Seminars in Nephrology
Volume 26, Issue 5 , Pages 386-392 , September 2006

Na+, K+-ATPase: An Indispensable Ion Pumping-Signaling Mechanism Across Mammalian Cell Membranes

  • A. Ariel Jaitovich
  • ,
  • Alejandro M. Bertorello

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Dr. Alejandro M. Bertorello, King Gustaf V Research Institute, Karolinska University Hospital-Solna, M1:01, 171 76 Stockholm, Sweden.

References 

  1. Skou JC. Nobel lecture (The identification of the sodium pump). Biosci Rep. 1998;18:155–169
  2. Glynn IM. A hundred years of sodium pumping. Annu Rev Physiol. 2002;64:1–18
  3. 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. 1972;247:6530–6540
  4. Stein WD. The sodium pump in the evolution of animal cells. Philos Trans R Soc Lond B Biol Sci. 1995;349:263–269
  5. Blumwald E, Aharon GS, Apse MP. Sodium transport in plant cells. Biochim Biophys Acta. 2000;1465:140–151
  6. Bohnert HJ, Nelson DE, Jensen RG. Adaptations to environmental stresses. Plant Cell. 1995;7:1099–1111
  7. Kaplan JH. A moving new role for the sodium pump in epithelial cells and carcinomas. Sci STKE pe31. 2005;
  8. Kuhlbrandt W. Biology, structure and mechanism of P-type ATPases. Nat Rev Mol Cell Biol. 2004;5:282–295
  9. Stein WD. Cell volume homeostasis: Ionic and nonionic mechanisms: The sodium pump in the emergence of animal cells. Int Rev Cytol. 2002;215:231–258
  10. Alberts B. Molecular Biology of the Cell (ed 4). New York: Garland Science; 2002;
  11. Boron WF. Regulation of intracellular pH. Adv Physiol Educ. 2004;28:160–179
  12. Forsythe SM, Schmidt GA. Sodium bicarbonate for the treatment of lactic acidosis. Chest. 2000;117:260–267
  13. Burnay M, Crambert G, Kharoubi-Hess S, et al. Electrogenicity of Na,K- and H,K-ATPase activity and presence of a positively charged amino acid in the fifth transmembrane segment. J Biol Chem. 2003;278:19237–19244
  14. Palmgren MG, Axelsen KB. Evolution of P-type ATPases. Biochim Biophys Acta. 1998;1365:37–45
  15. Xie Z, Askari A. Na(+)/K(+)-ATPase as a signal transducer. Eur J Biochem. 2002;269:2434–2439
  16. Xie Z, Cai T. Na+-K+-ATPase-mediated signal transduction: From protein interaction to cellular function. Mol Interv. 2003;3:157–168
  17. Schoner W, Scheiner-Bobis G. Endogenous cardiac glycosides: Hormones using the sodium pump as signal transducer. Semin Nephrol. 2005;25:343–351
  18. Ward SC, Hamilton BP, Hamlyn JM. Novel receptors for ouabain: Studies in adrenocortical cells and membranes. Hypertension. 2002;39:536–542
  19. Contreras RG, Shoshani L, Flores-Maldonado C, et al. Relationship between Na(+),K(+)-ATPase and cell attachment. J Cell Sci. 1999;112:4223–4232
  20. Cereijido M, Contreras RG, Shoshani L. Cell adhesion, polarity, and epithelia in the dawn of metazoans. Physiol Rev. 2004;84:1229–1262
  21. Cereijido M, Contreras RG, Shoshani L, et al. Membrane targeting. Prog Biophys Mol Biol. 2003;81:81–115
  22. Rajasekaran SA, Barwe SP, Rajasekaran AK. Multiple functions of Na,K-ATPase in epithelial cells. Semin Nephrol. 2005;25:328–334
  23. Gottardi CJ, Caplan MJ. An ion-transporting ATPase encodes multiple apical localization signals. J Cell Biol. 2003;121:283–293
  24. Muth TR, Caplan MJ. Transport protein trafficking in polarized cells. Annu Rev Cell Dev Biol. 2003;19:333–366
  25. Dunbar LA, Caplan MJ. Ion pumps in polarized cells: Sorting and regulation of the Na+, K+- and H+, K+-ATPases. J Biol Chem. 2001;276:29617–29620
  26. Rodriguez-Boulan E, Zurzolo C. Polarity signals in epithelial cells. J Cell Sci Suppl. 1993;17:9–12
  27. Zurzolo C, Lisanti MP, Caras IW, et al. Glycosylphosphatidylinositol-anchored proteins are preferentially targeted to the basolateral surface in Fischer rat thyroid epithelial cells. J Cell Biol. 1993;121:1031–1039
  28. Shoshani L, Contreras RG, Roldan ML, et al. The polarized expression of Na+,K+-ATPase in epithelia depends on the association between beta-subunits located in neighboring cells. Mol Biol Cell. 2005;16:1071–1081
  29. Okamura H, Yasuhara JC, Fambrough DM, et al. P-type ATPases in Caenorhabditis and Drosophila: Implications for evolution of the P-type ATPase subunit families with special reference to the Na,K-ATPase and H,K-ATPase subgroup. J Membr Biol. 2003;191:13–24
  30. Okamura H, Denawa M, Ohniwa R, et al. P-type ATPase superfamily: Evidence for critical roles for kingdom evolution. Ann N Y Acad Sci. 2003;986:219–223
  31. Dostanic-Larson I, Van Huysse JW, Lorenz JN, et al. The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation. Proc Natl Acad Sci U S A. 2005;102:15845–15850
  32. Kaplan JH. The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase. Proc Natl Acad Sci U S A. 2005;102:15723–15724
  33. Hamlyn JM, Ringel R, Schaeffer J, et al. A circulating inhibitor of (Na+ + K+) ATPase associated with essential hypertension. Nature. 1982;300:650–652
  34. Manunta P, Stella P, Rivera R, et al. Left ventricular mass, stroke volume, and ouabain-like factor in essential hypertension. Hypertension. 1999;34:450–456
  35. 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. 1997;94:1800–1805
  36. Juhaszova M, Blaustein MP. Distinct distribution of different Na+ pump alpha subunit isoforms in plasmalemma (Physiological implications). Ann N Y Acad Sci. 1997;834:524–536
  37. Arnon A, Hamlyn JM, Blaustein MP. Ouabain augments Ca(2+) transients in arterial smooth muscle without raising cytosolic Na(+). Am J Physiol. 2000;279:H679–H691
  38. Bianchi G. Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: From gene polymorphism to clinical symptoms. Am J Physiol. 2005;289:R1536–R1549
  39. Efendiev R, Krmar RT, Ogimoto O, et al. Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-μ2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res. 2004;95:1100–1108
  40. Tripodi G, Valtorta F, Torielli L, et al. Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest. 1996;97:2815-2228
  41. Psaty BM, Smith NL, Heckbert SR, et al. Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA. 2002;287:1680–1689
  42. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413–2446
  43. Ferrari P, Ferrandi M, Torielli L, et al. Antihypertensive compounds that modulate the Na-K pump. Ann N Y Acad Sci. 2003;986:694–701
  44. Aurigemma GP, Gaasch WH. Clinical practice (Diastolic heart failure). N Engl J Med. 2004;351:1097–1105
  45. Schnermann J, Briggs JP. The macula densa is worth its salt. J Clin Invest. 1999;104:1007–1009
  46. McDonough AA, Leong PK, Yang LE. Mechanisms of pressure natriuresis: How blood pressure regulates renal sodium transport. Ann N Y Acad Sci. 2003;986:669–677
  47. Magyar CE, Zhang Y, Holstein-Rathlou NH, et al. Downstream shift in sodium pump activity along the nephron during acute hypertension. J Am Soc Nephrol. 2001;12:2231–2240
  48. Bertorello AM, Katz AI. Short-term regulation of renal Na-K-ATPase activity: Physiological relevance and cellular mechanisms. Am J Physiol. 1993;265:F743–F755
  49. Efendiev R, Budu CE, Cinelli AR, et al. Intracellular Na+ regulates dopamine and angiotensin II receptors availability at the plasma membrane and their cellular responses in renal epithelia. J Biol Chem. 2003;278:28719–28726
  50. Bertorello AM, Sznajder JI. The dopamine paradox in lung and kidney epithelia: Sharing the same target but operating different signaling networks. Am J Respir Cell Mol Biol. 2005;33:432–437
  51. Liu J, Kesiry R, Periyasamy SM, et al. Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism. Kidney Int. 2004;66:227–241
  52. Periyasamy SM, Liu J, Tanta F, et al. Salt loading induces redistribution of the plasmalemmal Na/K-ATPase in proximal tubule cells. Kidney Int. 2005;67:1868–1877
  53. Aiton JF, Lamb JF, Ogden P. Down-regulation of the sodium pump following chronic exposure of HeLa cells and chick embryo heart cells to ouabain. Br J Pharmacol. 1981;73:333–340
  54. Mohammadi K, Kometiani P, Xie Z, et al. Role of protein kinase C in the signal pathways that link Na+/K+-ATPase to ERK1/2. J Biol Chem. 2001;276:42050–42056
  55. Kometiani P, Li J, Gnudi L. Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes (The roles of Ras and mitogen-activated protein kinases). J Biol Chem. 1998;273:15249–15256
  56. Xie Z, Kometiani P, Liu J, et al. Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. J Biol Chem. 1999;274:19323–19328
  57. Garner MH. Na,K-ATPase in the nuclear envelope regulates Na+:K+ gradients in hepatocyte nuclei. J Membr Biol. 2002;187:97–115
  58. Amlal H, Chen Q, Greeley T, et al. Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading. Kidney Int. 2001;60:1824–1836
  59. Fish EM, Molitoris BA. Alterations in epithelial polarity and the pathogenesis of disease states. N Engl J Med. 1994;330:1580–1588
  60. Molitoris BA. Ischemia-induced loss of epithelial polarity: Potential role of the actin cytoskeleton. Am J Physiol. 1991;260:F769–F778
  61. Molitoris BA. Na(+)-K(+)-ATPase that redistributes to apical membrane during ATP depletion remains functional. Am J Physiol. 1993;265:F693–F697
  62. Hochachka PW, Buck LT, Doll CJ, et al. Unifying theory of hypoxia tolerance: Molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci U S A. 1996;93:9493–9498
  63. Dada LA, Chandel NS, Ridge KM, et al. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta. J Clin Invest. 2003;111:1057–1064
  64. Planes C, Friedlander G, Loiseau A, et al. Inhibition of Na-K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line. Am J Physiol. 1996;271:L70–L78
  65. Comellas A, Dada LA, Lecuona E, et al. Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system. Circ Res. 2006;26:1314–1322
  66. Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev. 2002;82:569–600
  67. Sznajder JI. Alveolar edema must be cleared for the acute respiratory distress syndrome patient to survive. Am J Respir Crit Care Med. 2001;163:1293–1294
  68. Fink MP. Cytopathic hypoxia (Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis). Crit Care Clin. 2001;17:219–237
  69. Fink MP, Delude RL. Epithelial barrier dysfunction: A unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level. Crit Care Clin. 2005;21:177–196
  70. Sugi K, Musch MW, Field M, et al. Inhibition of Na+,K+-ATPase by interferon gamma down-regulates intestinal epithelial transport and barrier function. Gastroenterology. 2001;120:1393–1403
  71. Qayyum I, Zubrow AB, Ashraf QM, et al. Nitration as a mechanism of Na+, K+-ATPase modification during hypoxia in the cerebral cortex of the guinea pig fetus. Neurochem Res. 2001;26:1163–1169
  72. Mishra OP, Delivoria-Papadopoulos M, Cahillane G, et al. Lipid peroxidation as the mechanism of modification of the affinity of the Na+, K+-ATPase active sites for ATP, K+, Na+, and strophanthidin in vitro. Neurochem Res. 1989;14:845–851
  73. Saltiel A, Sanfilippo DJ, Hendler R, et al. Oxygen transport during anemic hypoxia in pigs: Effects of digoxin on metabolism. Am J Physiol. 1992;263:H208–H217
  74. Berman W, Lister G, Alverson D, et al. Ouabain effects on oxygen physiology in anemic lambs. Pediatr Res. 1987;21:447–452
  75. Harrigan MR. Cerebral salt wasting syndrome. Crit Care Clin. 2001;17:125–138
  76. Wijdicks EF, Vermeulen M, van Brummelen P, et al. Digoxin-like immunoreactive substance in patients with aneurysmal subarachnoid haemorrhage. BMJ. 1987;294:729–732
  77. Palmer BF. Hyponatremia in patients with central nervous system disease: SIADH versus CSW. Trends Endocrinol Metab. 2003;14:182–187
  78. Menezes JC, Troster EJ, Dichtchekenian V. Digoxin antibody decreases natriuresis and diuresis in cerebral hemorrhage. Intensive Care Med. 2003;29:2291–2296
  79. Katz AI. Role of the Na:K pump in potassium handling by the distal nephron: Implications for renal K adaptation. Contrib Nephrol. 1991;95:155–161
  80. Mennitt PA, Frindt G, Silver RB, et al. Potassium restriction downregulates ROMK expression in rat kidney. Am J Physiol. 2000;278:F916–F924
  81. McDonough AA, Youn JH. Role of muscle in regulating extracellular [K+]. Semin Nephrol. 2005;25:335–342
  82. McDonough AA, Thompson CB, Youn JH. Skeletal muscle regulates extracellular potassium. Am J Physiol. 2002;282:F967–F974

 Supported in part by Swedish Research Council grants 32X-10860 and 32P-1489.

PII: S0270-9295(06)00079-9

doi: 10.1016/j.semnephrol.2006.07.002

Seminars in Nephrology
Volume 26, Issue 5 , Pages 386-392 , September 2006