feschenko P, Salazar C, Cook JF, Demarest S, Brashear A, Ozelius LJ, Sweadner KJ. Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition. Neurobiol Dis 132: 104577, 2019. DOI: 10.1016/j.nbd.2019.104577.
 10.Arystarkhova E, Ralph DL, Liu YB, Bouley R, McDonough AA, Sweadner KJ. Paradoxical activation of the sodium chloride cotransporter (NCC) without hypertension in kidney deficient in a regulatory subunit of Na,K‐ATPase, FXYD2. Physiol Rep 2: e12226, 2014. DOI: 10.14814/phy2.12226.
 11.Arystarkhova E, Sweadner KJ. Tissue‐specific expression of the Na,K‐ATPase β3 subunit: The presence of β3 in lung and liver addresses the problem of the missing subunit. J Biol Chem 272: 22405‐22408, 1997. DOI: 10.1074/jbc.272.36.22405.
 12.Arystarkhova E, Wetzel RK, Sweadner KJ. Distribution and oligomeric association of splice forms of Na+‐K+‐ATPase regulatory γ‐subunit in rat kidney. Am J Physiol Renal Physiol 282: F393‐F407, 2002. DOI: 10.1152/ajprenal.00146.2001.
 13.Askari A. The other functions of the sodium pump. Cell Calcium 84: 102105, 2019. DOI: 10.1016/j.ceca.2019.102105.
 14.Askari A. The sodium pump and digitalis drugs: Dogmas and fallacies. Pharmacol Res Perspect 7, 2019. DOI: 10.1002/prp2.505.
 15.Askari A, Kakar SS, Huang WH. Ligand binding sites of the ouabain‐complexed (Na++ K+)‐ATPase. J Biol Chem 263: 235‐242, 1988.
 16.Axelsen KB, Palmgren MG. Evolution of substrate specificities in the P‐type ATPase superfamily. J Mol Evol 46: 84‐101, 1998. DOI: 10.1007/pl00006286.
 17.Azarias G, Kruusmagi M, Connor S, Akkuratov EE, Liu XL, Lyons D, Brismar H, Broberger C, Aperia A. A specific and essential role for Na,K‐ATPase alpha3 in neurons co‐expressing alpha1 and alpha3. J Biol Chem 288: 2734‐2743, 2013. DOI: 10.1074/jbc.M112.425785.
 18.Azizan EAB, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AED, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GSH, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 45: 1055‐1060, 2013. DOI: 10.1038/ng.2716.
 19.Bab‐Dinitz E, Albeck S, Peleg Y, Brumfeld V, Gottschalk KE, Karlish SJD. A C‐terminal lobe of the β subunit of Na,K‐ATPase and H,K‐ATPase resembles cell adhesion molecules. Biochemistry 48: 8684‐8691, 2009. DOI: 10.1021/bi900868e.
 20.Barcroft LC, Moseley AE, Lingrel JB, Watson AJ. Deletion of the Na/K‐ATPase α1‐subunit gene (Atp1a1) does not prevent cavitation of the preimplantation mouse embryo. Mech Dev 121: 417‐426, 2004. DOI: 10.1016/j.mod.2004.04.005.
 21.Baxter NJ, Blackburn GM, Marston JP, Hounslow AM, Cliff MJ, Bermel W, Williams NH, Hollfelder F, Wemmer DE, Waltho JP. Anionic charge is prioritized over geometry in aluminum and magnesium fluoride transition state analogs of phosphoryl transfer enzymes. J Am Chem Soc 130: 3952‐3958, 2008. DOI: 10.1021/ja078000n.
 22.Beaugé L. Activation by lithium ions of the inside sodium sites in (Na++ K+)‐ATPase. Biochim Biophys Acta 527: 472‐484, 1978. DOI: 10.1016/0005‐2744(78)90361‐3.
 23.Beggah AT, Jaunin P, Geering K. Role of glycosylation and disulfide bond formation in the β subunit in the folding and functional expression of Na,K‐ATPase. J Biol Chem 272: 10318‐10326, 1997. DOI: 10.1074/jbc.272.15.10318.
 24.Beguin P. The gamma subunit is a specific component of the Na,K‐ATPase and modulates its transport function. EMBO J 16: 4250‐4260, 1997. DOI: 10.1093/emboj/16.14.4250.
 25.Beguin P. FXYD7 is a brain‐specific regulator of Na,K‐ATPase alpha1‐beta isozymes. EMBO J 21: 3264‐3273, 2002. DOI: 10.1093/emboj/cdf330.
 26.Béguin P, Crambert G, Guennoun S, Garty H, Horisberger JD, Geering K. CHIF, a member of the FXYD protein family, is a regulator of Na,K‐ATPase distinct from the gamma‐subunit. EMBO J 20: 3993‐4002, 2001. DOI: 10.1093/emboj/20.15.3993.
 27.Berry RG, Despa S, Fuller W, Bers DM, Shattock MJ. Differential distribution and regulation of mouse cardiac Na+/K+‐ATPase alpha1 and alpha2 subunits in T‐tubule and surface sarcolemmal membranes. Cardiovasc Res 73: 92‐100, 2007. DOI: 10.1016/j.cardiores.2006.11.006.
 28.Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson‐Couterie B, Benecke A, Quinkler M, Fallo F, Plouin P‐F, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro M‐C, Strom TM, Reincke M. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone‐producing adenomas and secondary hypertension. Nat Genet 45: 440‐444, 2013. DOI: 10.1038/ng.2550.
 29.Bibert S, Roy S, Schaer D, Felley‐Bosco E, Geering K. Structural and functional properties of two human FXYD3 (Mat‐8) isoforms. J Biol Chem 281: 39142‐39151, 2006. DOI: 10.1074/jbc.M605221200.
 30.Bibert S, Roy S, Schaer D, Horisberger J‐D, Geering K. Phosphorylation of phospholemman (FXYD1) by protein kinases A and C modulates distinct Na,K‐ATPase isozymes. J Biol Chem 283: 476‐486, 2008. DOI: 10.1074/jbc.M705830200.
 31.Blanco G, Melton RJ, Sánchez G, Mercer RW. Functional characterization of a testes‐specific α‐subunit isoform of the sodium/potassium adenosinetriphosphatase. Biochemistry 38: 13661‐13669, 1999. DOI: 10.1021/bi991207b.
 32.Blanco G, Mercer RW. Isozymes of the Na‐K‐ATPase: Heterogeneity in structure, diversity in function. Am J Physiol Renal Physiol 275: F633‐F650, 1998. DOI: 10.1152/ajprenal.1998.275.5.F633.
 33.Blanco G, Sánchez G, Melton RJ, Tourtellotte WG, Mercer RW. The alpha4 isoform of the Na,K‐ATPase is expressed in the germ cells of the testes. J Histochem Cytochem 48: 1023‐1032, 2000. DOI: 10.1177/002215540004800801.
 34.Blanco G, Sanchez G, Mercer RW. Comparison of the enzymic properties of the Na,K‐ATPase .alpha.3.beta.1 and .alpha.3.beta.2 isoenzymes. Biochemistry 34: 9897‐9903, 1995. DOI: 10.1021/bi00031a011.
 35.Blaustein MP, Hamlyn JM. Ouabain, endogenous ouabain and ouabain‐like factors: The Na(+) pump/ouabain receptor, its linkage to NCX, and its myriad functions. Cell Calcium 86: 102159, 2020. DOI: 10.1016/j.ceca.2020.102159.
 36.Blaustein MP, Lederer WJ. Sodium/calcium exchange: Its physiological implications. Physiol Rev 79: 763‐854, 1999. DOI: 10.1152/physrev.1999.79.3.763.
 37.Blostein R. Proton‐activated rubidium transport catalyzed by the sodium pump. J Biol Chem 260: 829‐833, 1985.
 38.Bossuyt J, Despa S, Han F, Hou Z, Robia SL, Lingrel JB, Bers DM. Isoform specificity of the Na/K‐ATPase association and regulation by phospholemman. J Biol Chem 284: 26749‐26757, 2009. DOI: 10.1074/jbc.M109.047357.
 39.Bøttger P, Tracz Z, Heuck A, Nissen P, Romero‐Ramos M, Lykke‐Hartmann K. Distribution of Na/K‐ATPase alpha 3 isoform, a sodium‐potassium P‐type pump associated with rapid‐onset of dystonia parkinsonism (RDP) in the adult mouse brain. J Comp Neurol 519: 376‐404, 2011. DOI: 10.1002/cne.22524.
 40.Brashear A, Sweadner KJ, Cook JF, Swoboda KJ, Ozelius L. ATP1A3‐related neurologic disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle, p. 1993.
 41.Brophy JM. Rehabilitating digoxin. Eur Heart J 27: 127‐129, 2006. DOI: 10.1093/eurheartj/ehi686.
 42.Bublitz M, Poulsen H, Morth JP, Nissen P. In and out of the cation pumps: P‐Type ATPase structure revisited. Curr Opin Struct Biol 20: 431‐439, 2010. DOI: 10.1016/j.sbi.2010.06.007.
 43.Burrow CR, Devuyst O, Li X, Gatti L, Wilson PD. Expression of the β2‐subunit and apical localization of Na+‐K+‐ATPase in metanephric kidney. Am J Physiol Renal Physiol 277: F391‐F403, 1999. DOI: 10.1152/ajprenal.1999.277.3.F391.
 44.Capasso JM, Hoving S, Tal DM, Goldshleger R, Karlish SJ. Extensive digestion of Na+,K(+)‐ATPase by specific and nonspecific proteases with preservation of cation occlusion sites. J Biol Chem 267: 1150‐1158, 1992.
 45.Castro J, Farley RA. Proteolytic fragmentation of the catalytic subunit of the sodium and potassium adenosine triphosphatase. Alignment of tryptic and chymotryptic fragments and location of sites labeled with ATP and iodoacetate. J Biol Chem 254: 2221‐2228, 1979.
 46.Cha JK, Christ WJ, Finan JM, Fujioka H, Kishi Y, Klein LL, Ko SS, Leder J, McWhorter WW, Pfaff K‐P, Yonaga M. Stereochemistry of palytoxin. Part 4. Complete structure. J Am Chem Soc 104: 7369‐7371, 1982. DOI: 10.1021/ja00389a101.
 47.Chan H, Babayan V, Blyumin E, Gandhi C, Hak K, Harake D, Kumar K, Lee P, Li TT, Liu HY, Lo TCT, Meyer CJ, Stanford S, Zamora KS, Saier MH Jr. The P‐type ATPase superfamily. J Mol Microbiol Biotechnol 19: 5‐104, 2010. DOI: 10.1159/000319588.
 48.Chan PC, Calabrese V, Theil LS. Species differences in the effect of sodium and potassium ions on the atpase of erythrocyte membranes. Biochim Biophys Acta 79: 424‐426, 1964.
 49.Clausen JD, Bublitz M, Arnou B, Olesen C, Andersen JP, Moller JV, Nissen P. Crystal structure of the vanadate‐inhibited Ca(2+)‐ATPase. Structure 24: 617‐623, 2016. DOI: 10.1016/j.str.2016.02.018.
 50.Clausen MV, Hilbers F, Poulsen H. The structure and function of the Na,K‐ATPase isoforms in health and disease. Front Physiol 8: 371, 2017. DOI: 10.3389/fphys.2017.00371.
 51.Cohen E, Goldshleger R, Shainskaya A, Tal DM, Ebel C, le Maire M, Karlish SJD. Purification of Na+,K+‐ATPase expressed in Pichia pastoris reveals an essential role of phospholipid‐protein interactions. J Biol Chem 280: 16610‐16618, 2005. DOI: 10.1074/jbc.M414290200.
 52.Consortium EAHoCAG, Consortium BeRCplEAIBA, Consortium ENfRoAHEfSaM‐sES, Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E, Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L, Huff C, Jorde LB, Reyna SP, Murphy KJ, Shianna KV, Gumbs CE, Little L, Silver K, Ptáček LJ, Haan J, Ferrari MD, Bye AM, Herkes GK, Whitelaw CM, Webb D, Lynch BJ, Uldall P, King MD, Scheffer IE, Neri G, Arzimanoglou A, van den Maagdenberg AMJM, Sisodiya SM, Mikati MA, Goldstein DB. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 44: 1030‐1034, 2012. DOI: 10.1038/ng.2358.
 53.Cornelius F, Fedosova NU, Klodos I. E2P Phosphoforms of Na,K‐ATPase. II. Interaction of Substrate and Cation‐Binding Sites in Pi Phosphorylation of Na,K‐ATPase. Biochemistry 37: 16686‐16696, 1998. DOI: 10.1021/bi981571v.
 54.Cornelius F, Habeck M, Kanai R, Toyoshima C, Karlish SJD. General and specific lipid–protein interactions in Na,K‐ATPase. Biochim Biophys Acta Biomembr 1848: 1729‐1743, 2015. DOI: 10.1016/j.bbamem.2015.03.012.
 55.Cornelius F, Mahmmoud YA, Toyoshima C. Metal Fluoride Complexes of Na,K‐ATPase: Characterization of fluoride‐stabilized phosphoenzyme analogues and their interaction with cardiotonic steroids. J Biol Chem 286: 29882‐29892, 2011. DOI: 10.1074/jbc.M111.259663.
 56.Crambert G, Hasler U, Beggah AT, Yu C, Modyanov NN, Horisberger JD, Lelièvre L, Geering K. Transport and pharmacological properties of nine different human Na, K‐ATPase isozymes. J Biol Chem 275: 1976‐1986, 2000. DOI: 10.1074/jbc.275.3.1976.
 57.Crambert G, Li C, Claeys D, Geering K. FXYD3 (Mat‐8), a new regulator of Na,K‐ATPase. Mol Biol Cell 16: 2363‐2371, 2005. DOI: 10.1091/mbc.e04‐10‐0878.
 58.Crambert G, Schaer D, Roy S, Geering K. New molecular determinants controlling the accessibility of ouabain to its binding site in human Na,K‐ATPase α isoforms. Mol Pharmacol 65: 335‐341, 2004. DOI: 10.1124/mol.65.2.335.
 59.Crans DC, Smee JJ, Gaidamauskas E, Yang L. The chemistry and biochemistry of vanadium and the biological activities exerted by vanadium compounds. Chem Rev 104: 849‐902, 2004. DOI: 10.1021/cr020607t.
 60.Dalla S, Baum M, Dobler S. Substitutions in the cardenolide binding site and interaction of subunits affect kinetics besides cardenolide sensitivity of insect Na,K‐ATPase. Insect Biochem Mol Biol 89: 43‐50, 2017. DOI: 10.1016/j.ibmb.2017.08.005.
 61.Danielli J. Morphological and molecular aspects of active transport. Symposia of the Society for Experimental Biology, Company of Biologists Ltd, University of Cambridge, Cambridge, 1954, p. 502‐516.
 62.Danko S, Daiho T, Yamasaki K, Liu X, Suzuki H. Formation of the stable structural analog of ADP‐sensitive phosphoenzyme of Ca2+‐ATPase with occluded Ca2+ by beryllium fluoride: Structural changes during phosphorylation and isomerization. J Biol Chem 284: 22722‐22735, 2009. DOI: 10.1074/jbc.M109.029702.
 63.Danko S, Yamasaki K, Daiho T, Suzuki H. Distinct natures of beryllium fluoride‐bound, aluminum fluoride‐bound, and magnesium fluoride‐bound stable analogues of an ADP‐insensitive phosphoenzyme intermediate of sarcoplasmic reticulum Ca2+ ‐ATPase: Changes in catalytic and transport sites during phosphoenzyme hydrolysis. J Biol Chem 279: 14991‐14998, 2004. DOI: 10.1074/jbc.M313363200.
 64.Dard R, Mignot C, Durr A, Lesca G, Sanlaville D, Roze E, Mochel F. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation. Dev Med Child Neurol 57: 1183‐1186, 2015. DOI: 10.1111/dmcn.12927.
 65.David P, Karlish SJ. Characterization of lanthanides as competitors of Na+ and K+ in occlusion sites of renal (Na+,K+)‐ATPase. J Biol Chem 266: 14896‐14902, 1991.
 66.David P, Mayan H, Cohen H, Tal DM, Karlish SJ. Guanidinium derivatives act as high affinity antagonists of Na+ ions in occlusion sites of Na+,K(+)‐ATPase. J Biol Chem 267: 1141‐1149, 1992.
 67.Delprat B, Schaer D, Roy S, Wang J, Puel J‐L, Geering K. FXYD6 is a novel regulator of Na,K‐ATPase expressed in the inner ear. J Biol Chem 282: 7450‐7456, 2007. DOI: 10.1074/jbc.M609872200.
 68.Dempski RE, Friedrich T, Bamberg E. The beta subunit of the Na+/K+‐ATPase follows the conformational state of the holoenzyme. J Gen Physiol 125: 505‐520, 2005. DOI: 10.1085/jgp.200409186.
 69.DiFranco M, Hakimjavadi H, Lingrel JB, Heiny JA. Na,K‐ATPase α2 activity in mammalian skeletal muscle T‐tubules is acutely stimulated by extracellular K+. J Gen Physiol 146: 281‐294, 2015. DOI: 10.1085/jgp.201511407.
 70.Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336: 525‐533, 1997. DOI: 10.1056/NEJM199702203360801.
 71.Dobretsov M, Stimers JR. Neuronal function and alpha3 isoform of the Na/K‐ATPase. Front Biosci 10: 2373‐2396, 2005. DOI: 10.2741/1704.
 72.Dostanic‐Larson I, Lorenz JN, Van Huysse JW, Neumann JC, Moseley AE, Lingrel JB. Physiological role of the α1‐ and α2‐isoforms of the Na+‐K+‐ATPase and biological significance of their cardiac glycoside binding site. Am J Physiol Regul Integr Comp Physiol 290: R524‐R528, 2006. DOI: 10.1152/ajpregu.00838.2005.
 73.Dunham PB. Ion transport in sheep red blood cells. Comp Biochem Physiol Comp Physiol 102: 625‐630, 1992. DOI: 10.1016/0300‐9629(92)90715‐3.
 74.Dürr KL, Tavraz NN, Zimmermann D, Bamberg E, Friedrich T. Characterization of Na,K‐ATPase and H,K‐ATPase enzymes with glycosylation‐deficient β‐subunit variants by voltage‐clamp fluorometry in Xenopus oocytes †. Biochemistry 47: 4288‐4297, 2008. DOI: 10.1021/bi800092k.
 75.Eakle KA, Kabalin MA, Wang SG, Farley RA. The influence of beta subunit structure on the stability of Na+/K(+)‐ATPase complexes and interaction with K+. J Biol Chem 269: 6550‐6557, 1994.
 76.Edwards IJ, Bruce G, Lawrenson C, Howe L, Clapcote SJ, Deuchars SA, Deuchars J. Na+/K+ ATPase 1 and 3 isoforms are differentially expressed in ‐ and ‐motoneurons. J Neurosci 33: 9913‐9919, 2013. DOI: 10.1523/JNEUROSCI.5584‐12.2013.
 77.Edwards RA, Lutz PL, Baden DG. Relationship between energy expenditure and ion channel density in the turtle and rat brain. Am J Physiol Regul Integr Comp Physiol 257: R1354‐R1358, 1989. DOI: 10.1152/ajpregu.1989.257.6.R1354.
 78.Esmann M, Karlish SJD, Sottrup‐Jensen L, Marsh D. Structural integrity of the membrane domains in extensively trypsinized Na,K‐ATPase from shark rectal glands. Biochemistry 33: 8044‐8050, 1994. DOI: 10.1021/bi00192a008.
 79.Esmann M, Skou JC. Occlusion of Na+ by the Na, K‐ATPase in the presence of oligomycin. Biochem Biophys Res Commun 127: 857‐863, 1985. DOI: 10.1016/S0006‐291X(85)80022‐X.
 80.Fahn S, Koval GJ, Albers RW. Sodium‐potassium‐activated adenosine triphosphatase of Electrophorus electric organ. V. Phosphorylation by adenosine triphosphate‐32P. J Biol Chem 243: 1993‐2002, 1968.
 81.Faraj SE, Centeno M, Rossi RC, Montes MR. A kinetic comparison between E2P and the E2P‐like state induced by a beryllium fluoride complex in the Na,K‐ATPase. Interactions with Rb+. Biochim Biophys Acta Biomembr 1861: 355‐365, 2019. DOI: 10.1016/j.bbamem.2018.10.020.
 82.Fedosova NU, Cornelius F, Klodos I. E2P phosphoforms of Na,K‐ATPase. I. Comparison of phosphointermediates formed from ATP and Pi by their reactivity toward hydroxylamine and vanadate. Biochemistry 37: 13634‐13642, 1998. DOI: 10.1021/bi980703h.
 83.Feschenko MS, Donnet C, Wetzel RK, Asinovski NK, Jones LR, Sweadner KJ. Phospholemman, a single‐span membrane protein, is an accessory protein of Na,K‐ATPase in cerebellum and choroid plexus. J Neurosci 23: 2161‐2169, 2003. DOI: 10.1523/JNEUROSCI.23‐06‐02161.2003.
 84.Floyd RV, Wray S, Martín‐Vasallo P, Mobasheri A. Differential cellular expression of FXYD1 (phospholemman) and FXYD2 (gamma subunit of Na, K‐ATPase) in normal human tissues: A study using high density human tissue microarrays. Ann Anat 192: 7‐16, 2010. DOI: 10.1016/j.aanat.2009.09.003.
 85.Forbush B. Cardiotonic steroid binding to Na,K‐ATPase. In: Bronner F, Kleinzeller A, editors. Current Topics in Membranes and Transport. Structure, Mechanism and Function of the Na/K Pump. NY, London: Academic Press, 1983, vol. 19, p. 167‐201.
 86.Forbush B. Rapid release of 42K or 86Rb from two distinct transport sites on the Na,K‐pump in the presence of Pi or vanadate. J Biol Chem 262: 11116‐11127, 1987.
 87.Forbush B. The interaction of amines with the occluded state of the Na,K‐pump. J Biol Chem 263: 7979‐7988, 1988.
 88.Forbush B, Kaplan JH, Hoffman JF. Characterization of a new photoaffinity derivative of ouabain: Labeling of the large polypeptide and of a proteolipid component of the (sodium‐potassium ion)‐dependent ATPase. Biochemistry 17: 3667‐3676, 1978. DOI: 10.1021/bi00610a037.
 89.Friedrich T, Tavraz NN, Junghans C. ATP1A2 mutations in migraine: Seeing through the facets of an ion pump onto the neurobiology of disease. Front Physiol 7: 239, 2016. DOI: 10.3389/fphys.2016.00239.
 90.Fusco MD, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33: 192‐196, 2003. DOI: 10.1038/ng1081.
 91.Gadsby DC. Ion channels versus ion pumps: The principal difference, in principle. Nat Rev Mol Cell Biol 10: 344‐352, 2009. DOI: 10.1038/nrm2668.
 92.Garty H, Karlish SJD. Role of FXYD proteins in ion transport. Annu Rev Physiol 68: 431‐459, 2006. DOI: 10.1146/annurev.physiol.68.040104.131852.
 93.Garty H, Lindzen M, Scanzano R, Aizman R, Füzesi M, Goldshleger R, Farman N, Blostein R, Karlish SJD. A functional interaction between CHIF and Na‐K‐ATPase: Implication for regulation by FXYD proteins. Am J Physiol Renal Physiol 283: F607‐F615, 2002. DOI: 10.1152/ajprenal.00112.2002.
 94.Geering K. The functional role of beta subunits in oligomeric P‐type ATPases. J Bioenerg Biomembr 33: 425‐438, 2001. DOI: 10.1023/a:1010623724749.
 95.Geering K. Functional roles of Na,K‐ATPase subunits. Curr Opin Nephrol Hypertens 17: 526‐532, 2008. DOI: 10.1097/MNH.0b013e3283036cbf.
 96.Geering K, Theulaz I, Verrey F, Häuptle MT, Rossier BC. A role for the beta‐subunit in the expression of functional Na+‐K+‐ATPase in Xenopus oocytes. Am J Physiol 257: C851‐C858, 1989. DOI: 10.1152/ajpcell.1989.257.5.C851.
 97.Gibson JS. Comparative physiology of red cell membrane transport. In: Bernhardt I, Ellory JC, editors. Red Cell Membrane Transport in Health and Disease. Berlin, Heidelberg: Springer Berlin Heidelberg, 2003, p. 721‐734.
 98.Gloor S, Antonicek H, Sweadner KJ, Pagliusi S, Frank R, Moos M, Schachner M. The adhesion molecule on glia (AMOG) is a homologue of the beta subunit of the Na,K‐ATPase. J Cell Biol 110: 165‐174, 1990. DOI: 10.1083/jcb.110.1.165.
 99.Glynn IM. Annual review prize lecture. ‘All hands to the sodium pump’. J Physiol 462: 1‐30, 1993. DOI: 10.1113/jphysiol.1993.sp019540.
 100.Glynn IM, Hara Y, Richards DE. The occlusion of sodium ions within the mammalian sodium‐potassium pump: Its role in sodium transport. J Physiol 351: 531‐547, 1984. DOI: 10.1113/jphysiol.1984.sp015261.
 101.González‐Martínez LM, Avila J, Martí E, Lecuona E, Martín‐Vasallo P. Expression of the β‐subunit isoforms of the Na, K‐ATpase in rat embryo tissues, inner ear and choroid plexus. Biol Cell 81: 215‐222, 1994. DOI: 10.1016/0248‐4900(94)90003‐5.
 102.Gregersen JL, Mattle D, Fedosova NU, Nissen P, Reinhard L. Isolation, crystallization and crystal structure determination of bovine kidney Na+,K+‐ATPase. Acta Crystallogr Sect F Struct Biol Commun 72: 282‐287, 2016. DOI: 10.1107/S2053230X1600279X.
 103.Guennoun‐Lehmann S, Fonseca JE, Horisberger J‐D, Rakowski RF. Palytoxin acts on Na(+),K(+)‐ATPase but not nongastric H(+),K(+)‐ATPase. J Membr Biol 216: 107‐116, 2007. DOI: 10.1007/s00232‐007‐9040‐1.
 104.Habeck M, Kapri‐Pardes E, Sharon M, Karlish SJD. Specific phospholipid binding to Na,K‐ATPase at two distinct sites. Proc Natl Acad Sci 114: 2904‐2909, 2017. DOI: 10.1073/pnas.1620799114.
 105.Habeck M, Tokhtaeva E, Nadav Y, Ben Zeev E, Ferris SP, Kaufman RJ, Bab‐Dinitz E, Kaplan JH, Dada LA, Farfel Z, Tal DM, Katz A, Sachs G, Vagin O, Karlish SJD. Selective assembly of Na,K‐ATPase α2β2 heterodimers in the heart: Distinct functional properties and isoform‐selective inhibitors. J Biol Chem 291: 23159‐23174, 2016. DOI: 10.1074/jbc.M116.751735.
 106.Habermann E. Palytoxin acts through Na+,K+‐ATPase. Toxicon 27: 1171‐1187, 1989. DOI: 10.1016/0041‐0101(89)90026‐3.
 107.Habermann E, Chhatwal GS. Ouabain inhibits the increase due to palytoxin of cation permeability of erythrocytes. Naunyn Schmiedeberg's Arch Pharmacol 319: 101‐107, 1982. DOI: 10.1007/bf00503920.
 108.Hansen O. Vanadate and phosphotransferases with special emphasis on ouabain/na,k‐atpase interaction. Acta Pharmacol Toxicol (Copenh) 52 Suppl 1: 1‐19, 1983. DOI: 10.1111/j.1600‐0773.1983.tb02475.x.
 109.Hansen O, Clausen TN. Electrolyte composition of mink (Mustela vison) erythrocytes and active cation transporters of the cell membrane. Acta Vet Scand 42: 261‐270, 2001. DOI: 10.1186/1751‐0147‐42‐261.
 110.Harada K, Lin H, Endo Y, Fujishiro N, Sakamoto Y, Inoue M. Subunit composition and role of Na+,K+‐ATPases in ventricular myocytes. J Physiol Sci 56: 113‐121, 2006. DOI: 10.2170/physiolsci.RP001905.
 111.Harmel N, Apell H‐J. Palytoxin‐induced effects on partial reactions of the Na,K‐ATPase. J Gen Physiol 128: 103‐118, 2006. DOI: 10.1085/jgp.200609505.
 112.Hatzold J, Beleggia F, Herzig H, Altmüller J, Nürnberg P, Bloch W, Wollnik B, Hammerschmidt M. Tumor suppression in basal keratinocytes via dual non‐cell‐autonomous functions of a Na,K‐ATPase beta subunit. elife 5: e14277, 2016. DOI: 10.7554/eLife.14277.
 113.Hauck C, Potter T, Bartz M, Wittwer T, Wahlers T, Mehlhorn U, Scheiner‐Bobis G, McDonough AA, Bloch W, Schwinger RHG, Müller‐Ehmsen J. Isoform specificity of cardiac glycosides binding to human Na+,K+‐ATPase alpha1beta1, alpha2beta1 and alpha3beta1. Eur J Pharmacol 622: 7‐14, 2009. DOI: 10.1016/j.ejphar.2009.08.039.
 114.He J, Guo L, Lin S, Chen W, Xu G, Cai B, Xu L, Hong J, Qiu L, Wang N, Chen W. ATP1A1 mutations cause intermediate Charcot‐Marie‐Tooth disease. Hum Mutat 40: 2334‐2343, 2019. DOI: 10.1002/humu.23886.
 115.Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Jóhannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 13: 503‐514, 2014. DOI: 10.1016/S1474‐4422(14)70011‐0.
 116.Hilbers F, Kopec W, Isaksen TJ, Holm TH, Lykke‐Hartmann K, Nissen P, Khandelia H, Poulsen H. Tuning of the Na,K‐ATPase by the beta subunit. Sci Rep 6, 2016. DOI: 10.1038/srep20442.
 117.Hirsh JK, Wu CH. Palytoxin‐induced single‐channel currents from the sodium pump synthesized by in vitro expression. Toxicon 35: 169‐176, 1997. DOI: 10.1016/S0041‐0101(96)00136‐5.
 118.Hlivko JT, Chakraborty S, Hlivko TJ, Sengupta A, James PF. The human Na,K‐ATPase alpha4 isoform is a ouabain‐sensitive alpha isoform that is expressed in sperm. Mol Reprod Dev 73: 101‐115, 2006. DOI: 10.1002/mrd.20383.
 119.Hoffman JF. The red cell membrane and the transport of sodium and potassium. Am J Med 41: 666‐680, 1966. DOI: 10.1016/0002‐9343(66)90029‐5.
 120.Hoffman JF. Active transport of Na+ and K+ by red blood cells. In: Andreoli TE, Hoffman JF, Fanestil DD, Schultz SG, editors. Membrane Physiology. Boston, MA: Springer US, 1987, p. 221‐234.
 121.Holm TH, Lykke‐Hartmann K. Insights into the pathology of the α3 Na+/K+‐ATPase ion pump in neurological disorders; lessons from animal models. Front Physiol 7, 2016. DOI: 10.3389/fphys.2016.00209.
 122.Holmgren M, Wagg J, Bezanilla F, Rakowski RF, De Weer P, Gadsby DC. Three distinct and sequential steps in the release of sodium ions by the Na+/K+‐ATPase. Nature 403: 898‐901, 2000. DOI: 10.1038/35002599.
 123.Holzinger F, Frick C, Wink M. Molecular basis for the insensitivity of the Monarch (Danaus plexippus) to cardiac glycosides. FEBS Lett 314: 477‐480, 1992. DOI: 10.1016/0014‐5793(92)81530‐Y.
 124.Horisberger J‐D, Kharoubi‐Hess S. Functional differences between alpha subunit isoforms of the rat Na,K‐ATPase expressed in Xenopus oocytes. J Physiol 539: 669‐680, 2002. DOI: 10.1113/jphysiol.2001.013201.
 125.Ikeda K. Malfunction of respiratory‐related neuronal activity in Na+, K+‐ATPase 2 subunit‐deficient mice is attributable to abnormal Cl‐homeostasis in brainstem neurons. J Neurosci 24: 10693‐10701, 2004. DOI: 10.1523/JNEUROSCI.2909‐04.2004.
 126.Ikeda M, Mitani K, Ito K. Palytoxin induces a nonselective cation channel in single ventricular cells of rat. Naunyn Schmiedeberg's Arch Pharmacol 337, 1988. DOI: 10.1007/BF00182738.
 127.Inaba M, Maede Y. Na,K‐ATPase in dog red cells. Immunological identification and maturation‐associated degradation by the proteolytic system. J Biol Chem 261: 16099‐16105, 1986.
 128.Isaksen TJ, Lykke‐Hartmann K. Insights into the pathology of the α2‐Na+/K+‐ATPase in neurological disorders; lessons from animal models. Front Physiol 7, 2016. DOI: 10.3389/fphys.2016.00161.
 129.Ishida Y, Takagi K, Takahashi M, Satake N, Shibata S. Palytoxin isolated from marine coelenterates. The inhibitory action on (Na,K)‐ATPase. J Biol Chem 258: 7900‐7902, 1983.
 130.Jimenez T, McDermott JP, Sánchez G, Blanco G. Na,K‐ATPase alpha4 isoform is essential for sperm fertility. Proc Natl Acad Sci U S A 108: 644‐649, 2011. DOI: 10.1073/pnas.1016902108.
 131.Jimenez T, Sánchez G, Wertheimer E, Blanco G. Activity of the Na,K‐ATPase α4 isoform is important for membrane potential, intracellular Ca2+, and pH to maintain motility in rat spermatozoa. Reproduction 139: 835‐845, 2010. DOI: 10.1530/REP‐09‐0495.
 132.Jones DH, Li TY, Arystarkhova E, Barr KJ, Wetzel RK, Peng J, Markham K, Sweadner KJ, Fong G‐H, Kidder GM. Na,K‐ATPase from mice lacking the γ subunit (FXYD2) exhibits altered Na+ affinity and decreased thermal stability. J Biol Chem 280: 19003‐19011, 2005. DOI: 10.1074/jbc.M500697200.
 133.Jørgensen PL, Petersen J. Purification and characterization of (Na+, K+)‐ATPase. V. Conformational changes in the enzyme. Transitions between the Na‐form and the K‐form studied with tryptic digestion as a tool. Biochim Biophys Acta Biomembr 401: 399‐415, 1975. DOI: 10.1016/0005‐2736(75)90239‐4.
 134.Juhaszova M, Blaustein MP. Na+ pump low and high ouabain affinity alpha subunit isoforms are differently distributed in cells. Proc Natl Acad Sci U S A 94: 1800‐1805, 1997. DOI: 10.1073/pnas.94.5.1800.
 135.Kanai R, Cornelius F, Ogawa H, Motoyama K, Vilsen B, Toyoshima C. Binding of cardiotonic steroids to Na(+),K(+)‐ATPase in the E2P state. Proc Natl Acad Sci U S A 118, 2021. DOI: 10.1073/pnas.2020438118.
 136.Kanai R, Ogawa H, Vilsen B, Cornelius F, Toyoshima C. Crystal structure of a Na+‐bound Na+,K+‐ATPase preceding the E1P state. Nature 502: 201‐206, 2013. DOI: 10.1038/nature12578.
 137.Kapakos JG, Steinberg M. Fluorescent labeling of (Na++ K+)‐ATPase by 5‐iodoacetamidofluorescein. Biochim Biophys Acta Biomembr 693: 493‐496, 1982. DOI: 10.1016/0005‐2736(82)90458‐8.
 138.Kapri‐Pardes E, Katz A, Haviv H, Mahmmoud Y, Ilan M, Khalfin‐Penigel I, Carmeli S, Yarden O, Karlish SJD. Stabilization of the α2 isoform of Na,K‐ATPase by mutations in a phospholipid binding pocket. J Biol Chem 286: 42888‐42899, 2011. DOI: 10.1074/jbc.M111.293852.
 139.Karlish SJ, Goldshleger R, Stein WD. A 19‐kDa C‐terminal tryptic fragment of the alpha chain of Na/K‐ATPase is essential for occlusion and transport of cations. Proc Natl Acad Sci 87: 4566‐4570, 1990. DOI: 10.1073/pnas.87.12.4566.
 140.Karlish SJD. Characterization of conformational changes in (Na,K) ATPase labeled with fluorescein at the active site. J Bioenerg Biomembr 12: 111‐136, 1980. DOI: 10.1007/BF00744678.
 141.Karlish SJD, Yates DW, Glynn IM. Conformational transitions between Na+‐bound and K+‐bound forms of (Na++ K+)‐ATPase, studied with formycin nucleotides. Biochim Biophys Acta 525: 252‐264, 1978. DOI: 10.1016/0005‐2744(78)90219‐X.
 142.Katz A, Lifshitz Y, Bab‐Dinitz E, Kapri‐Pardes E, Goldshleger R, Tal DM, Karlish SJD. Selectivity of digitalis glycosides for isoforms of human Na,K‐ATPase. J Biol Chem 285: 19582‐19592, 2010. DOI: 10.1074/jbc.M110.119248.
 143.Katz A, Tal DM, Heller D, Habeck M, Ben Zeev E, Rabah B, Bar Kana Y, Marcovich AL, Karlish SJD. Digoxin derivatives with selectivity for the α2β3 isoform of Na,K‐ATPase potently reduce intraocular pressure. Proc Natl Acad Sci 112: 13723‐13728, 2015. DOI: 10.1073/pnas.1514569112.
 144.Klodos I, Nørby JG, Plesner IW. The steady‐state kinetic mechanism of ATP hydrolysis catalyzed by membrane‐bound (Na+ + K+)‐ATPase from ox brain II. Kinetic characterization of phosphointermediates. Biochim Biophys Acta Biomembr 643: 463‐482, 1981. DOI: 10.1016/0005‐2736(81)90089‐4.
 145.Knepper MA, Packer R, Good DW. Ammonium transport in the kidney. Physiol Rev 69: 179‐249, 1989. DOI: 10.1152/physrev.1989.69.1.179.
 146.Küster B, Shainskaya A, Pu HX, Goldshleger R, Blostein R, Mann M, Karlish SJD. A new variant of the γ subunit of renal Na,K‐ATPase: Identification by mass spectrometry, antibody binding, and expression in cultured cells. J Biol Chem 275: 18441‐18446, 2000. DOI: 10.1074/jbc.M001411200.
 147.Kutz LC, Mukherji ST, Wang X, Bryant A, Larre I, Heiny JA, Lingrel JB, Pierre SV, Xie Z. Isoform‐specific role of Na/K‐ATPase α1 in skeletal muscle. Am J Physiol Endocrinol Metab 314: E620‐E629, 2018. DOI: 10.1152/ajpendo.00275.2017.
 148.Labeyrie E, Dobler S. Molecular adaptation of Chrysochus leaf beetles to toxic compounds in their food plants. Mol Biol Evol 21: 218‐221, 2004. DOI: 10.1093/molbev/msg240.
 149.Larsen BR, Assentoft M, Cotrina ML, Hua SZ, Nedergaard M, Kaila K, Voipio J, MacAulay N. Contributions of the Na+/K+‐ATPase, NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses: Mechanisms of K+ clearance in the brain. Glia 62: 608‐622, 2014. DOI: 10.1002/glia.22629.
 150.Lassuthova P, Rebelo AP, Ravenscroft G, Lamont PJ, Davis MR, Manganelli F, Feely SM, Bacon C, Brožková DŠ, Haberlova J, Mazanec R, Tao F, Saghira C, Abreu L, Courel S, Powell E, Buglo E, Bis DM, Baxter MF, Ong RW, Marns L, Lee Y‐C, Bai Y, Isom DG, Barro‐Soria R, Chung KW, Scherer SS, Larsson HP, Laing NG, Choi B‐O, Seeman P, Shy ME, Santoro L, Zuchner S. Mutations in ATP1A1 cause dominant charcot‐marie‐tooth type 2. Am J Hum Genet 102: 505‐514, 2018. DOI: 10.1016/j.ajhg.2018.01.023.
 151.Laughery MD, Clifford RJ, Chi Y, Kaplan JH. Selective basolateral localization of overexpressed Na‐K‐ATPase β1‐ and β2‐subunits is disrupted by butryate treatment of MDCK cells. Am J Physiol Renal Physiol 292: F1718‐F1725, 2007. DOI: 10.1152/ajprenal.00360.2006.
 152.Laursen M, Gregersen JL, Yatime L, Nissen P, Fedosova NU. Structures and characterization of digoxin‐ and bufalin‐bound Na+,K+‐ATPase compared with the ouabain‐bound complex. Proc Natl Acad Sci 112: 1755‐1760, 2015. DOI: 10.1073/pnas.1422997112.
 153.Laursen M, Yatime L, Nissen P, Fedosova NU. Crystal structure of the high‐affinity Na+,K+‐ATPase‐ouabain complex with Mg2+ bound in the cation binding site. Proc Natl Acad Sci 110: 10958‐10963, 2013. DOI: 10.1073/pnas.1222308110.
 154.Lecuona E, Luquín S, Avila J, García‐Segura LM, Martín‐Vasallo P. Expression of the β1 and β2(AMOG) subunits of the Na,K‐ATPase in neural tissues: Cellular and developmental distribution patterns. Brain Res Bull 40: 167‐174, 1996. DOI: 10.1016/0361‐9230(96)00042‐1.
 155.Lee JA, Fortes PAG. Labeling of the glycoprotein subunit of sodium‐potassium ATPase with fluorescent probes. Biochemistry 24: 322‐330, 1985. DOI: 10.1021/bi00323a013.
 156.Lee P, Miles PR. Density distribution and cation composition of red blood cells in newborn puppies. J Cell Physiol 79: 377‐388, 1972. DOI: 10.1002/jcp.1040790308.
 157.Lian W‐N. Deglycosylation of Na+/K+‐ATPase causes the basolateral protein to undergo apical targeting in polarized hepatic cells. J Cell Sci 119: 11‐22, 2006. DOI: 10.1242/jcs.02706.
 158.Lin H, Ozaki S, Fujishiro N, Takeda K, Imanaga I, Prestwich GD, Inoue M. Subunit composition and role of Na+,K+‐ATPases in adrenal chromaffin cells. J Physiol 564: 161‐172, 2005. DOI: 10.1113/jphysiol.2004.081455.
 159.Lingrel JB. The physiological significance of the cardiotonic steroid/ouabain‐binding site of the Na,K‐ATPase. Annu Rev Physiol 72: 395‐412, 2010. DOI: 10.1146/annurev‐physiol‐021909‐135725.
 160.Lubarski I, Karlish SJD, Garty H. Structural and functional interactions between FXYD5 and the Na+‐K+‐ATPase. Am J Physiol Renal Physiol 293: F1818‐F1826, 2007. DOI: 10.1152/ajprenal.00367.2007.
 161.Lubarski I, Pihakaski‐Maunsbach K, Karlish SJD, Maunsbach AB, Garty H. Interaction with the Na,K‐ATPase and tissue distribution of F X YD5 (related to ion channel). J Biol Chem 280: 37717‐37724, 2005. DOI: 10.1074/jbc.M506397200.
 162.Lubin M. Intracellular potassium and macromolecular synthesis in mammalian cells. Nature 213: 451‐453, 1967. DOI: 10.1038/213451a0.
 163.Lubin M, Ennis HL. On the role of intracellular potassium in protein synthesis. Biochim Biophys Acta 80: 614‐631, 1964. DOI: 10.1016/0926‐6550(64)90306‐8.
 164.Lutsenko S, Kaplan JH. An essential role for the extracellular domain of the Na,K‐ATPase beta‐subunit in cation occlusion. Biochemistry 32: 6737‐6743, 1993. DOI: 10.1021/bi00077a029.
 165.Maede Y, Inaba M. (Na,K)‐ATPase and ouabain binding in reticulocytes from dogs with high K and low K erythrocytes and their changes during maturation. J Biol Chem 260: 3337‐3343, 1985.
 166.Manoharan P, Radzyukevich TL, Hakim Javadi H, Stiner CA, Landero Figueroa JA, Lingrel JB, Heiny JA. Phospholemman is not required for the acute stimulation of Na(+)‐K(+)‐ATPase alpha(2)‐activity during skeletal muscle fatigue. Am J Physiol Cell Physiol 309: C813‐C822, 2015. DOI: 10.1152/ajpcell.00205.2015.
 167.Masuzawa T, Ohta T, Kawamura M, Nakahara N, Sato F. Immunohistochemical localization of Na+, K+‐ATPase in the choroid plexus. Brain Res 302: 357‐362, 1984. DOI: 10.1016/0006‐8993(84)90250‐6.
 168.McDonough AA, Geering K, Farley RA. The sodium pump needs its beta subunit. FASEB J 4: 1598‐1605, 1990. DOI: 10.1096/fasebj.4.6.2156741.
 169.McDonough AA, Zhang Y, Shin V, Frank JS. Subcellular distribution of sodium pump isoform subunits in mammalian cardiac myocytes. Am J Physiol 270: C1221‐C1227, 1996. DOI: 10.1152/ajpcell.1996.270.4.C1221.
 170.McGrail K, Phillips J, Sweadner K. Immunofluorescent localization of three Na,K‐ATPase isozymes in the rat central nervous system: Both neurons and glia can express more than one Na,K‐ATPase. J Neurosci 11: 381‐391, 1991. DOI: 10.1523/JNEUROSCI.11‐02‐00381.1991.
 171.Meier S, Tavraz NN, Dürr KL, Friedrich T. Hyperpolarization‐activated inward leakage currents caused by deletion or mutation of carboxy‐terminal tyrosines of the Na+/K+‐ATPase α subunit. J Gen Physiol 135: 115‐134, 2010. DOI: 10.1085/jgp.200910301.
 172.Mercer RW, Biemesderfer D, Bliss DP, Collins JH, Forbush B. Molecular cloning and immunological characterization of the gamma polypeptide, a small protein associated with the Na,K‐ATPase. J Cell Biol 121: 579‐586, 1993. DOI: 10.1083/jcb.121.3.579.
 173.Meyer DJ, Gatto C, Artigas P. On the effect of hyperaldosteronism‐inducing mutations in Na/K pumps. J Gen Physiol 149: 1009‐1028, 2017. DOI: 10.1085/jgp.201711827.
 174.Mijatovic T, Van Quaquebeke E, Delest B, Debeir O, Darro F, Kiss R. Cardiotonic steroids on the road to anti‐cancer therapy. Biochim Biophys Acta 1776: 32‐57, 2007. DOI: 10.1016/j.bbcan.2007.06.002.
 175.Mishra NK, Peleg Y, Cirri E, Belogus T, Lifshitz Y, Voelker DR, Apell H‐J, Garty H, Karlish SJD. FXYD Proteins Stabilize Na,K‐ATPase: Amplification of specific phosphatidylserine‐protein interactions. J Biol Chem 286: 9699‐9712, 2011. DOI: 10.1074/jbc.M110.184234.
 176.Mitchell P. A general theory of membrane transport from studies of bacteria. Nature 180: 134‐136, 1957. DOI: 10.1038/180134a0.
 177.Mitchell Travis J, Zugarramurdi C, Olivera JF, Gatto C, Artigas P. Sodium and proton effects on inward proton transport through Na/K pumps. Biophys J 106: 2555‐2565, 2014. DOI: 10.1016/j.bpj.2014.04.053.
 178.Modyanov NN, Mathews PM, Grishin AV, Beguin P, Beggah AT, Rossier BC, Horisberger JD, Geering K. Human ATP1AL1 gene encodes a ouabain‐sensitive H‐K‐ATPase. Am J Physiol 269: C992‐C997, 1995. DOI: 10.1152/ajpcell.1995.269.4.C992.
 179.Møller JV, Olesen C, Winther A‐ML, Nissen P. The sarcoplasmic Ca2+‐ATPase: Design of a perfect chemi‐osmotic pump. Q Rev Biophys 43: 501‐566, 2010. DOI: 10.1017/S003358351000017X.
 180.Montes MR, Ferreira‐Gomes MS, Centeno M, Rossi RC. The E2P‐like state induced by magnesium fluoride complexes in the Na,K‐ATPase. Kinetics of formation and interaction with Rb+. Biochim Biophys Acta Biomembr 1848: 1514‐1523, 2015. DOI: 10.1016/j.bbamem.2015.03.023.
 181.Morth JP, Pedersen BP, Toustrup‐Jensen MS, Sørensen TL‐M, Petersen J, Andersen JP, Vilsen B, Nissen P. Crystal structure of the sodium–potassium pump. Nature 450: 1043‐1049, 2007. DOI: 10.1038/nature06419.
 182.Moseley AE, Lieske SP, Wetzel RK, James PF, He S, Shelly DA, Paul RJ, Boivin GP, Witte DP, Ramirez JM, Sweadner KJ, Lingrel JB. The Na,K‐ATPase α2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice. J Biol Chem 278: 5317‐5324, 2003. DOI: 10.1074/jbc.M211315200.
 183.Moseley AE, Williams MT, Schaefer TL, Bohanan CS, Neumann JC, Behbehani MM, Vorhees CV, Lingrel JB. Deficiency in Na,K‐ATPase isoform genes alters spatial learning, motor activity, and anxiety in mice. J Neurosci 27: 616‐626, 2007. DOI: 10.1523/JNEUROSCI.4464‐06.2007.
 184.Müller‐Ehmsen J, Juvvadi P, Thompson CB, Tumyan L, Croyle M, Lingrel JB, Schwinger RHG, McDonough AA, Farley RA. Ouabain and substrate affinities of human Na+‐K+‐ATPase α1β1, α2β1, and α3β1 when expressed separately in yeast cells. Am J Physiol Cell Physiol 281: C1355‐C1364, 2001. DOI: 10.1152/ajpcell.2001.281.4.C1355.
 185.Munakata H, Schmid K, Collins JH, Zot AS, Lane LK, Schwartz A. The alpha and beta subunits of lamb kidney Na,K‐ATPase are both glycoproteins. Biochem Biophys Res Commun 107: 229‐231, 1982. DOI: 10.1016/0006‐291x(82)91693‐x.
 186.Nagai M, Taniguchi K, Kangawa K, Matsuo H, Nakamura S, Iida S. Identification of N‐[p‐(2‐benzimidazolyl)phenyl]maleimide‐modified residue participating in dynamic fluorescence changes accompanying Na+,K+‐dependent ATP hydrolysis. J Biol Chem 261: 13197‐13202, 1986.
 187.Newport TD, Sansom MSP, Stansfeld PJ. The MemProtMD database: A resource for membrane‐embedded protein structures and their lipid interactions. Nucleic Acids Res 47: D390‐D397, 2019. DOI: 10.1093/nar/gky1047.
 188.Nielsen H, Nielsen K, editors. Neighbouring Nobel: The History of Thirteen Danish Nobel Prizes. Aarhus: Aarhus University Press, 2001, p. 624.
 189.Ning G, Maunsbach AB, Esmann M. Ultrastructure of membrane‐bound Na,K‐ATPase after extensive tryptic digestion. FEBS Lett 330: 19‐22, 1993. DOI: 10.1016/0014‐5793(93)80910‐M.
 190.Noguchi S, Mishina M, Kawamura M, Numa S. Expression of functional (Na+ + K+)‐ATPase from cloned cDNAs. FEBS Lett 225: 27‐32, 1987. DOI: 10.1016/0014‐5793(87)81125‐0.
 191.Nørby JG, Klodos I, Christiansen NO. Kinetics of Na‐ATPase activity by the Na,K pump. Interactions of the phosphorylated intermediates with Na+, Tris+, and K+. J Gen Physiol 82: 725‐759, 1983. DOI: 10.1085/jgp.82.6.725.
 192.Nyblom M, Poulsen H, Gourdon P, Reinhard L, Andersson M, Lindahl E, Fedosova N, Nissen P. Crystal structure of Na+, K+‐ATPase in the Na+‐bound state. Science 342: 123‐127, 2013. DOI: 10.1126/science.1243352.
 193.Ogawa H, Cornelius F, Hirata A, Toyoshima C. Sequential substitution of K+ bound to Na+,K+‐ATPase visualized by X‐ray crystallography. Nat Commun 6, 2015. DOI: 10.1038/ncomms9004.
 194.Ogawa H, Shinoda T, Cornelius F, Toyoshima C. Crystal structure of the sodium‐potassium pump (Na+,K+‐ATPase) with bound potassium and ouabain. Proc Natl Acad Sci 106: 13742‐13747, 2009. DOI: 10.1073/pnas.0907054106.
 195.Olesen C, Picard M, Winther AM, Gyrup C, Morth JP, Oxvig C, Moller JV, Nissen P. The structural basis of calcium transport by the calcium pump. Nature 450: 1036‐1042, 2007. DOI: 10.1038/nature06418.
 196.Or E, David P, Shainskaya A, Tal DM, Karlish SJ. Effects of competitive sodium‐like antagonists on Na,K‐ATPase suggest that cation occlusion from the cytoplasmic surface occurs in two steps. J Biol Chem 268: 16929‐16937, 1993.
 197.Or E, Goldshleger R, Tal DM, Karlish SJD. Solubilization of a complex of tryptic fragments of Na,K‐ATPase containing occluded Rb ions and bound ouabain†. Biochemistry 35: 6853‐6864, 1996. DOI: 10.1021/bi960093q.
 198.Paciorkowski AR, McDaniel SS, Jansen LA, Tully H, Tuttle E, Ghoneim DH, Tupal S, Gunter SA, Vasta V, Zhang Q, Tran T, Liu YB, Ozelius LJ, Brashear A, Sweadner KJ, Dobyns WB, Hahn S. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 56: 422‐430, 2015. DOI: 10.1111/epi.12914.
 199.Palmer CJ, Scott BT, Jones LR. Purification and complete sequence determination of the major plasma membrane substrate for cAMP‐dependent protein kinase and protein kinase C in myocardium. J Biol Chem 266: 11126‐11130, 1991.
 200.Parker JC. Dog red blood cells. Adjustment of density in vivo. J Gen Physiol 61: 146‐157, 1973. DOI: 10.1085/jgp.61.2.146.
 201.Peluffo RD, González‐Lebrero RM, Kaufman SB, Kortagere S, Orban B, Rossi RC, Berlin JR. Quaternary benzyltriethylammonium ion binding to the Na,K‐ATPase: A tool to investigate extracellular K+ binding reactions. Biochemistry 48: 8105‐8119, 2009. DOI: 10.1021/bi900687u.
 202.Peng L, Martin‐Vasallo P, Sweadner KJ. Isoforms of Na,K‐ATPase α and β subunits in the rat cerebellum and in granule cell cultures. J Neurosci 17: 3488‐3502, 1997. DOI: 10.1523/JNEUROSCI.17‐10‐03488.1997.
 203.Pestov NB, Ahmad N, Korneenko TV, Zhao H, Radkov R, Schaer D, Roy S, Bibert S, Geering K, Modyanov NN. Evolution of Na,K‐ATPase betam‐subunit into a coregulator of transcription in placental mammals. Proc Natl Acad Sci 104: 11215‐11220, 2007. DOI: 10.1073/pnas.0704809104.
 204.Plesner L, Plesner IW. Kinetics of oligomycin inhibition and activation of Na+/K(+)‐ATPase. Biochim Biophys Acta 1076: 421‐426, 1991. DOI: 10.1016/0167‐4838(91)90486‐j.
 205.Pollay M, Hisey B, Reynolds E, Tomkins P, Stevens FA, Smith R. Choroid plexus Na+/K+‐activated adenosine triphosphatase and cerebrospinal fluid formation. Neurosurgery 17: 768‐772, 1985. DOI: 10.1227/00006123‐198511000‐00007.
 206.Polvani C, Blostein R. Protons as substitutes for sodium and potassium in the sodium pump reaction. J Biol Chem 263: 16757‐16763, 1988.
 207.Post RL. Seeds of sodium, potassium ATPase. Annu Rev Physiol 51: 1‐16, 1989. DOI: 10.1146/annurev.ph.51.030189.000245.
 208.Post RL, Hegyvary C, Kume S. Activation by adenosine triphosphate in the phosphorylation kinetics of sodium and potassium ion transport adenosine triphosphatase. J Biol Chem 247: 6530‐6540, 1972.
 209.Post RL, Kume S, Rogers FN. Alternating paths of phosphorylation of the sodium and potassium ion pump of plasma membranes. In: Azzone GF, Ernster L, Papa S, Quagliariello E, Silliprandi N, editors. Mechanisms in Bioenergetics. NY, London: Academic Press, 1973, p. 203‐218.
 210.Post RL, Kume S, Tobin T, Orcutt B, Sen AK. Flexibility of an active center in sodium‐plus‐potassium adenosine triphosphatase. J Gen Physiol 54: 306‐326, 1969. DOI: 10.1085/jgp.54.1.306.
 211.Post RL, Toda G, Rogers FN. Phosphorylation by inorganic phosphate of sodium plus potassium ion transport adenosine triphosphatase. Four reactive states. J Biol Chem 250: 691‐701, 1975.
 212.Poulsen H, Khandelia H, Morth JP, Bublitz M, Mouritsen OG, Egebjerg J, Nissen P. Neurological disease mutations compromise a C‐terminal ion pathway in the Na(+)/K(+)‐ATPase. Nature 467: 99‐102, 2010. DOI: 10.1038/nature09309.
 213.Price EM, Lingrel JB. Structure‐function relationships in the sodium‐potassium ATPase .alpha. subunit: Site‐directed mutagenesis of glutamine‐111 to arginine and asparagine‐122 to aspartic acid generates a ouabain‐resistant enzyme. Biochemistry 27: 8400‐8408, 1988. DOI: 10.1021/bi00422a016.
 214.Qiu LY, Krieger E, Schaftenaar G, Swarts HGP, Willems PHGM, De Pont JJHHM, Koenderink JB. Reconstruction of the complete ouabain‐binding pocket of Na,K‐ATPase in gastric H,K‐ATPase by substitution of only seven amino acids. J Biol Chem 280: 32349‐32355, 2005. DOI: 10.1074/jbc.M505168200.
 215.Radzyukevich TL, Neumann JC, Rindler TN, Oshiro N, Goldhamer DJ, Lingrel JB, Heiny JA. Tissue‐specific role of the Na,K‐ATPase α2 isozyme in skeletal muscle. J Biol Chem 288: 1226‐1237, 2013. DOI: 10.1074/jbc.M112.424663.
 216.Rakowski RF, Vasilets LA, LaTona J, Schwarz W. A negative slope in the current‐voltage relationship of the Na+/K+ pump in Xenopus oocytes produced by reduction of external [K+]. J Membr Biol 121: 177‐187, 1991. DOI: 10.1007/BF01870531.
 217.Robinson JD, Davis RL, Steinberg M. Fluoride and beryllium interact with the (Na + K)‐dependent ATPase as analogs of phosphate. J Bioenerg Biomembr 18: 521‐531, 1986. DOI: 10.1007/bf00743148.
 218.Sanchez G, Nguyen AN, Timmerberg B, Tash JS, Blanco G. The Na,K‐ATPase alpha4 isoform from humans has distinct enzymatic properties and is important for sperm motility. Mol Hum Reprod 12: 565‐576, 2006. DOI: 10.1093/molehr/gal062.
 219.Scheiner‐Bobis G, Meyer zu Heringdorf D, Christ M, Habermann E. Palytoxin induces K+ efflux from yeast cells expressing the mammalian sodium pump. Mol Pharmacol 45: 1132‐1136, 1994.
 220.Schlingmann KP, Bandulik S, Mammen C, Tarailo‐Graovac M, Holm R, Baumann M, König J, Lee JJY, Drögemöller B, Imminger K, Beck BB, Altmüller J, Thiele H, Waldegger S, van't Hoff W, Kleta R, Warth R, van Karnebeek CDM, Vilsen B, Bockenhauer D, Konrad M. Germline de novo mutations in ATP1A1 cause renal hypomagnesemia, refractory seizures, and intellectual disability. Am J Hum Genet 103: 808‐816, 2018. DOI: 10.1016/j.ajhg.2018.10.004.
 221.Schneeberger A, Apell H‐J. Ion selectivity of the cytoplasmic binding sites of the Na,K‐ATPase: II. Competition of various cations. J Membr Biol 179: 263‐273, 2001. DOI: 10.1007/s002320010051.
 222.Schoner W, Scheiner‐Bobis G. Endogenous and exogenous cardiac glycosides: Their roles in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol 293: C509‐C536, 2007. DOI: 10.1152/ajpcell.00098.2007.
 223.Schwappach B, Stürmer W, Apell HJ, Karlish SJ. Binding of sodium ions and cardiotonic steroids to native and selectively trypsinized Na,K pump, detected by charge movements. J Biol Chem 269: 21620‐21626, 1994.
 224.Shamraj OI, Lingrel JB. A putative fourth Na+,K(+)‐ATPase alpha‐subunit gene is expressed in testis. Proc Natl Acad Sci U S A 91: 12952‐12956, 1994. DOI: 10.1073/pnas.91.26.12952.
 225.Shinoda T, Ogawa H, Cornelius F, Toyoshima C. Crystal structure of the sodium–potassium pump at 2.4 Å resolution. Nature 459: 446‐450, 2009. DOI: 10.1038/nature07939.
 226.Shull GE, Greeb J, Lingrel JB. Molecular cloning of three distinct forms of the Na+,K+‐ATPase .alpha.‐subunit from rat brain. Biochemistry 25: 8125‐8132, 1986. DOI: 10.1021/bi00373a001.
 227.Skou JC. The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim Biophys Acta 23: 394‐401, 1957. DOI: 10.1016/0006‐3002(57)90343‐8.
 228.Skou JC. The identification of the sodium‐pump as the membrane‐bound Na+/K+‐ATPase: A commentary on ‘The Influence of Some Cations on an Adenosine Triphosphatase from Peripheral Nerves’. Biochim Biophys Acta 1000: 435‐438, 1989. DOI: 10.1016/s0006‐3002(89)80038‐1.
 229.Skou JC, Esmann M. Eosin, a fluorescent probe of ATP binding to the (Na+ + K+)‐ATPase. Biochim Biophys Acta Biomembr 647: 232‐240, 1981. DOI: 10.1016/0005‐2736(81)90251‐0.
 230.Skou JC, Esmann M. The effects of Na+ and K+ on the conformational transitions of (Na+ + K+)‐ATPase. Biochim Biophys Acta Protein Struct Mol Enzymol 746: 101‐113, 1983. DOI: 10.1016/0167‐4838(83)90016‐X.
 231.Smedemark‐Margulies N, Brownstein CA, Vargas S, Tembulkar SK, Towne MC, Shi J, Gonzalez‐Cuevas E, Liu KX, Bilguvar K, Kleiman RJ, Han MJ, Torres A, Berry GT, Yu TW, Beggs AH, Agrawal PB, Gonzalez‐Heydrich J. A novel de novo mutation in ATP1A3 and childhood‐onset schizophrenia. Cold Spring Harb Mol Case Stud 2: a001008, 2016. DOI: 10.1101/mcs.a001008.
 232.Stanley KS, Meyer DJ, Gatto C, Artigas P. Intracellular requirements for passive proton transport through the Na+,K+‐ATPase. Biophys J 111: 2430‐2439, 2016. DOI: 10.1016/j.bpj.2016.09.042.
 233.Stekhoven FMAHS, Swarts HGP, de Pont JJHHM, Bonting SL. Na+‐like effect of imidazole on the phosphorylation of (Na+ + K+)‐ATPase. Biochim Biophys Acta Biomembr 815: 16‐24, 1985. DOI: 10.1016/0005‐2736(85)90468‐7.
 234.Stoica A, Larsen BR, Assentoft M, Holm R, Holt LM, Vilhardt F, Vilsen B, Lykke‐Hartmann K, Olsen ML, MacAulay N. The α2β2 isoform combination dominates the astrocytic Na+/K+‐ATPase activity and is rendered nonfunctional by the α2.G301R familial hemiplegic migraine type 2‐associated mutation. Glia 65: 1777‐1793, 2017. DOI: 10.1002/glia.23194.
 235.Suh EM, Kishi Y. Synthesis of palytoxin from palytoxin carboxylic acid. J Am Chem Soc 116: 11205‐11206, 1994. DOI: 10.1021/ja00103a065.
 236.Sundaram SM, Safina D, Ehrkamp A, Faissner A, Heumann R, Dietzel ID. Differential expression patterns of sodium potassium ATPase alpha and beta subunit isoforms in mouse brain during postnatal development. Neurochem Int 128: 163‐174, 2019. DOI: 10.1016/j.neuint.2019.04.009.
 237.Sweadner KJ. Two molecular forms of (Na+ + K+)‐stimulated ATPase in brain. Separation, and difference in affinity for strophanthidin. J Biol Chem 254: 6060‐6067, 1979.
 238.Sweadner KJ, Arystarkhova E, Penniston JT, Swoboda KJ, Brashear A, Ozelius LJ. Genotype‐structure‐phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3. Neurol Genet 5: e303, 2019. DOI: 10.1212/NXG.0000000000000303.
 239.Sweadner KJ, Rael E. The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics 68: 41‐56, 2000. DOI: 10.1006/geno.2000.6274.
 240.Sweadner KJ, Toro C, Whitlow CT, Snively BM, Cook JF, Ozelius LJ, Markello TC, Brashear A. ATP1A3 mutation in adult rapid‐onset ataxia. PLoS One 11: e0151429, 2016. DOI: 10.1371/journal.pone.0151429.
 241.Syeda SS, Sánchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G. Design, synthesis, and in vitro and in vivo evaluation of ouabain analogues as potent and selective Na,K‐ATPase α4 isoform inhibitors for male contraception. J Med Chem 61: 1800‐1820, 2018. DOI: 10.1021/acs.jmedchem.7b00925.
 242.Takeda K, Noguchi S, Sugino A, Kawamura M. Functional activity of oligosaccharide‐deficient (Na,K)ATPase expressed in Xenopus oocytes. FEBS Lett 238: 201‐204, 1988. DOI: 10.1016/0014‐5793(88)80256‐4.
 243.Takeyasu K, Lemas V, Fambrough DM. Stability of Na(+)‐K(+)‐ATPase alpha‐subunit isoforms in evolution. Am J Physiol Cell Physiol 259: C619‐C630, 1990. DOI: 10.1152/ajpcell.1990.259.4.C619.
 244.Thever MD, Saier MH. Bioinformatic characterization of P‐Type ATPases encoded within the fully sequenced genomes of 26 eukaryotes. J Membr Biol 229: 115‐130, 2009. DOI: 10.1007/s00232‐009‐9176‐2.
 245.Thomas RC. Electrogenic sodium pump in nerve and muscle cells. Physiol Rev 52: 563‐594, 1972. DOI: 10.1152/physrev.1972.52.3.563.
 246.Tokhtaeva E, Clifford RJ, Kaplan JH, Sachs G, Vagin O. Subunit isoform selectivity in assembly of Na,K‐ATPase α‐β heterodimers. J Biol Chem 287: 26115‐26125, 2012. DOI: 10.1074/jbc.M112.370734.
 247.Tosteson MT, Thomas J, Arnadottir J, Tosteson DC. Effects of palytoxin on cation occlusion and phosphorylation of the (Na+,K+)‐ATPase. J Membr Biol 192: 181‐189, 2003. DOI: 10.1007/s00232‐002‐1074‐9.
 248.Toustrup‐Jensen MS, Holm R, Einholm AP, Schack VR, Morth JP, Nissen P, Andersen JP, Vilsen B. The C terminus of Na+,K+‐ATPase controls Na+ affinity on both sides of the membrane through Arg935. J Biol Chem 284: 18715‐18725, 2009. DOI: 10.1074/jbc.M109.015099.
 249.Toyoshima C. How Ca2+‐ATPase pumps ions across the sarcoplasmic reticulum membrane. Biochim Biophys Acta, Mol Cell Res 1793: 941‐946, 2009. DOI: 10.1016/j.bbamcr.2008.10.008.
 250.Toyoshima C, Inesi G. Structural basis of ion pumping by Ca2+‐ATPase of the sarcoplasmic reticulum. Annu Rev Biochem 73: 269‐292, 2004. DOI: 10.1146/annurev.biochem.73.011303.073700.
 251.Vagin O, Dada LA, Tokhtaeva E, Sachs G. The Na‐K‐ATPase α1β1 heterodimer as a cell adhesion molecule in epithelia. Am J Physiol Cell Physiol 302: C1271‐C1281, 2012. DOI: 10.1152/ajpcell.00456.2011.
 252.Vagin O, Turdikulova S, Sachs G. Recombinant addition of N‐glycosylation sites to the basolateral Na,K‐ATPase β1 subunit results in its clustering in caveolae and apical sorting in HGT‐1 cells. J Biol Chem 280: 43159‐43167, 2005. DOI: 10.1074/jbc.M508262200.
 253.Van Quaquebeke E, Simon G, André A, Dewelle J, El Yazidi M, Bruyneel F, Tuti J, Nacoulma O, Guissou P, Decaestecker C, Braekman J‐C, Kiss R, Darro F. Identification of a novel cardenolide (2″‐oxovoruscharin) from Calotropis procera and the hemisynthesis of novel derivatives displaying potent in vitro antitumor activities and high in vivo tolerance: Structure‐activity relationship analyses. J Med Chem 48: 849‐856, 2005. DOI: 10.1021/jm049405a.
 254.Vedovato N, Gadsby DC. The two C‐terminal tyrosines stabilize occluded Na/K pump conformations containing Na or K ions. J Gen Physiol 136: 63‐82, 2010. DOI: 10.1085/jgp.201010407.
 255.Vedovato N, Gadsby DC. Route, mechanism, and implications of proton import during Na+/K+ exchange by native Na+/K+‐ATPase pumps. J Gen Physiol 143: 449‐464, 2014. DOI: 10.1085/jgp.201311148.
 256.Voldsgaard Clausen M, Nissen P, Poulsen H. The α4 isoform of the Na+,K+‐ATPase is tuned for changing extracellular environments. FEBS J 283: 282‐293, 2016. DOI: 10.1111/febs.13567.
 257.Walaas SI, Horn RS, Nairn AC, Walaas O, Adler A. Skeletal muscle sarcolemma proteins as targets for adenosine 3′:5′‐monophosphate‐dependent and calcium‐dependent protein kinases. Arch Biochem Biophys 262: 245‐258, 1988. DOI: 10.1016/0003‐9861(88)90186‐5.
 258.Wall SM. Ammonium transport and the role of the Na,K‐ATPase. Miner Electrolyte Metab 22: 311‐317, 1996.
 259.Wang X, Horisberger JD. A conformation of Na(+)‐K+ pump is permeable to proton. Am J Physiol 268: C590‐C595, 1995. DOI: 10.1152/ajpcell.1995.268.3.C590.
 260.Wasserstrom JA, Aistrup GL. Digitalis: New actions for an old drug. Am J Physiol Heart Circ Physiol 289: H1781‐H1793, 2005. DOI: 10.1152/ajpheart.00707.2004.
 261.Weidemann H. Na/K‐ATPase, endogenous digitalis‐like compounds and cancer development ‐ A hypothesis. Front Biosci 10: 2165, 2005. DOI: 10.2741/1688.
 262.Weidmann S. Effects of palytoxin on the electrical activity of dog and rabbit heart. Experientia 33: 1487‐1489, 1977. DOI: 10.1007/BF01918825.
 263.Weigand KM, Laursen M, Swarts HGP, Engwerda AHJ, Prüfert C, Sandrock J, Nissen P, Fedosova NU, Russel FGM, Koenderink JB. Na+,K+‐ATPase isoform selectivity for digitalis‐like compounds is determined by two amino acids in the first extracellular loop. Chem Res Toxicol 27: 2082‐2092, 2014. DOI: 10.1021/tx500290k.
 264.Wetzel RK, Sweadner KJ. Immunocytochemical localization of NaK‐ATPase isoforms in the rat and mouse ocular ciliary epithelium. Invest Ophthalmol Vis Sci 42: 763‐769, 2001.
 265.Whittam R, Willis JS. Ion movements and oxygen consumption in kidney cortex slices. J Physiol 168: 158‐177, 1963. DOI: 10.1113/jphysiol.1963.sp007184.
 266.Williams TA, Monticone S, Schack VR, Stindl J, Burrello J, Buffolo F, Annaratone L, Castellano I, Beuschlein F, Reincke M, Lucatello B, Ronconi V, Fallo F, Bernini G, Maccario M, Giacchetti G, Veglio F, Warth R, Vilsen B, Mulatero P. Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone‐producing adenomas. Hypertension 63: 188‐195, 2014. DOI: 10.1161/HYPERTENSIONAHA.113.01733.
 267.Wilson PD, Devuyst O, Li X, Gatti L, Falkenstein D, Robinson S, Fambrough D, Burrow CR. Apical plasma membrane mispolarization of NaK‐ATPase in polycystic kidney disease epithelia is associated with aberrant expression of the β2 isoform. Am J Pathol 156: 253‐268, 2000. DOI: 10.1016/S0002‐9440(10)64726‐8.
 268.Wilson PD, Sherwood AC, Palla K, Du J, Watson R, Norman JT. Reversed polarity of Na(+)‐K(+)‐ATPase: Mislocation to apical plasma membranes in polycystic kidney disease epithelia. Am J Physiol 260: F420‐F430, 1991. DOI: 10.1152/ajprenal.1991.260.3.F420.
 269.Woo AL, James PF, Lingrel JB. Characterization of the Fourth α Isoform of the Na,K‐ATPase. J Membr Biol 169: 39‐44, 1999. DOI: 10.1007/PL00005899.
 270.Woo AL, James PF, Lingrel JB. Sperm motility is dependent on a unique isoform of the Na,K‐ATPase. J Biol Chem 275: 20693‐20699, 2000. DOI: 10.1074/jbc.M002323200.
 271.Xu ZC, Dunham PB, Dyer B, Blostein R. Decline in number of Na‐K pumps on low‐K+ sheep reticulocytes during maturation is modulated by Lp antigen. Am J Physiol Cell Physiol 266: C1173‐C1181, 1994. DOI: 10.1152/ajpcell.1994.266.5.C1173.
 272.Yatime L, Laursen M, Morth JP, Esmann M, Nissen P, Fedosova NU. Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+‐ATPase. J Struct Biol 174: 296‐306, 2011. DOI: 10.1016/j.jsb.2010.12.004.
 273.Zamofing D, Rossier BC, Geering K. Role of the Na,K‐ATPaseβ‐subunit in the cellular accumulation and maturation of the enzyme as assessed by glycosylation inhibitors. J Membr Biol 104: 69‐79, 1988. DOI: 10.1007/BF01871903.
 274.Zamofing D, Rossier BC, Geering K. Inhibition of N‐glycosylation affects transepithelial Na+ but not Na+‐K+‐ATPase transport. Am J Physiol Cell Physiol 256: C958‐C966, 1989. DOI: 10.1152/ajpcell.1989.256.5.C958.
 275.Zhou Y, Wu F, Zhang M, Xiong Z, Yin Q, Ru Y, Shi H, Li J, Mao S, Li Y, Cao X, Hu R, Liew CW, Ding Q, Wang X, Zhang Y. EMC10 governs male fertility via maintaining sperm ion balance. J Mol Cell Biol 10: 503‐514, 2018. DOI: 10.1093/jmcb/mjy024.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Natalya U. Fedosova, Michael Habeck, Poul Nissen. Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump. Compr Physiol 2021, 12: 2659-2679. doi: 10.1002/cphy.c200018