Seminars in Nephrology
Volume 25, Issue 5 , Pages 292-303 , September 2005

Na,K-ATPase Subunit Heterogeneity as a Mechanism for Tissue-Specific Ion Regulation

  • Gustavo Blanco

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Gustavo Blanco, MD, PhD, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160.

References 

  1. Skou JC , Esmann M . The Na,K-ATPase . J Bioenerg Biomembr . 1992;24:249–261
  2. Feraille E , Doucet A . Sodium-potassium-adenosine triphosphatase-dependent sodium transport in the kidney (Hormonal control) . Physiol Rev . 2001;81:345–418
  3. Ghosh S , Hernando N , Martin-Alonso JM , et al.   Expression of multiple Na,K-ATPase genes reveals a gradient of isoforms along the nonpigmented ciliary epithelium (Functional implications in aqueous humor secretion) . J Cell Physiol . 1991;149:184–194
  4. Peters TA , Kuijpers W , Curfs JH . Occurrence of Na,K-ATPase isoforms during rat inner ear development and functional implications . Eur Arch Otorhinolaryngol . 2001;258:67–73
  5. Zlokovic BV , Mackic JB , Wang L , et al.   Differential expression of Na,K-ATPase α and β subunit isoforms at the blood-brain barrier and the choroid plexus . J Biol Chem . 1993;268:8019–8025
  6. Fambrough DM . The sodium pump becomes a family . Trends Neurosci . 1988;11:325–328
  7. Sweadner KJ . Isozymes of the Na+/K+-ATPase . Biochim Biophys Acta . 1989;988:185–220
  8. Levenson R . Isoforms of the Na,K-ATPase (Family members in search of function) . Rev Physiol Biochem Pharmacol . 1994;123:1–45
  9. Blanco G , Mercer RW . Isozymes of the Na,K-ATPase (Heterogeneity in structure, diversity in function) . Am J Physiol . 1998;275:F633–F650
  10. Mobasheri A , Avila J , Cozar-Castellano I , et al.   Na+,K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions . Biosci Rep . 2000;20:51–91
  11. Kaplan JH . Biochemistry of Na,K-ATPase . Annu Rev Biochem . 2002;71:511–535
  12. Jorgensen PL , Hakansson KO , Karlish JD . Structure and mechanism of Na,K-ATPase . Annu Rev Physiol . 2003;65:817–849
  13. Ogawa H , Toyoshima C . Homology modeling of the cation binding sites of Na,K-ATPase . Proc Natl Acad Sci U S A . 2002;99:15977–15982
  14. Geering K . The functional role of beta subunits in oligomeric P-type ATPases . J Bioenerg Biomembr . 2001;33:425–438
  15. 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 Na, K-ATPase) . Biochemistry . 1978;17:3667–3676
  16. Sweadner KJ , Rael E . The FXYD gene family of small ion transport regulators or channels (cDNA sequence, protein signature sequence, and expression) . Genomics . 2000;68:41–56
  17. Hansen O . Non-uniform populations of g-strophanthin binding sites of (Na+ + K+)-activated ATPase. Apparent conversion to uniformity by K+ . Biochim Biophys Acta . 1976;433:383–392
  18. Sweadner KJ . Two molecular forms of (Na+ + K+)-stimulated ATPase in brain. Separation, and difference in affinity for strophanthidin . J Biol Chem . 1979;254:6060–6067
  19. Lytton J . The catalytic subunits of the (Na+,K+)-ATPase α and α(+) isozymes are the products of different genes . Biochem Biophys Res Commun . 1985;132:764–769
  20. Shull GE , Greeb J , Lingrel JB . Molecular cloning of three distinct forms of the Na+,K+-ATPase α subunit from rat brain . Biochemistry . 1986;25:8125–8132
  21. Sverdlov ED , Monastyrskaya GS , Broude NE , et al.   The family of human Na+,K+-ATPase genes. No less than five genes and/or pseudogenes related to the α subunit . FEBS Lett . 1987;217:275–278
  22. Shamraj OI , Lingrel JB . A putative fourth Na+,K+-ATPase α subunit gene is expressed in testis . Proc Natl Acad Sci U S A . 1994;91:12952–12956
  23. Underhill DA , Canfield VA , Dahl JP , et al.   The Na,K-ATPase alpha4 gene (Atp1a4) encodes a ouabain-resistant alpha subunit and is tightly linked to the alpha2 gene (Atp1a2) on mouse chromosome 1 . Biochemistry . 1999;38:14746–14751
  24. Wheeler DL , Barrett T , Benson DA , et al.   Database resources of the National Center for Biotechnology Information . Nucleic Acids Res . 2005;33:D39–D45
  25. Hubbard T , Andrews D , Caccamo M , et al.   Ensembl 2005 . Nucleic Acids Res . 2005;33:D447–D453
  26. Pierre SV , Duran MJ , Carr DL , et al.   Structure/function analysis of Na+-K+-ATPase central isoform-specific region (Involvement in PKC regulation) . Am J Physiol . 2002;283:F1066–F1074
  27. Canfield VA , Xu KY , D’Aquila T , et al.   Molecular cloning and characterization of Na,K-ATPase from Hydra vulgaris (Implications for enzyme evolution and ouabain sensitivity) . New Biol . 1992;4:339–348
  28. Baxter-Lowe LA , Guo JZ , Bergstrom EE , et al.   Molecular cloning of the Na,K-ATPase α subunit in developing brine shrimp and sequence comparison with higher organisms . FEBS Lett . 1989;257:181–187
  29. Pardon RS , Noel F . Heterogeneity of ouabain binding sites in Schistosoma mansoni. First evidence for the presence of two (Na+ + K+)-ATPase isoforms in platyhelminths . Biochem Pharmacol . 1994;47:331–336
  30. Rajarao SJ , Canfield VA , Mohideen MA , et al.   The repertoire of Na,K-ATPase α and β subunit genes expressed in the zebrafish, Danio rerio . Genome Res . 2001;11:1211–1220
  31. Martin-Vasallo P , Dackowski W , Emanuel JR , et al.   Identification of a putative isoform of the Na,K-ATPase beta subunit. Primary structure and tissue-specific expression . J Biol Chem . 1989;264:4613–4618
  32. Gloor S , Antonicek H , Sweadner KJ , et al.   The adhesion molecule on glia (AMOG) is a homologue of the β subunit of the Na,K-ATPase . J Cell Biol . 1990;110:165–174
  33. Malik N , Canfield VA , Beckers MC , et al.   Identification of the mammalian Na,K-ATPase β3 subunit . J Biol Chem . 1996;271:22754–22758
  34. Pestov NB , Adams G , Shakhparonov MI , et al.   Identification of a novel gene of the X,K-ATPase beta-subunit family that is predominantly expressed in skeletal and heart muscles . FEBS Lett . 1999;456:243–248
  35. Zhao H , Pestov NB , Korneenko TV , et al.   Accumulation of beta(m), a structural member of X,K-ATPase beta-subunit family, in nuclear envelopes of perinatal myocytes . Am J Physiol . 2004;286:C757–C767
  36. Medford RM , Hyman R , Ahmad M , et al.   Vascular smooth muscle expresses a truncated Na+, K+-ATPase α1 subunit isoform . J Biol Chem . 1991;266:18308–18312
  37. Allen JC , Zhao X , Odebunmi T , et al.   Alpha 1T can support Na,K-ATPase (Na+ pump functions in expression systems) . Ann N Y Acad Sci . 1997;834:457–458
  38. Ruiz A , Bhat SP , Bok D . Characterization and quantification of full-length and truncated Na,K-ATPase α1 and β1 RNA transcripts expressed in human retinal pigment epithelium . Gene . 1995;155:179–184
  39. Burgener-Kairuz P , Horisberger JD , Geering K , et al.   Functional expression of N-terminal truncated α subunits of Na,K-ATPase in Xenopus laevis oocytes . FEBS Lett . 1991;290:83–86
  40. Therien AG , Pu HX , Karlish SJ , et al.   Molecular and functional studies of the gamma subunit of the sodium pump . J Bioenerg Biomembr . 2001;33:407–414
  41. Kuster B , Shainskaya A , Pu HX , et al.   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 . 2000;275:18441–18446
  42. Wetzel RK , Sweadner KJ . Immunocytochemical localization of Na-K-ATPase α and γ subunits in rat kidney . Am J Physiol . 2001;281:F531–F545
  43. Pu HX , Cluzeaud F , Goldshleger R , et al.   Functional role and immunocytochemical localization of the γa and γb forms of the Na,K-ATPase γ subunit . J Biol Chem . 2001;276:20370–20378
  44. Jones DH , Golding MC , Barr KJ , et al.   The mouse Na+-K+-ATPase γ subunit gene (Fxyd2) encodes three developmentally regulated transcripts . Physiol Genom . 2001;6:129–135
  45. Lemas MV , Yu HY , Takeyasu K . Assembly of Na,K-ATPase α subunit isoforms with Na,K-ATPase β subunit isoforms and H,K-ATPase β subunit . J Biol Chem . 1994;269:18651–18655
  46. Blanco G , Koster JC , Sanchez G , et al.   Kinetic properties of the α2β1 and α2β2 isozymes of the Na,K-ATPase . Biochemistry . 1995;34:319–325
  47. Blanco G , Sanchez G , Mercer RW . Comparison of the enzymatic properties of the Na,K-ATPase α3β1 and α3β2 isozymes . Biochemistry . 1995;34:9897–9903
  48. Blanco G , Melton RJ , Sanchez G , et al.   Functional characterization of a testes-specific α subunit isoform of the Na,K-ATPase . Biochemistry . 1999;38:13661–13669
  49. Yu CL , Xie ZJ , Askari A , et al.   Enzymatic properties of human Na,K-ATPase α1β3 isozyme . Arch Biochem Biophys . 1997;345:143–149
  50. Crambert G , Hasler U , Beggah AT , et al.   Transport and pharmacological properties of nine different human Na, K-ATPase isozymes . J Biol Chem . 2000;275:1976–1986
  51. Taniguchi K , Kaya S , Abe K , et al.   The oligomeric nature of Na/K-transport ATPase . J Biochem . 2001;129:335–342
  52. Blanco G , Koster JC , Mercer RW . The α subunit of the Na,K-ATPase specifically and stably associates into oligomers . Proc Natl Acad Sci U S A . 1994;91:8542–8546
  53. Arystarkhova EK , Sweadner J . 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 . 1997;272:22405–22408
  54. Fink DJ , Fang D , Li T , et al.   Na,K-ATPase beta subunit isoform expression in the peripheral nervous system of the rat . Neurosci Lett . 1995;183:206–209
  55. Zahler R , Gilmore-Hebert M , Baldwin JC , et al.   Expression of alpha isoforms of the Na,K-ATPase in human heart . Biochim Biophys Acta . 1993;1149:189–194
  56. Pierre S , Compe E , Grillasca JP , et al.   RT-PCR detection of Na,K-ATPase subunit isoforms in human umbilical vein endothelial cells (HUVEC) (Evidence for the presence of α1 and β3) . Cell Mol Biol . 2001;47:319–324
  57. Noel F , Quintas LE , Freitas E , et al.   Quantitative analysis of the high-affinity binding sites for [3H]ouabain in the rat vas deferens and their immunological identification as the α2 isoform of Na,K-ATPase . Biochem Pharmacol . 1998;55:1531–1535
  58. Mobasheri A , Pestov NB , Papanicolaou S , et al.   Expression and cellular localization of Na,K-ATPase isoforms in the rat ventral prostate . BJU Int . 2003;92:793–802
  59. Ong MD , Payne DM , Garner MH . Differential protein expression in lens epithelial whole-mounts and lens epithelial cell cultures . Exp Eye Res . 2003;77:35–49
  60. Floyd R , Mobasheri A , Martin-Vasallo P , et al.   Na,K-ATPase isoforms in pregnant and nonpregnant rat uterus . Ann N Y Acad Sci . 2003;986:614–616
  61. Esplin MS , Fausett MB , Faux DS , et al.   Changes in the isoforms of the sodium pump in the placenta and myometrium of women in labor . Am J Obstet Gynecol . 2003;188:759–764
  62. Blanco G , Sanchez G , Melton RJ , et al.   The α4 isoform of the Na,K-ATPase is expressed in the germ cells of the testes . J Histochem Cytochem . 2000;48:1023–1032
  63. Hoffman JF , Wikrema A , Potapova O , et al.   Na pump isoforms in human erythroid progenitor cells and mature erythrocytes . Proc Natl Acad Sci U S A . 2002;99:14572–14577
  64. Martin-Vasallo P , Wetzel RK , Garcia-Segura LM , et al.   Oligodendrocytes in brain and optic nerve express the β3 subunit isoform of Na,K-ATPase . Glia . 2000;31:206–218
  65. Wetzel RK , Arystarkhova E , Sweadner KJ . Cellular and subcellular specification of Na,K-ATPase α and β isoforms in the postnatal development of mouse retina . J Neurosci . 1999;19:9878–9889
  66. Keryanov S , Gardner KL . Physical mapping and characterization of the human Na,K-ATPase isoform, ATP1A4 . Gene . 2002;292:151–166
  67. Sweadner KJ , Herrera VL , Amato S , et al.   Immunologic identification of Na,K-ATPase isoforms in myocardium . Isoform change in deoxycorticosterone acetate-salt hypertension. Circ Res . 1994;74:669–678
  68. Orlowski J , Lingrel JB . Tissue-specific and developmental regulation of rat Na,K-ATPase catalytic α and β subunit mRNAs . J Biol Chem . 1988;263:10436–10442
  69. Lucchesi PA , Sweadner KJ . Postnatal changes in Na,K-ATPase isoform expression in rat cardiac ventricle. Conservation of biphasic ouabain affinity . J Biol Chem . 1991;266:9327–9331
  70. Moseley AE , Lieske SP , Wetzel RK , et al.   The Na,K-ATPase α2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice . J Biol Chem . 2003;278:5317–5324
  71. Therien AG , Blostein R . Mechanisms of sodium pump regulation . Am J Physiol . 2000;279:C541–C566
  72. Ewart HS , Klip A . Hormonal regulation of the Na,K-ATPase (Mechanisms underlying rapid and sustained changes in pump activity) . Am J Physiol . 1995;269:C295–C311
  73. Ng YC , Nagarajan M , Jew KN , et al.   Exercise training differentially modifies age-associated alteration in expression of Na+-K+-ATPase subunit isoforms in rat skeletal muscles . Am J Physiol . 2003;285:R733–R740
  74. Muller-Ehmsen J , McDonough AA , Farley RA , et al.   Sodium pump isoform expression in heart failure (Implication for treatment) . Basic Res Cardiol . 2002;97(suppl 1):I25–I30
  75. Sweadner KJ . Enzymatic properties of separated isozymes of the Na,K-ATPase. Substrate affinities, kinetic cooperativity, and ion transport stoichiometry . J Biol Chem . 1985;260:11508–11513
  76. Munzer JS , Daly SE , Jewell-Motz EA , et al.   Tissue- and isoform-specific kinetic behavior of the Na,K-ATPase . J Biol Chem . 1994;269:16668–16676
  77. Brodsky JL , Guidotti G . Sodium affinity of brain Na+-K+-ATPase is dependent on isozyme and environment of the pump . Am J Physiol . 1990;258:C803–C811
  78. Shyjan AW , Cena V , Klein DC , et al.   Differential expression and enzymatic properties of the Na+,K+-ATPase α3 isoenzyme in rat pineal glands . Proc Natl Acad Sci U S A . 1990;87:1178–1182
  79. Hara YO , Urayama K , Kawakami H , et al.   The third type of alpha subunit of Na,K-ATPase . Prog Clin Biol Res . 1988;268A:73–78
  80. Kolansky DM , Brines ML , Gilmore-Hebert M , et al.   The A2 isoform of rat Na+,K+-adenosine triphosphatase is active and exhibits high ouabain affinity when expressed in transfected fibroblasts . FEBS Lett . 1992;303:147–153
  81. Jewell EA , Lingrel JB . Comparison of the substrate dependence properties of the rat Na,K-ATPase α1, α2, and α3 isoforms expressed in HeLa cells . J Biol Chem . 1991;266:16925–16930
  82. Balshaw DM , Millette LA , Tepperman K , et al.   Combined allosteric and competitive interaction between extracellular Na+ and K+ during ion transport by the α1, α2, and α3 isoforms of the Na, K-ATPase . Biophys J . 2000;79:853–862
  83. Petrosian SA , Carr DL , Guerrero G , et al.   Mutagenesis disrupts posttranslational processing of the Na,K-ATPase catalytic subunit . Arch Biochem Biophys . 1998;357:249–258
  84. Daly SE , Lane LK , Blostein R . Structure/function analysis of the amino-terminal region of the α1 and α2 subunits of Na,K-ATPase . J Biol Chem . 1996;271:23683–23689
  85. Segall L , Daly SE , Blostein R . Mechanistic basis for kinetic differences between the rat α1, α2, and α3 isoforms of the Na,K-ATPase . J Biol Chem . 2001;276:31535–31541
  86. Horowitz B , Eakle KA , Scheiner-Bobis G , et al.   Synthesis and assembly of functional mammalian Na,K-ATPase in yeast . J Biol Chem . 1990;265:4189–4192
  87. Eakle KA , Kabalin MA , Wang SG , et al.   The influence of β subunit structure on the stability of Na+/K+-ATPase complexes and interaction with K+ . J Biol Chem . 1994;269:6550–6557
  88. Eakle KA , Lyu RM , Farley RA . The influence of β subunit structure on the interaction of Na+/K+-ATPase complexes with Na+. A chimeric β subunit reduces the Na+ dependence of phosphoenzyme formation from ATP . J Biol Chem . 1995;270:13937–13947
  89. Muller-Ehmsen J , Juvvadi P , Thompson CB , et al.   Ouabain and substrate affinities of human Na,K-ATPase α1β1, α2β1, and α3β1 when expressed separately in yeast cells . Am J Physiol . 2001;281:C1355–C1364
  90. Jaisser FP , Jaunin K , Geering BC , et al.   Modulation of the Na,K-pump function by β subunit isoforms . J Gen Physiol . 1994;103:605–623
  91. Blanco G , Xie ZJ , Mercer RW . Functional expression of the α2 and α3 isoforms of the Na,K-ATPase in baculovirus-infected insect cells . Proc Natl Acad Sci U S A . 1993;90:1824–1828
  92. Erdmann E , Werdan K , Brown L . Evidence for two kinetically and functionally different types of cardiac glycoside receptors in the heart . Eur Heart J . 1984;5:297–302
  93. Wang J , Velotta JB , McDonough AA , et al.   All human Na,K-ATPase α subunit isoforms have a similar affinity for cardiac glycosides . Am J Physiol . 2001;281:C1336–C1343
  94. Blaustein MP . Physiological effects of endogenous ouabain (Control of intracellular Ca2+ stores and cell responsiveness) . Am J Physiol . 1993;264:C1367–C1387
  95. Schoner W . Endogenous cardiac glycosides, a new class of steroid hormones . Eur J Biochem . 2002;269:2440–2448
  96. Woo AL , James PF , Lingrel JB . Characterization of the fourth alpha isoform of the Na,K-ATPase . J Membr Biol . 1999;169:39–44
  97. Blanco G . Functional expression of the α4 isoform of the Na,K-ATPase in both diploid and haploid germ cells of male rats . Ann N Y Acad Sci . 2003;986:536–538
  98. Arystarkhova E , Donnet C , Asinovski NK , et al.   Differential regulation of renal Na,K-ATPase by splice variants of the γ subunit . J Biol Chem . 2002;277:10162–10172
  99. Crambert G , Fuzesi M , Garty H , et al.   Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its transport properties . Proc Natl Acad Sci U S A . 2002;99:11476–11481
  100. Beguin P , Crambert G , Guennoun S , et al.   CHIF, a member of the FXYD protein family, is a regulator of Na,K-ATPase distinct from the gamma-subunit . EMBO J . 2001;20:3993–4002
  101. Geering K , Beguin P , Garty H , et al.   FXYD proteins (New tissue- and isoform-specific regulators of Na,K-ATPase) . Ann N Y Acad Sci . 2003;986:388–394
  102. Marette A , Krischer J , Lavoie L , et al.   Insulin increases the Na,K-ATPase alpha 2-subunit in the surface of rat skeletal muscle (Morphological evidence) . Am J Physiol . 1993;265:C1716–C1722
  103. Teixeira VL , Katz AI , Pedemonte CH , et al.   Isoform-specific regulation of Na,K-ATPase endocytosis and recruitment to the plasma membrane . Ann N Y Acad Sci . 2003;986:587–594
  104. Nishi A , Fisone G , Snyder GL , et al.   Regulation of Na,K-ATPase isoforms in rat neostriatum by dopamine and protein kinase C . J Neurochem . 1999;73:1492–1501
  105. Blanco G , Sanchez G , Mercer RW . Differential regulation of Na,K-ATPase isozymes by protein kinases and arachidonic acid . Arch Biochem Biophys . 1998;359:139–150
  106. Shelly DA , He S , Moseley A , et al.   Na pump α2 isoform specifically couples to contractility in vascular smooth muscle (Evidence from gene-targeted neonatal mice) . Am J Physiol . 2004;286:C813–C820
  107. He S , Shelly DA , Moseley AE , et al.   The α1 and α2 isoforms of Na-K-ATPase play different roles in skeletal muscle contractility . Am J Physiol . 2001;281:R917–R925
  108. Hartford AK , Messer ML , Moseley AE . Na,K-ATPase α2 inhibition alters calcium responses in optic nerve astrocytes . Glia . 2004;45:229–237
  109. Golovina VA , Song H , James PF , et al.   Na pump α2 subunit expression modulates Ca2+ signaling . Am J Physiol . 2003;284:C475–C486
  110. 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
  111. Dostanic I , Lorenz JN , Schultz JJ , et al.   The α2 isoform of Na,K-ATPase mediates ouabain-induced cardiac inotropy in mice . J Biol Chem . 2003;278:53026–53034
  112. McDonough AA , Thompson CB , Youn JH . Skeletal muscle regulates extracellular potassium . Am J Physiol . 2002;282:F967–F974
  113. Woo AL , James PF , Lingrel JB . Sperm motility is dependent on a unique isoform of the Na,K-ATPase . J Biol Chem . 2000;275:20693–20699
  114. Woo AL , James PF , Lingrel JB . Roles of the Na,K-ATPase α4 isoform and the Na+/H+ exchanger in sperm motility . Mol Reprod Dev . 2002;62:348–356
  115. Magyar JP , Bartsch U , Wang Z-Q , et al.   Degeneration of neural cells in the central nervous system of mice deficient in the gene for the adhesion molecule on glia, the β2 subunit of murine Na,K-ATPase . J Cell Biol . 1994;127:835–845
  116. Senner V , Schmidtpeter S , Braune S , et al.   AMOG/β2 and glioma invasion (Does loss of AMOG make tumour cells run amok?) . Neuropathol Appl Neurobiol . 2003;29:370–377

 Supported by National Institutes of Health grant HD043044.

PII: S0270-9295(05)00047-1

doi: 10.1016/j.semnephrol.2005.03.004

Seminars in Nephrology
Volume 25, Issue 5 , Pages 292-303 , September 2005