Abstract
The Na⁺/K⁺-ATPase, molecular target of drugs known as cardiac glycosides, has an important role in the cellular physiology as well as in cardiovascular therapeutics. Nevertheless, for a better understanding of these aspects, a deeper knowledge of what really is the Na⁺/K⁺-ATPase is necessary. This article has the objective to describe structural, regulatory and pathophysiological characteristics of the enzyme isoforms.

Full text (english) para suscriptores/ assinantes

Bibliografía del artículo

1. Allen JC, Zhao X, Odebunmi T, Jemelka S, Medford RM, Pressley, TA & Mercer RW: (1998) ?1T can support Na⁺/K⁺-ATPase: Na⁺ pump functions in expression systems. Ann. N. Y. Acad. Sci., 834:457-458.
2. Alves CMA, Silva C.L.M., Moura G.M. & Noël F. (1995) Decrease in the ratio of high- to low-affinity isozymes of (Na++K+)-ATPase during the development of rat cardiac ventricles. Braz. J. Med. Biol. Res., 28:363-367.
3. Aperia A., Holtback U., Syren M.-L., Svensson L.-B., Fryckstedt J. & Greengard P. (1994) Activation/deactivation of renal Na,K-ATPase: a final common pathway for regulation of natriuresis. FASEB J., 8:436-439.
4. Aperia A., Ibarra F., Svensson L.B., Klee C. & Greengard P. (1992) Calcineurin mediates ?-adrenergic stimulation of Na+,K+-ATPase activity in renal tubule cells. Proc. Natl. Acad. Sci. U.S.A., 89:7394-7397.
5. Arai M., Matsui H. & Periasamy M. (1994) Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res, 74:555-564.
6. Azuma, K.K., Hensley, C.B., Tang, M.-J. & MCdonough, A. (1993) Thyroid hormone specifically regulates skeletal muscle Na+-K+-ATPase *2- and *2-isoforms. Am. J. Physiol., 265:C680-C687.
7. Bertorello, A.M. & Katz, A.I. (1993) Short-term regulation of renal Na-K-ATPase activity: physiological relevance and cellular mechanisms. Am. J. Physiol., 265:F743- F755.
8. Bia, M.J. & Defronzo, R.A. (1981) Extrarenal potassium homeostasis. Am. J. Physiol., 240:F257-F268.
9. Blanco, G., Koster, J.C., Sanchez, G. & Mercer, R.W. (1995) Kinetic properties of the ?2?1 and ?2?2 isozymes of the Na,K-ATPase. Biochemistry, 34:319-325.
10. Blanco, G. & Mercer, R.W. (1998) Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol, 275:F633-F650.
11. Blanco, G., Sanchez, G., Melton, R.J., Tourtellotte, W.G. & Mercer.W. (2000) The ?4 isoform of the Na,K-ATPase is expressed in the germ cells of the testes. J. Histochem. Cytochem., 48:1023-1032.
12. Blanco, G., Sanchez, G. & Mercer, R.W. (1995) Comparison of the enzymatic properties of the Na,K-ATPase ?3?1 and ?3?2 isozymes. Biochemistry, 34:9897-9903.
13. Bundgaard, H. & Kjeldsen, K. (1996) Human myocardial Na,K-ATPase concentration in heart failure. Mol. Cell. Biochem., 163/164:277-283.
14. Cameron, R., Klein, L., Shyjan, A.W., Rakic, P. & Levenson, R. (1994) Neurons and astroglia express distinct subsets of Na,K-ATPase ? and ? subunits. Mol. Brain Res., 21:333-343.
15. Canfield, V.A., Xu, K.-Y., D'aquila, T., Shyjan, A.W. & Levenson, R. (1992) Molecular cloning and characterization of Na,K-ATPase from Hydra vulgaris: implications for enzyme evolution and ouabain sensitivity. New Biol., 4:339-348.
16. Charlemagne, D., Orlowski, J., Oliviero, P., Rannou, F., Sainte Beuve, C., Swynghedauw, B. & Lane, L.K. (1994) Alteration of Na,K-ATPase subunit mRNA and protein levels in hypertrophied rat heart. J. Biol. Chem., 269:1541-1547.
17. Everts, M.E. & Clausen, T. (1988) Effects of thyroid hormone on Na+-K+ transport in resting and stimulated rat skeletal muscle. Am. J. Physiol., 255:E604-E612.
18. Ewart, H.S. & Klip, A. (1995) Hormonal regulation of the Na+-K+-ATPase: mechanisms underlying rapid and sustained changes in pump activity. Am. J. Physiol., 269:C295-C311.
19. Farman, N., Bonvalet, J.-P. & Seckl, J.R. (1994) Aldosterone selectively increases Na+-K+-ATPase ?3-subunit mRNA expression in rat hippocampus. Am. J. Physiol., 266:C423-C428.
20. Feraille, E., Carranza, M.L., Rousselot, M. & Favre, H. (1994) Insulin enhances sodium sensitivity of Na-K-ATPase in isolated rat proximal convoluted tubule. Am. J. Physiol., 267:F55-F62.
21. Fujii, Y., Takemoto, F. & Katz, A.I. (1990) Early effects of aldosterone on Na-K pump in rat cortical collecting tubules. Am. J. Physiol., 259:F40-F45.
22. Gick, G.G., Melikian, J. & Ismail-Beigi, F. (1990) Thyroidal enhancement of rat myocardial Na,K-ATPase: preferential expression of *2 activity and mRNA abundance. J. Memb. Biol., 115:273-282.
23. Glynn, I.M. (1993) All hands to the sodium pump. J. Physiol., 462:1-30.
24. Hardwicke, P.M. & Freytag, J.W. (1981) A proteolipid associated with Na,K- ATPase is not essential for ATPase activity. Biochem. Biophys. Res. Commun., 102:250- 257.
25. Hensley, C.B., Azuma, K.K., Tang, M.-J. & MCdonough, A.A. (1992) Thyroid hormone induction of rat myocardial Na+-K+-ATPase: ?1-, ?2-, and ?1-mRNA and - protein levels at steady state. Am. J. Physiol., 262:C484-C492.
26. Herrera, V.L.M., Chobanian, A.V. & Ruiz-Opazo, N. (1988) Isoform-specific modulation of Na+,K+-ATPase *-subunit gene expression in hypertension. Science, 241:221- 223.
27. Hershman, K.M., Taylor, D.A. & Fleming, W.W. (1993) Adaptive supersensitivity in the guinea pig vas deferens is associated with a reduction in the abundance of the ?2 subunit isoform of Na+/K+-ATPase. Mol. Pharmacol., 43:833-837.
28. Holzinger, F., Frick, C. & Wink, M. (1992) Molecular basis for the insensitivity of the Monarch (Danaus plexippus) to cardiac glycosides. FEBS Lett., 314:477-480.
29. Horisberger, J. & Rossier, B.C. (1992) Aldosterone regulation of gene transcription leading to control of ion transport. Hypertension, 19:221-227.
30. Hundal, H.S., Marette, A., Mitsumoto, Y., Ramlal, T., Blostein, R. & Klip A. (1992) Insulin induces translocation of the ?2 and ?1 subunits of the Na+/K+-ATPase from intracellular compartments to the plasma membrane in mammalian skeletal muscle. J. Biol. Chem., 267:5040-5043.
31. Kawakami, K., Nojima, H., Ohta, T. & Nagano, K. (1986) Molecular cloning and sequence analysis of human Na+,K+-ATPase ?-subunit. Nucleic Acids Res., 14: 2833- 2844.
32. Kawakami, K., Ohta, T., Nojima, H. & Nagano, K. (1986) Primary structure of the ?-subunit of human Na,K-ATPase from cDNA sequence. J. Biochem., 100:389-397.
33. Kowluru, R., Bitensky, M.W., Kowluru, A., Dembo, M., Keaton, P.A. & Buican, T. (1989) Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: effects on filtrability and implications for microangiopathy. Proc. Natl. Acad. Sci. U.S.A., 86:3327- 3333.
34. Lambert, R.W., Maves, C.A. & Mircheff, A.K. (1993) Carbachol-induced increase of Na+/H+ antiport and recruitment of Na+,K+-ATPase in rabbit lacrimal acini. Curr. Eye Res., 12:539-551.
35. Liu, X. & Songu-Mize, E. (1997) Alterations in alpha subunit expression of cardiac Na+,K+-ATPase in spontaneously hypertensive rats: effect of antihypertensive therapy. Eur. J. Pharmacol., 327:151-156.
36. Lopez, L.B., Quintas, L.E.M. & Noël, F. (2002) Influence of development on Na+/K+-ATPase expression: isoform- and tissue-dependency. Comp. Biochem. Physiol. A, 131:323-333.
37. Luchesi, P.A. & Sweadner, K.J. (1991) Postnatal changes in Na+,K+-ATPase isoform expression in rat cardiac ventricle. Conservation of biphasic ouabain affinity. J. Biol. Chem., 266:9327-9331.
38. Lynch, C.J., Wilson, P.B., Blackmore, P.F. & Exton, J.H. (1986) The hormone- sensitive hepatic Na+-pump. Evidence for regulation by diacylglycerol and tumor promoters. J. Biol. Chem., 261:14551-14556.
39. Marks, M.J. & Seeds, N.W. (1978) Ouabain-ATPase interaction in brain cells maintained as reaggregates or surface cultures. Life Sci., 23: 2745-2755.
40. Matsuda, T., Iwata, H. & Cooper, J.R. (1984) Specific inactivation of ?(+) molecular form of (Na++K+)-ATPase by pyrithiamin. J. Biol. Chem., 259:3858-3863.
41. Matsuda, T., Murata, Y., Kawamura, N., Hayashi, M., Tamada, K., Takuma, K., Maeda, S. & Baba, A. (1993) Selective induction of ?1 isoform of (Na-K)-ATPase by insulin/insulin-like growth factor-1 in cultured rat astrocytes. Arch. Biochem. Biophys., 307:175-182.
42. Mayol, V., Dignat-George, F., Gerbi, A., Martin-Vasallo, P., Lesaule, G., Sampol, J. & Maixent, J.M. (1998) Evidence that human endothelial cells express different isoforms of Na,K-ATPase. J. Hypertens., 16:145-150.
43. MCgrail, K.M. & SWEADNER, K.J. (1989) Complex expression patterns for Na+,K+-ATPase isoforms in retina and optic nerve. Eur. J. Neurosci., 2:170-176.
44. MCgrail, K.M., PHILLIPS, J.M. & SWEADNER, K.J. (1991) Immunofluorescent localization of three Na,K-ATPase isozymes in the rat centralnervous system: both neurons and glia can express more than one Na,K-ATPase. J. Neurosci., 11:381-391.
45. Medford, R.M., Hyman, R., Ahmad, M., Allen, J.C., Pressley, T.A., Allen, P.D. & Nadal-Ginard, B. (1991) Vascular smooth muscle expresses a truncated Na+,K+-ATPase ?-1 subunit isoform. J. Biol. Chem., 266:18308-18312.
46. Mercer, R.W. (1993) Structure of the Na,K-ATPase. Int. Rev. Cytol., 137C:139-168.
47. Miller, R.P. & Farley, R.A. (1990) ?-Subunit of (Na+,K+)-ATPase contains three disulfide bonds. Biochemistry, 29:1524-1532.
48. Mobasheri, A., Mobasheri, R., Francis, M.J., Trujillo, E., Alvarez De La Rosa, D. & Martin-Vasallo, P. (1998) Ion transport in chondrocytes: membrane transporters involved in intracellularion homeostasis and the regulation of cell volume, free [Ca2+] and pH. Histol. Histopathol., 13:893-910.
49. Morris, J.F., Ismail-Beigi, F., Butler, V.P. Jr., Gati, I. & Lichtstein, D. (1997) Ouabain-sensitive Na+,K+-ATPase activity in toad brain. Comp. Biochem. Physiol. A, 118:599-606.
50. Noël, F. & Godfraind, T. (1984) Heterogeneity of ouabain specific binding sites and (Na++K+)-ATPase inhibition in microsomes from rat heart. Biochem. Pharmacol.¸ 33:47- 53.
51. Noël, F., Quintas, L.E.M., Caricati-Neto, A., Lafayette, S.S.L. & Jurkiewicz, A. (1997) Characterization of an isoform of Na+/K+-ATPase with high affinity for [3H]ouabain in the rat vas deferens. Ann. N. Y. Acad. Sci., 834:115-118.
52. Noël, F., Quintas, L.E.M., Freitas, E., Caricati-Neto, A., Lafayette, S.S.L., Wanderley, A.G. & Jurkiewicz, A. (1998) Quantitative analysis of the high-affinity binding sites for [3H]ouabain in the rat vas deferens and their immunological identification as the ?2 isoform of Na+/K+-ATPase. Biochem. Pharmacol., 55:1531-1535.
53. N*Rgaard, A., Baandrup, U., Larsen, J.S. & Kjeldsen, K. (1987) Heart Na,K-ATPase activity in cardiomyopathic hamsters as estimated from 3-O-MFPase activity in crude homogenates. J. Mol. Cell. Cardiol., 19:589-594.
54. N*Rgaard, A., Bagger, J.P., Bjerregaard, P., Baandrup, U., Kjeldsen, K. & Thomsen, P.E.B. (1988) Relation of left ventricular function and Na+/K+-pump concentration in suspected dilated cardiomyopathy. Am. J. Cardiol., 61:1312-1315.
55. N*Rgaard, A., Bjerregaard, P., Baandrup, U., Kjeldsen, K., Reske-Nielsen, E. & Thomsen, P.E.B. (1990) The concentration of the Na+/K+-pump in skeletal and heart muscle in congestive heart failure. Int. J. Cardiol., 26:185-190.
56. Ohta, T., Yoshida, M., Hirano, K. & Kawamura, M. (1986) Structure of extra- membranous domain of the ?-subunit of (Na,K)-ATPase revealed by the sequences of its tryptic peptides. FEBS Lett., 204:297-301.
57. Omatsu-Kanbe, M. & Kitasato, H. (1990) Insulin stimulates the translocation of Na+/K+-dependent ATPase molecules from intracellular stores to the plasma membrane in frog skeletal muscle. Biochem. J., 272:727-733.
58. Orlowski, J. & Lingrel, J.B. (1988) Tissue-specific and developmental regulation of rat Na+,K+-ATPase catalytic ? isoform and ? subunit mRNAs. J. Biol. Chem., 263:10436- 10442.
59. orlowski, j. & lingrel, j.b. (1990) Thyroid and glucocorticoid hormones regulate the expression of multiple Na,K-ATPase genes in cultured neonatal rat cardiac myocytes. J. Biol. Chem., 265:3462-3470.
60. Packer, M. (1993) The development of positive inotropic agents for chronic heart failure: how have we gone astray? J. Am. Coll. Cardiol., 22 (suppl. A):119A-126A.
61. Peterson, G.L., Ewing, R.D., Hootman, S.R. & Conte, F.P. (1978) Large scale partial purification and molecular and kinetic properties of the (Na+ + K+)-activated adenosine triphosphatase from Artemia salina Nauplii. J. Biol. Chem., 253: 4762-4770.
62. Price, E.M. & Lingrel, J.B. (1988) Structure-function relationship in the Na,K- ATPase ? subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine- 122 to aspartic acid generates a ouabain-resistant enzyme. Biochemistry, 27:8400-8408.
63. Quintas, L.E.M. (1996) Na+,K+-ATPase e dimorfismo sexual no rato. Tese de Mestrado em Farmacologia * Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 49 p.
64. Quintas, L.E.M., Caricati-Neto, A., Lafayette, S.S.L., Jurkiewicz, A., Noël, F. (2000) Down-regulation of Na+/K+-ATPase ?2 isoform in denervated rat vas deferens. Biochem. Pharmacol., 60, 741-747.
65. Quintas, L.E.M., Noël, F., Godfraind, T. & Wibo, M. (1998) Cardiac glycosides receptors (Na,K-ATPase ? subunit isoforms) in hearts of Wistar-Kyoto normotensive and stroke-prone spontaneously hypertensive rats. Naunyn-Schmiedeberg's Arch. Pharmacol., 358 (suppl.1):R273.
66. Reeves, A.S., Collins, J.H. & Schwartz, A. (1980) Isolation and characterization of (Na,K)-ATPase proteolipid. Biochem. Biophys. Res. Commun., 95:1591-1598.
67. Repke, K.R., Megges, R. & Weiland, J. (1997) Differentiation between various types of inotropes through discovery of differences in their ability to detect isoforms of Na+/K(+)-ATPase. J. Enzyme Inhib., 12:53-58.
68. Repke, K.R., Sweadner, K.J., Weiland, J., Megges, R. & Schon, R. (1996) In search of ideal inotropic steroids: recent progress. Prog. Drug Res., 47:9-52.
69. Rosic, N.K., Standaert, M.L. & Pollet, R.J. (1985) The mechanism of insulin stimulation of (Na,K)-ATPase transport activity in muscle. J. Biol. Chem., 260:6206- 6212.
70. Ruiz-Opazo, N., Xiang, X.H. & Herrera, V.L.M. (1997) Pressure-overload deinduction of human ?2 Na,K-ATPase gene expression in transgenic rats. Hypertension 29:606-612.
71. Sahin-Erdemli, I., Medford, R.M. & Songu-Mize, E. (1995) Regulation of Na+,K(+)- ATPase ?-subunit isoforms in rat tissues during hypertension. Eur. J. Pharmacol., 292:163-171.
72. Sargeant, R.J., Liu, Z. & Klip, A. (1995) Action of insulin on Na+-K+-ATPase and the Na+-K+-2Cl- cotransporter in 3T3-L1 adipocytes. Am. J. Physiol., 269:C217-C225.
73. Schmidt, T.A., Larsen, J.S. & Kjeldsen, K. (1992) Quantification of rat cerebral cortex Na+,K+-ATPase: effect of age and potassium depletion. J. Neurochem., 59:2094- 2104.
74. SCHMITT, C.A. & MCdonough, A.A. (1986) Developmental and thyroid hormone regulation of two molecular forms of Na+-K+-ATPase in brain. J. Biol. Chem. 261:10439- 10444.
75. Schmitt, C.A. & Mcdonough, A.A. (1988) Thyroid hormone regulates ? and ?+ isoforms of Na,K-ATPase during development in neonatal rat brain. J. Biol. Chem., 263:17643-17649.
76. Schwinger, R.H., Wang, J., Frank, K., Muller-Ehmsen, J., Brixius, K., Mcdonough, A.A. & Erdmann, E. (1999) Reduced sodium pump ?1, ?3, and ?1-isoform protein levels and Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levels in human heart failure. Circulation, 99:2105-2112.
77. Shahedi, M., Laborde, K., Bussières, L. & Sachs, C. (1993) Acute and early effects of aldosterone on Na-K-ATPase activity in Madin-Darby canine kidney epithelial cells. Am. J. Physiol., 264:F1021-1026.
78. Shamraj, O.I. & Lingrel, J.B. (1994) A putative fourth Na+,K+-ATPase ?-subunit gene is expressed in testis. Proc. Natl. Acad. Sci. U. S. A., 91: 12952-12956.
79. Sharabani-Yosef, O., Bak, A., Langzam, L., Lui, Z., Nir, U., Braiman, L., Sweadner, K.J. & Sampson, S.R. (1999) Rat skeletal muscle in culture expresses the ?1 but not the ?2 protein subunit isoform of the Na+/K+ pump. J. Cell. Physiol., 180:236-244.
80. Shull, G.E., Greeb, J. & Lingrel, J.B. (1986) Molecular cloning of three distinct forms of the Na+,K+-ATPase ? subunit from rat brain. Biochemistry, 25:8125-8132.
81. Shull, G.E., Lane, L.K. & Lingrel, J.B. (1986) Amino-acid sequence of the ?-subunit of the (Na++K+)ATPase deduced from cDNA. Nature, 321:429-431
82. Shyjan, A.W. & Levenson, R. (1989) Antisera specific for the ?1, ?2, ?3 and ? subunits of the Na,K-ATPase: differential expression of ? and ? subunit in the rat tissue membranes. Biochemistry, 28:4531-4535.
83. Shyjan, A.W., Cena, V., Klein, D.C. & Levenson, R. (1990) Differential expression and enzymatic properties of the Na,K-ATPase ?3 isoenzyme in rat pineal glands. Proc. Natl. Acad. Sci. U.S.A., 87:1178-1182.
84. Skou, J.C. (1957) The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim. Biophys. Acta, 23:394-401.
85. Souto-Pardon, R. & Noël, F. (1994) Heterogeneity of ouabain binding sites in Schistosoma mansoni: first evidence for the presence of two (Na+,K+)-ATPase isoforms in platyhelminths. Biochem. Pharmacol., 47:331-336.
86. Specht, S.C., Lopez-Rosado, R., Santos-Berrios, C. & Figueroa-Nieves, R. (1995) An ouabain-sensitive Na+,K+-ATPase in tentacles of the sea anemone Stichodactyla helianthus. Comp. Biochem. Physiol., 110B:555-563.
87. Spinale, F.G., Clayton, C., Tanaka, R., Fulbright, B.M., Mukherjee, R., Schulte, B.A., Crawford, F.A. & Zile, M.R. (1992) Myocardial Na+,K+-ATPase in tachycardia- induced cardiomyopathy. J. Mol. Cell. Cardiol., 24: 277-294.
88. Sweadner, K.J. (1979) Two molecular forms of (Na++K+)-stimulated ATPase in rat brain: separation and difference in affinity for strophantidin. J. Biol. Chem., 254:6060- 6067.
89. Sweadner, K.J. (1989) Isozymes of the Na+/K+-ATPase. Biochim. Biophys. Acta, 988:185-220.
90. Takeyasu, K., Lemas, V. & Fambrough, D.M. (1990) Stability of Na+,K+-ATPase ?- subunit isoforms in evolution. Am. J. Physiol., 259:C619-C630.
91. Tilupattur, P.R., Ram, J.L., Standley, P.R. & Sowers, J.R. (1993) Regulation of Na,K-ATPase gene expression by insulin in vascular smooth muscle cells. Am. J. Hypertens., 6:626-629.
92. Trujillo, E., Alvarez De La Rosa, D., Mobasheri, A., Avila, J., Gonzalez, T. & Martin-Vasallo, P. (1999) Sodium transport systems in human chondrocytes. I. Morphological and functional expression of the Na+,K+-ATPase ? and ? subunit isoforms in healthy and arthritic chondrocytes. Histol. Histopathol., 14:1011-1022.
93. Urayama, O., Shutt, H. & Sweadner, K.J. (1989) Identification of three isozyme proteins of the catalytic subunit of the Na+,K+-ATPase in rat brain. J. Biol. Chem., 264:8271- 8280.
94. Vasilets, L.A. & Schwarz, W. (1993) Structure-function relationships of cation binding in the Na+/K+-ATPase. Biochim. Biophys. Acta, 1154:201-222.
95. Wang, J., Schwinger, R.H., Frank, K., Muller-Ehmsen, J., Martin-Vasallo, P., Pressley, T.A., Xiang, A., Erdmann, E. & Mcdonough, A.A. (1996) Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart. J. Clin. Invest., 98:1650-1658.
96. Wibo, M., Kolar, F., Zheng, L. & Godfraind, T. (1995) Influence of thyroidal status on postnatal maturation of calcium channels, *-adrenoceptors and cation transport ATPases in rat ventricular tissue. J. Mol. Cell. Cardiol., 27:1731-1743.
97. Woo, A.L., James, P.F., Lingrel, J.B. (2000) Sperm motility is dependent on a unique isoform of the Na,K-ATPase. J. Biol. Chem., 275:20693-20699.
98. Zahler, R., Brines, M., Kashgarian, M., Benz, E.J. JR & Gilmore-Hebert, M. (1992) The cardiac conduction system in the rat expresses the ?2 and ?3 isoforms of the Na+,K+- ATPase. Proc. Natl. Acad. Sci. U.S.A., 89:99-103.