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The Na + /K + -ATPase as a Drug Target for Ischemic Stroke

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New Strategies in Stroke Intervention

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

The Na+/K+-ATPase (also known as the “sodium–potassium pump” or just “sodium pump”) is a ubiquitous and critically important protein complex in the human body. In the brain, between 40 and 70% of all energy is spent maintaining its ionic transport activity [1,2,3]. This energy is used for the active exchange of cytosolic sodium for extracellular potassium in a 3:2 ratio, a process required for the maintenance of transmembrane ionic gradients for all mammalian cells, which in turn is essential for setting the cellular resting potential, regulating osmolarity, and powering the secondary transport of other important solutes like calcium (via the sodium–calcium exchanger) and protons (via the sodium–hydrogen exchanger)

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References

  1. Clausen T, Van Hardeveld C, and Everts ME. Significance of cation transport in control of energy metabolism and thermogenesis. Physiol Rev 71: 733–774, 1991.

    PubMed  CAS  Google Scholar 

  2. Friberg H and Wieloch T. Mitochondrial permeability transition in acute neurodegeneration. Biochimie 84: 241–250, 2002.

    Article  PubMed  CAS  Google Scholar 

  3. Astrup J. Energy-requiring cell functions in the ischemic brain. Their critical supply and possible inhibition in protective therapy. J Neurosurg 56: 482–497, 1982.

    Article  PubMed  CAS  Google Scholar 

  4. Skou JC. The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim Biophys Acta 23: 394–401, 1957.

    Article  PubMed  CAS  Google Scholar 

  5. Skou JC. The influence of some cations on an adenosine triphosphatase from peripheral nerves. 1957. Biochim Biophys Acta 1000: 439–446, 1989.

    PubMed  CAS  Google Scholar 

  6. Kaplan JH. Biochemistry of Na,K-ATPase. Annu Rev Biochem 71: 511–535, 2002.

    Article  PubMed  CAS  Google Scholar 

  7. Scheiner-Bobis G. The sodium pump. Its molecular properties and mechanics of ion transport. Eur J Biochem 269: 2424–2433, 2002.

    Article  PubMed  CAS  Google Scholar 

  8. Lingrel JB, Young RM, and Shull MM. Multiple forms of the Na,K-ATPase: their genes and tissue specific expression. Prog Clin Biol Res 268B: 105–112, 1988.

    PubMed  CAS  Google Scholar 

  9. Zurzolo C and Rodriguez-Boulan E. Delivery of Na+,K(+)-ATPase in polarized epithelial cells. Science 260: 550–552; author reply 554–556, 1993.

    Article  PubMed  CAS  Google Scholar 

  10. Gottardi CJ and Caplan MJ. Delivery of Na+,K(+)-ATPase in polarized epithelial cells. Science 260: 552–554; author reply 554–6, 1993.

    Article  PubMed  CAS  Google Scholar 

  11. Fambrough DM, Lemas MV, Hamrick M, Emerick M, Renaud KJ, Inman EM, Hwang B, and Takeyasu K. Analysis of subunit assembly of the Na-K-ATPase. Am J Physiol 266: C579–C589, 1994.

    PubMed  CAS  Google Scholar 

  12. Radzyukevich TL, Moseley AE, Shelly DA, Redden GA, Behbehani MM, Lingrel JB, Paul RJ, and Heiny JA. The Na(+)-K(+)-ATPase alpha2-subunit isoform modulates contractility in the perinatal mouse diaphragm. Am J Physiol Cell Physiol 287: C1300–C1310, 2004.

    Article  PubMed  CAS  Google Scholar 

  13. Moseley AE, Williams MT, Schaefer TL, Bohanan CS, Neumann JC, Behbehani MM, Vorhees CV, and Lingrel JB. Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice. J Neurosci 27: 616–626, 2007.

    Article  PubMed  CAS  Google Scholar 

  14. Castro MJ, Nunes B, de Vries B, Lemos C, Vanmolkot KR, van den Heuvel JJ, Temudo T, Barros J, Sequeiros J, Frants RR, Koenderink JB, Pereira-Monteiro JM, and van den Maagdenberg AM. Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes. Clin Genet 73: 37–43, 2008.

    Article  PubMed  CAS  Google Scholar 

  15. Geering K. The functional role of beta subunits in oligomeric P-type ATPases. J Bioenerg Biomembr 33: 425–438, 2001.

    Article  PubMed  CAS  Google Scholar 

  16. Lutsenko S and Kaplan JH. An essential role for the extracellular domain of the Na,K-ATPase beta-subunit in cation occlusion. Biochemistry 32: 6737–6743, 1993.

    Article  PubMed  CAS  Google Scholar 

  17. Hardwicke PM and Freytag JW. A proteolipid associated with Na,K-ATPase is not essential for ATPase activity. Biochem Biophys Res Commun 102: 250–257, 1981.

    Article  PubMed  CAS  Google Scholar 

  18. Beguin P, Wang X, Firsov D, Puoti A, Claeys D, Horisberger JD, and Geering K. The gamma subunit is a specific component of the Na,K-ATPase and modulates its transport function. Embo J 16: 4250–4260, 1997.

    Article  PubMed  CAS  Google Scholar 

  19. Scheiner-Bobis G and Farley RA. Subunit requirements for expression of functional sodium pumps in yeast cells. Biochim Biophys Acta 1193: 226–234, 1994.

    Article  PubMed  CAS  Google Scholar 

  20. Sweadner KJ, Arystarkhova E, Donnet C, and Wetzel RK. FXYD proteins as regulators of the Na,K-ATPase in the kidney. Ann N Y Acad Sci 986: 382–387, 2003.

    Article  PubMed  CAS  Google Scholar 

  21. Geering K, Beguin P, Garty H, Karlish S, Fuzesi M, Horisberger JD, and Crambert G. FXYD proteins: new tissue- and isoform-specific regulators of Na,K-ATPase. Ann N Y Acad Sci 986: 388–394, 2003.

    Article  PubMed  CAS  Google Scholar 

  22. Therien AG, Karlish SJ, and Blostein R. Expression and functional role of the gamma subunit of the Na, K-ATPase in mammalian cells. J Biol Chem 274: 12252–12256, 1999.

    Article  PubMed  CAS  Google Scholar 

  23. Palmer CJ, Scott BT, and 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.

    PubMed  CAS  Google Scholar 

  24. Attali B, Latter H, Rachamim N, and Garty H. A corticosteroid-induced gene expressing an “IsK-like” K+ channel activity in Xenopus oocytes. Proc Natl Acad Sci USA 92: 6092–6096, 1995.

    Article  PubMed  CAS  Google Scholar 

  25. Morrison BW and Leder P. Neu and ras initiate murine mammary tumors that share genetic markers generally absent in c-myc and int-2-initiated tumors. Oncogene 9: 3417–3426, 1994.

    PubMed  CAS  Google Scholar 

  26. Mercer RW, Biemesderfer D, Bliss DP Jr., Collins JH, Forbush B 3rd. 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.

    Article  PubMed  CAS  Google Scholar 

  27. McGrail KM, Phillips JM, and Sweadner KJ. 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.

    PubMed  CAS  Google Scholar 

  28. Herrera VL, Cova T, Sassoon D, and Ruiz-Opazo N. Developmental cell-specific regulation of Na(+)-K(+)-ATPase alpha 1-, alpha 2-, and alpha 3-isoform gene expression. Am J Physiol 266: C1301–C1312, 1994.

    PubMed  CAS  Google Scholar 

  29. Lu XP and Leffert HL. Induction of sodium pump beta 1-subunit mRNA expression during hepatocellular growth transitions in vitro and in vivo. J Biol Chem 266: 9276–9284, 1991.

    PubMed  CAS  Google Scholar 

  30. Watts AG, Sanchez-Watts G, Emanuel JR, and Levenson R. Cell-specific expression of mRNAs encoding Na+,K(+)-ATPase alpha- and beta-subunit isoforms within the rat central nervous system. Proc Natl Acad Sci USA 88: 7425–7429, 1991.

    Article  PubMed  CAS  Google Scholar 

  31. Shull GE, Greeb J, and Lingrel JB. Molecular cloning of three distinct forms of the Na+,K+-ATPase alpha-subunit from rat brain. Biochemistry 25: 8125–8132, 1986.

    Article  PubMed  CAS  Google Scholar 

  32. Shamraj OI and Lingrel JB. A putative fourth Na+,K(+)-ATPase alpha-subunit gene is expressed in testis. Proc Natl Acad Sci USA 91: 12952–12956, 1994.

    Article  PubMed  CAS  Google Scholar 

  33. Peng L, Martin-Vasallo P, and Sweadner KJ. Isoforms of Na,K-ATPase alpha and beta subunits in the rat cerebellum and in granule cell cultures. J Neurosci 17: 3488–3502, 1997.

    PubMed  CAS  Google Scholar 

  34. Moseley AE, Lieske SP, Wetzel RK, James PF, He S, Shelly DA, Paul RJ, Boivin GP, Witte DP, Ramirez JM, Sweadner KJ, and Lingrel JB. The Na,K-ATPase alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice. J Biol Chem 278: 5317–5324, 2003.

    Article  PubMed  CAS  Google Scholar 

  35. Emanuel JR, Garetz S, Stone L, and Levenson R. Differential expression of Na+,K+-ATPase alpha- and beta-subunit mRNAs in rat tissues and cell lines. Proc Natl Acad Sci USA 84: 9030–9034, 1987.

    Article  PubMed  CAS  Google Scholar 

  36. Shyjan AW, Gottardi C, and Levenson R. The Na,K-ATPase beta 2 subunit is expressed in rat brain and copurifies with Na,K-ATPase activity. J Biol Chem 265: 5166–5169, 1990.

    PubMed  CAS  Google Scholar 

  37. Arystarkhova E and Sweadner KJ. Tissue-specific expression of the Na,K-ATPase beta3 subunit. The presence of beta3 in lung and liver addresses the problem of the missing subunit. J Biol Chem 272: 22405–22408, 1997.

    Article  PubMed  CAS  Google Scholar 

  38. Cameron R, Klein L, Shyjan AW, Rakic P, and Levenson R. Neurons and astroglia express distinct subsets of Na,K-ATPase alpha and beta subunits. Brain Res Mol Brain Res 21: 333–343, 1994.

    Article  PubMed  CAS  Google Scholar 

  39. Lecuona E, Luquin S, Avila J, Garcia-Segura LM, and Martin-Vasallo P. Expression of the beta 1 and beta 2(AMOG) subunits of the Na,K-ATPase in neural tissues: cellular and developmental distribution patterns. Brain Res Bull 40: 167–174, 1996.

    Article  PubMed  CAS  Google Scholar 

  40. Brines ML and Robbins RJ. Cell-type specific expression of Na+, K(+)-ATPase catalytic subunits in cultured neurons and glia: evidence for polarized distribution in neurons. Brain Res 631: 1–11, 1993.

    Article  PubMed  CAS  Google Scholar 

  41. Wetzel RK, Arystarkhova E, and Sweadner KJ. Cellular and subcellular specification of Na,K-ATPase alpha and beta isoforms in the postnatal development of mouse retina. J Neurosci 19: 9878–9889, 1999.

    PubMed  CAS  Google Scholar 

  42. Juhaszova M and Blaustein MP. Distinct distribution of different Na+ pump alpha subunit isoforms in plasmalemma. Physiological implications. Ann N Y Acad Sci 834: 524–536, 1997.

    Article  PubMed  CAS  Google Scholar 

  43. Juhaszova M and Blaustein MP. Na+ pump low and high ouabain affinity alpha subunit isoforms are differently distributed in cells. Proc Natl Acad Sci USA 94: 1800–1805, 1997.

    Article  PubMed  CAS  Google Scholar 

  44. Chen Y, Cai T, Yang C, Turner DA, Giovannucci DR, and Xie Z. Regulation of inositol 1,4,5-trisphosphate receptor-mediated calcium release by the Na/K-ATPase in cultured renal epithelial cells. J Biol Chem 283: 1128–1136, 2008.

    Article  PubMed  CAS  Google Scholar 

  45. Dunbar LA and Caplan MJ. Ion pumps in polarized cells: sorting and regulation of the Na+, K+- and H+, K+-ATPases. J Biol Chem 276: 29617–29620, 2001.

    Article  PubMed  CAS  Google Scholar 

  46. Golovina V, Song H, James P, Lingrel J, and Blaustein M. Regulation of Ca2+ signaling by Na+ pump alpha-2 subunit expression. Ann N Y Acad Sci 986: 509–513, 2003.

    Article  PubMed  CAS  Google Scholar 

  47. Charnock JS and Post RL. Evidence of the mechanism of ouabain inhibition of cationactivated adenosine triphosphate. Nature 199: 910–911, 1963.

    Article  CAS  Google Scholar 

  48. Albers RW, Fahn S, and Koval GJ. The role of sodium ions in the activation of electrophorus electric organ adenosine triphosphatase. Proc Natl Acad Sci USA 50: 474–481, 1963.

    Article  PubMed  CAS  Google Scholar 

  49. Glynn IM. Annual review prize lecture. ‘All hands to the sodium pump’. J Physiol 462: 1–30, 1993.

    PubMed  CAS  Google Scholar 

  50. Clarke RJ and Kane DJ. Two gears of pumping by the sodium pump. Biophys J 93: 4187–4196, 2007.

    Article  PubMed  CAS  Google Scholar 

  51. Laughery M, Todd M, and Kaplan JH. Oligomerization of the Na,K-ATPase in cell membranes. J Biol Chem 279: 36339–36348, 2004.

    Article  PubMed  CAS  Google Scholar 

  52. Geering K, Beggah A, Good P, Girardet S, Roy S, Schaer D, and Jaunin P. Oligomerization and maturation of Na,K-ATPase: functional interaction of the cytoplasmic NH2 terminus of the beta subunit with the alpha subunit. J Cell Biol 133: 1193–1204, 1996.

    Article  PubMed  CAS  Google Scholar 

  53. Jorgensen PL, Hakansson KO, and Karlish SJ. Structure and mechanism of Na,K-ATPase: functional sites and their interactions. Annu Rev Physiol 65: 817–849, 2003.

    Article  PubMed  CAS  Google Scholar 

  54. Jones SW. On the resting potential of isolated frog sympathetic neurons. Neuron 3: 153–161, 1989.

    Article  PubMed  CAS  Google Scholar 

  55. Morth JP, Pedersen BP, Toustrup-Jensen MS, Sorensen TL, Petersen J, Andersen JP, Vilsen B, and Nissen P. Crystal structure of the sodium-potassium pump. Nature 450: 1043–1049, 2007.

    Article  PubMed  CAS  Google Scholar 

  56. Li C, Grosdidier A, Crambert G, Horisberger JD, Michielin O, and Geering K. Structural and functional interaction sites between Na,K-ATPase and FXYD proteins. J Biol Chem 279: 38895–38902, 2004.

    Article  PubMed  CAS  Google Scholar 

  57. Ogawa H and Toyoshima C. Homology modeling of the cation binding sites of Na+K+-ATPase. Proc Natl Acad Sci USA 99: 15977–15982, 2002.

    Article  PubMed  CAS  Google Scholar 

  58. Vilsen B, Ramlov D, and Andersen JP. Functional consequences of mutations in the transmembrane core region for cation translocation and energy transduction in the Na+,K(+)-ATPase and the SR Ca(2+)-ATPase. Ann N Y Acad Sci 834: 297–309, 1997.

    Article  PubMed  CAS  Google Scholar 

  59. Keenan SM, DeLisle RK, Welsh WJ, Paula S, Ball WJ Jr. Elucidation of the Na+, K+-ATPase digitalis binding site. J Mol Graph Model 23: 465–475, 2005.

    Article  PubMed  CAS  Google Scholar 

  60. Lowndes JM, Hokin-Neaverson M, and Ruoho AE. Photoaffinity labeling of (Na+K+)-ATPase with [125I]iodoazidocymarin. J Biol Chem 259: 10533–10538, 1984.

    PubMed  CAS  Google Scholar 

  61. Rogers TB and Lazdunski M. Photoaffinity labelling of a small protein component of a purified (Na+-K+)ATPase. FEBS Lett 98: 373–376, 1979.

    Article  PubMed  CAS  Google Scholar 

  62. Vale-Gonzalez C, Pazos MJ, Alfonso A, Vieytes MR, and Botana LM. Study of the neuronal effects of ouabain and palytoxin and their binding to Na,K-ATPases using an optical biosensor. Toxicon 50: 541–552, 2007.

    Article  PubMed  CAS  Google Scholar 

  63. Withering W. An Account of the Floxglove and Some of Its Medical Uses with Practical Remarks on Dropsy and Other Diseases. Birmingham, UK: M. Swinney, 1785.

    Google Scholar 

  64. Hirsh JK and Wu CH. Palytoxin-induced single-channel currents from the sodium pump synthesized by in vitro expression. Toxicon 35: 169–176, 1997.

    Article  PubMed  CAS  Google Scholar 

  65. Scheiner-Bobis G. Sanguinarine induces K+ outflow from yeast cells expressing mammalian sodium pumps. Naunyn Schmiedebergs Arch Pharmacol 363: 203–208, 2001.

    Article  PubMed  CAS  Google Scholar 

  66. Habermann E. Palytoxin acts through Na+,K+-ATPase. Toxicon 27: 1171–1187, 1989.

    Article  PubMed  CAS  Google Scholar 

  67. Takeuchi A, Reyes N, Artigas P, Gadsby DC. The ion pathway through the opened Na(+),K(+)-ATPase pump. Nature 456: 413–416, 2008.

    Article  PubMed  CAS  Google Scholar 

  68. Therien AG and Blostein R. Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol 279: C541–C566, 2000.

    PubMed  CAS  Google Scholar 

  69. Rayson BM. [Ca2+]i regulates transcription rate of the Na+/K(+)-ATPase alpha 1 subunit. J Biol Chem 266: 21335–21338, 1991.

    PubMed  CAS  Google Scholar 

  70. Pathak BG, Neumann JC, Croyle ML, and Lingrel JB. The presence of both negative and positive elements in the 5′-flanking sequence of the rat Na,K-ATPase alpha 3 subunit gene are required for brain expression in transgenic mice. Nucleic Acids Res 22: 4748–4755, 1994.

    Article  PubMed  CAS  Google Scholar 

  71. Wang G, Kawakami K, and Gick G. Divergent signaling pathways mediate induction of Na,K-ATPase alpha1 and beta1 subunit gene transcription by low potassium. Mol Cell Biochem 294: 73–85, 2007.

    Article  PubMed  CAS  Google Scholar 

  72. Guerrero C, Lecuona E, Pesce L, Ridge KM, and Sznajder JI. Dopamine regulates Na-K-ATPase in alveolar epithelial cells via MAPK-ERK-dependent mechanisms. Am J Physiol Lung Cell Mol Physiol 281: L79–L85, 2001.

    PubMed  CAS  Google Scholar 

  73. Kone BC and Higham S. Nitric oxide inhibits transcription of the Na+-K+-ATPase alpha1-subunit gene in an MTAL cell line. Am J Physiol 276: F614–F621, 1999.

    PubMed  CAS  Google Scholar 

  74. Kimura T, Allen PB, Nairn AC, and Caplan MJ. Arrestins and spinophilin competitively regulate Na+,K+-ATPase trafficking through association with a large cytoplasmic loop of the Na+,K+-ATPase. Mol Biol Cell 18: 4508–4518, 2007.

    Article  PubMed  CAS  Google Scholar 

  75. Dada LA, Novoa E, Lecuona E, Sun H, and Sznajder JI. Role of the small GTPase RhoA in the hypoxia-induced decrease of plasma membrane Na,K-ATPase in A549 cells. J Cell Sci 120: 2214–2222, 2007.

    Article  PubMed  CAS  Google Scholar 

  76. Vadasz I, Dada LA, Briva A, Trejo HE, Welch LC, Chen J, Toth PT, Lecuona E, Witters LA, Schumacker PT, Chandel NS, Seeger W, and Sznajder JI. AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis. J Clin Invest 118: 752–762, 2008.

    PubMed  CAS  Google Scholar 

  77. Namekata K, Harada C, Kohyama K, Matsumoto Y, and Harada T. Interleukin-1 stimulates glutamate uptake in glial cells by accelerating membrane trafficking of Na+/K+-ATPase via actin depolymerization. Mol Cell Biol 28: 3273–3280, 2008.

    Article  PubMed  CAS  Google Scholar 

  78. Soltoff SP and Mandel LJ. Active ion transport in the renal proximal tubule. II. Ionic dependence of the Na pump. J Gen Physiol 84: 623–642, 1984.

    Article  PubMed  CAS  Google Scholar 

  79. Garay RP and Garrahan PJ. The interaction of sodium and potassium with the sodium pump in red cells. J Physiol 231: 297–325, 1973.

    PubMed  CAS  Google Scholar 

  80. Soltoff SP and Mandel LJ. Active ion transport in the renal proximal tubule. III. The ATP dependence of the Na pump. J Gen Physiol 84: 643–662, 1984.

    Article  PubMed  CAS  Google Scholar 

  81. Fodor E, Fedosova NU, Ferencz C, Marsh D, Pali T, and Esmann M. Stabilization of Na,K-ATPase by ionic interactions. Biochim Biophys Acta 1778: 835–843, 2008.

    Article  PubMed  CAS  Google Scholar 

  82. Schoner W, Bauer N, Muller-Ehmsen J, Kramer U, Hambarchian N, Schwinger R, Moeller H, Kost H, Weitkamp C, Schweitzer T, Kirch U, Neu H, and Grunbaum EG. Ouabain as a mammalian hormone. Ann N Y Acad Sci 986: 678–684, 2003.

    Article  PubMed  CAS  Google Scholar 

  83. Schoner W. Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem 269: 2440–2448, 2002.

    Article  PubMed  CAS  Google Scholar 

  84. Petrushanko IY, Bogdanov NB, Lapina N, Boldyrev AA, Gassmann M, and Bogdanova AY. Oxygen-induced regulation of Na/K ATPase in cerebellar granule cells. J Gen Physiol 130: 389–398, 2007.

    Article  PubMed  CAS  Google Scholar 

  85. Dada LA, Welch LC, Zhou G, Ben-Saadon R, Ciechanover A, and Sznajder JI. Phosphorylation and ubiquitination are necessary for Na,K-ATPase endocytosis during hypoxia. Cell Signal 19: 1893–1898, 2007.

    Article  PubMed  CAS  Google Scholar 

  86. Comellas AP, Dada LA, Lecuona E, Pesce LM, Chandel NS, Quesada N, Budinger GR, Strous GJ, Ciechanover A, Sznajder JI. Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system. Circ Res 98: 1314–1322, 2006.

    Article  PubMed  CAS  Google Scholar 

  87. Dada LA, Chandel NS, Ridge KM, Pedemonte C, Bertorello AM, and Sznajder JI. Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta. J Clin Invest 111: 1057–1064, 2003.

    PubMed  CAS  Google Scholar 

  88. Ostadal P, Elmoselhi AB, Zdobnicka I, Lukas A, Chapman D, and Dhalla NS. Ischemia-reperfusion alters gene expression of Na+-K+ ATPase isoforms in rat heart. Biochem Biophys Res Commun 306: 457–462, 2003.

    Article  PubMed  CAS  Google Scholar 

  89. Hardman JG and Limbird LL. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. New York: McGraw-Hill, 1996.

    Google Scholar 

  90. Xie Z and Askari A. Na(+)/K(+)-ATPase as a signal transducer. Eur J Biochem 269: 2434–2439, 2002.

    Article  PubMed  CAS  Google Scholar 

  91. Xie Z and Cai T. Na+-K+-ATPase-mediated signal transduction: from protein interaction to cellular function. Mol Interv 3: 157–168, 2003.

    Article  PubMed  CAS  Google Scholar 

  92. Liang M, Tian J, Liu L, Pierre S, Liu J, Shapiro J, and Xie ZJ. Identification of a pool of non-pumping Na/K-ATPase. J Biol Chem 282: 10585–10593, 2007.

    Article  PubMed  CAS  Google Scholar 

  93. Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z. Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem 275: 27838–27844, 2000.

    PubMed  CAS  Google Scholar 

  94. Monteith GR and Blaustein MP. Different effects of low and high dose cardiotonic steroids on cytosolic calcium in spontaneously active hippocampal neurons and in co-cultured glia. Brain Res 795: 325–340, 1998.

    Article  PubMed  CAS  Google Scholar 

  95. Taguchi K, Kumanogoh H, Nakamura S, and Maekawa S. Ouabain-induced isoform-specific localization change of the Na+, K+-ATPase alpha subunit in the synaptic plasma membrane of rat brain. Neurosci Lett 413: 42–45, 2007.

    Article  PubMed  CAS  Google Scholar 

  96. Kometiani P, Li J, Gnudi L, Kahn BB, Askari A, and Xie Z. 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 273: 15249–15256, 1998.

    Article  PubMed  CAS  Google Scholar 

  97. Xie Z, Kometiani P, Liu J, Li J, Shapiro JI, and Askari A. Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. J Biol Chem 274: 19323–19328, 1999.

    Article  PubMed  CAS  Google Scholar 

  98. Aydemir-Koksoy A, Abramowitz J, and Allen JC. Ouabain-induced signaling and vascular smooth muscle cell proliferation. J Biol Chem 276: 46605–46611, 2001.

    Article  PubMed  CAS  Google Scholar 

  99. McConkey DJ, Lin Y, Nutt LK, Ozel HZ, and Newman RA. Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res 60: 3807–3812, 2000.

    PubMed  CAS  Google Scholar 

  100. Xiao AY, Wei L, Xia S, Rothman S, and Yu SP. Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons. J Neurosci 22: 1350–1362, 2002.

    PubMed  CAS  Google Scholar 

  101. Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF, Dawson TM, and Dawson VL. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl Acad Sci USA 97: 436–441, 2000.

    Article  PubMed  CAS  Google Scholar 

  102. Nicholls DG and Budd SL. Mitochondria and neuronal survival. Physiol Rev 80: 315–360, 2000.

    PubMed  CAS  Google Scholar 

  103. Mintorovitch J, Yang GY, Shimizu H, Kucharczyk J, Chan PH, and Weinstein PR. Diffusion-weighted magnetic resonance imaging of acute focal cerebral ischemia: comparison of signal intensity with changes in brain water and Na+,K(+)-ATPase activity. J Cereb Blood Flow Metab 14: 332–336, 1994.

    PubMed  CAS  Google Scholar 

  104. Jamme I, Petit E, Gerbi A, Maixent JM, MacKenzie ET, and Nouvelot A. Changes in ouabain affinity of Na+, K+-ATPase during focal cerebral ischaemia in the mouse. Brain Res 774: 123–130, 1997.

    Article  PubMed  CAS  Google Scholar 

  105. Tavalin SJ, Ellis EF, and Satin LS. Inhibition of the electrogenic Na pump underlies delayed depolarization of cortical neurons after mechanical injury or glutamate. J Neurophysiol 77: 632–638, 1997.

    PubMed  CAS  Google Scholar 

  106. Jung YW, Choi IJ, and Kwon TH. Altered expression of sodium transporters in ischemic penumbra after focal cerebral ischemia in rats. Neurosci Res 59: 152–159, 2007.

    Article  PubMed  CAS  Google Scholar 

  107. Sheldon C, Diarra A, Cheng YM, and Church J. Sodium influx pathways during and after anoxia in rat hippocampal neurons. J Neurosci 24: 11057–11069, 2004.

    Article  PubMed  CAS  Google Scholar 

  108. Lees GJ. Inhibition of sodium-potassium-ATPase: a potentially ubiquitous mechanism contributing to central nervous system neuropathology. Brain Res Brain Res Rev 16: 283–300, 1991.

    Article  PubMed  CAS  Google Scholar 

  109. Yu SP. Regulation and critical role of potassium homeostasis in apoptosis. Prog Neurobiol 70: 363–386, 2003.

    Article  PubMed  CAS  Google Scholar 

  110. Yu SP. Na(+), K(+)-ATPase: the new face of an old player in pathogenesis and apoptotic/hybrid cell death. Biochem Pharmacol 66: 1601–1609, 2003.

    Article  PubMed  CAS  Google Scholar 

  111. Bruer U, Weih MK, Isaev NK, Meisel A, Ruscher K, Bergk A, Trendelenburg G, Wiegand F, Victorov IV, and Dirnagl U. Induction of tolerance in rat cortical neurons: hypoxic preconditioning. FEBS Lett 414: 117–121, 1997.

    Article  PubMed  CAS  Google Scholar 

  112. Golden WC and Martin LJ. Low-dose ouabain protects against excitotoxic apoptosis and up-regulates nuclear Bcl-2 in vivo. Neuroscience 137: 133–144, 2006.

    Article  PubMed  CAS  Google Scholar 

  113. Isaev NK, Stelmashook EV, Halle A, Harms C, Lautenschlager M, Weih M, Dirnagl U, Victorov IV, and Zorov DB. Inhibition of Na(+),K(+)-ATPase activity in cultured rat cerebellar granule cells prevents the onset of apoptosis induced by low potassium. Neurosci Lett 283: 41–44, 2000.

    Article  PubMed  CAS  Google Scholar 

  114. Zhou X, Jiang G, Zhao A, Bondeva T, Hirszel P, and Balla T. Inhibition of Na,K-ATPase activates PI3 kinase and inhibits apoptosis in LLC-PK1 cells. Biochem Biophys Res Commun 285: 46–51, 2001.

    Article  PubMed  CAS  Google Scholar 

  115. Anderson CN and Tolkovsky AM. A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci 19: 664–673, 1999.

    PubMed  CAS  Google Scholar 

  116. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, and Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286: 1358–1362, 1999.

    Article  PubMed  CAS  Google Scholar 

  117. Atwal JK, Massie B, Miller FD, and Kaplan DR. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27: 265–277, 2000.

    Article  PubMed  CAS  Google Scholar 

  118. Perron JC and Bixby JL. Distinct neurite outgrowth signaling pathways converge on ERK activation. Mol Cell Neurosci 13: 362–378, 1999.

    Article  PubMed  CAS  Google Scholar 

  119. Wang JK, Portbury S, Thomas MB, Barney S, Ricca DJ, Morris DL, Warner DS, and Lo DC. Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform. Proc Natl Acad Sci USA 103: 10461–10466, 2006.

    Article  PubMed  CAS  Google Scholar 

  120. Grotta J. Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke 33: 306–307, 2002.

    PubMed  Google Scholar 

  121. Hochachka PW. Defense strategies against hypoxia and hypothermia. Science 231: 234–241, 1986.

    Article  PubMed  CAS  Google Scholar 

  122. McMullen DC and Storey KB. Suppression of Na(+)K(+)-ATPase activity by reversible phosphorylation over the winter in a freeze-tolerant insect. J Insect Physiol 54: 1023–1027, 2008.

    Article  PubMed  CAS  Google Scholar 

  123. Ramnanan CJ and Storey KB. Suppression of Na+/K+-ATPase activity during estivation in the land snail Otala lactea. J Exp Biol 209: 677–688, 2006.

    Article  PubMed  CAS  Google Scholar 

  124. Perez-Pinzon MA, Rosenthal M, Sick TJ, Lutz PL, Pablo J, and Mash D. Downregulation of sodium channels during anoxia: a putative survival strategy of turtle brain. Am J Physiol 262: R712–R715, 1992.

    PubMed  CAS  Google Scholar 

  125. MacDonald JA and Storey KB. Regulation of ground squirrel Na+K+-ATPase activity by reversible phosphorylation during hibernation. Biochem Biophys Res Commun 254: 424–429, 1999.

    Article  PubMed  CAS  Google Scholar 

  126. De Angelis C and Haupert GT Jr.. Hypoxia triggers release of an endogenous inhibitor of Na(+)-K(+)-ATPase from midbrain and adrenal. Am J Physiol 274: F182–F188, 1998.

    PubMed  Google Scholar 

  127. Liu L and Yenari MA. Therapeutic hypothermia: neuroprotective mechanisms. Front Biosci 12: 816–825, 2007.

    Article  PubMed  CAS  Google Scholar 

  128. Johnson EM Jr. and Deckwerth TL. Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci 16: 31–46, 1993.

    Article  PubMed  CAS  Google Scholar 

  129. Johnson EM Jr., Koike T, and Franklin J. A “calcium set-point hypothesis” of neuronal dependence on neurotrophic factor. Exp Neurol 115: 163–166, 1992.

    Article  PubMed  Google Scholar 

  130. Connor JA, Razani-Boroujerdi S, Greenwood AC, Cormier RJ, Petrozzino JJ, and Lin RC. Reduced voltage-dependent Ca2+ signaling in CA1 neurons after brief ischemia in gerbils. J Neurophysiol 81: 299–306, 1999.

    PubMed  CAS  Google Scholar 

  131. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, and Shohami E. Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci USA 101: 5117–5122, 2004.

    Article  PubMed  CAS  Google Scholar 

  132. Lee JM, Grabb MC, Zipfel GJ, and Choi DW. Brain tissue responses to ischemia. J Clin Invest 106: 723–731, 2000.

    Article  PubMed  CAS  Google Scholar 

  133. de Rezende Correa G, Araujo dos Santos A, Frederico Leite Fontes C, Giestal de Araujo E. Ouabain induces an increase of retinal ganglion cell survival in vitro: the involvement of protein kinase C. Brain Res 1049: 89–94, 2005.

    Article  PubMed  CAS  Google Scholar 

  134. Salthun-Lassalle B, Hirsch EC, Wolfart J, Ruberg M, and Michel PP. Rescue of mesencephalic dopaminergic neurons in culture by low-level stimulation of voltage-gated sodium channels. J Neurosci 24: 5922–5930, 2004.

    Article  PubMed  CAS  Google Scholar 

  135. Tzen JT, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, She H, Chen BC, Hsieh V, and Tu ML. Magnesium lithospermate B possesses inhibitory activity on Na+,K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacol Sin 28: 609–615, 2007.

    Article  PubMed  CAS  Google Scholar 

  136. Piccioni F, Roman BR, Fischbeck KH, and Taylor JP. A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor. Hum Mol Genet 13: 437–446, 2004.

    Article  PubMed  CAS  Google Scholar 

  137. von Moltke LL and Greenblatt DJ. Drug transporters revisited. J Clin Psychopharmacol 21: 1–3, 2001.

    Article  PubMed  CAS  Google Scholar 

  138. Beringer PM and Slaughter RL. Transporters and their impact on drug disposition. Ann Pharmacother 39: 1097–1108, 2005.

    Article  PubMed  CAS  Google Scholar 

  139. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, and Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96: 1698–1705, 1995.

    Article  PubMed  CAS  Google Scholar 

  140. Kawahara M, Sakata A, Miyashita T, Tamai I, and Tsuji A. Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice. J Pharm Sci 88: 1281–1287, 1999.

    Article  PubMed  CAS  Google Scholar 

  141. Sadeque AJ, Wandel C, He H, Shah S, and Wood AJ. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 68: 231–237, 2000.

    Article  PubMed  CAS  Google Scholar 

  142. Mayer U, Wagenaar E, Dorobek B, Beijnen JH, Borst P, and Schinkel AH. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 100: 2430–2436, 1997.

    Article  PubMed  CAS  Google Scholar 

  143. Fromm MF, Kim RB, Stein CM, Wilkinson GR, and Roden DM. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments]. Circulation 99: 552–557, 1999.

    PubMed  CAS  Google Scholar 

  144. Batrakova EV, Miller DW, Li S, Alakhov VY, Kabanov AV, and Elmquist W. Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. J Pharmacol Exp Ther 296: 551–557, 2001.

    PubMed  CAS  Google Scholar 

  145. Fricker G and Miller DS. Modulation of drug transporters at the blood-brain barrier. Pharmacology 70: 169–176, 2004.

    Article  PubMed  CAS  Google Scholar 

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  1. Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, 27710, Durham, NC, USA

    Melissa A Gottron & Donald C Lo

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  1. Melissa A Gottron
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  1. Fac. Medicina e Chirurgia, Università di Napoli, Via Sergio Pansini 5, Napoli, 80131, Italy

    Lucio Annunziato

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Gottron, M.A., Lo, D.C. (2009). The Na + /K + -ATPase as a Drug Target for Ischemic Stroke . In: Annunziato, L. (eds) New Strategies in Stroke Intervention. Contemporary Neuroscience. Humana Press. https://doi.org/10.1007/978-1-60761-280-3_8

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