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Am J Physiol Renal Physiol 275: F633-F650, 1998;
0363-6127/98 $5.00
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Vol. 275, Issue 5, F633-F650, November 1998

INVITED REVIEW
Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function

Gustavo Blanco and Robert W. Mercer

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

The Na-K-ATPase is characterized by a complex molecular heterogeneity that results from the expression and differential association of multiple isoforms of both its alpha - and beta -subunits. At present, as many as four different alpha -polypeptides (alpha 1, alpha 2, alpha 3, and alpha 4) and three distinct beta -isoforms (beta 1, beta 2, and beta 3) have been identified in mammalian cells. The stringent constraints on the structure of the Na pump isozymes during evolution and their tissue-specific and developmental pattern of expression suggests that the different Na-K-ATPases have evolved distinct properties to respond to cellular requirements. This review focuses on the functional properties, regulation, and possible physiological relevance of the Na pump isozymes. The coexistence of multiple alpha - and beta -isoforms in most cells has hindered the understanding of the roles of the individual polypeptides. The use of heterologous expression systems has helped circumvent this problem. The kinetic characteristics of different Na-K-ATPase isozymes to the activating cations (Na+ and K+), the substrate ATP, and the inhibitors Ca2+ and ouabain demonstrate that each isoform has distinct properties. In addition, intracellular messengers differentially regulate the activity of the individual Na-K-ATPase isozymes. Thus the regulation of specific Na pump isozymes gives cells the ability to precisely coordinate Na-K-ATPase activity to their physiological requirements.

ouabain; sodium pump; protein kinases


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Cellular Depolarization of Neurons in the Locus Ceruleus Region of the Guinea Pig Associated with the Development of Tolerance to Opioids
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[Abstract] [Full Text]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. He, D. A. Shelly, A. E. Moseley, P. F. James, J. H. James, R. J. Paul, and J. B. Lingrel
The {alpha}1- and {alpha}2-isoforms of Na-K-ATPase play different roles in skeletal muscle contractility
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R917 - R925.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
R. K. Wetzel and K. J. Sweadner
Immunocytochemical localization of Na-K-ATPase alpha - and gamma -subunits in rat kidney
Am J Physiol Renal Physiol, September 1, 2001; 281(3): F531 - F545.
[Abstract] [Full Text] [PDF]

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 J. Nutr.Home page
B. P. Bode
Recent Molecular Advances in Mammalian Glutamine Transport
J. Nutr., September 1, 2001; 131(9): 2475S - 2485.
[Abstract] [Full Text] [PDF]

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 Physiol. GenomicsHome page
D. H. JONES, M. C. GOLDING, K. J. BARR, G.-H. FONG, and G. M. KIDDER
The mouse Na+-K+-ATPase {gamma}-subunit gene (Fxyd2) encodes three developmentally regulated transcripts
Physiol Genomics, August 28, 2001; 6(3): 129 - 135.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. A. Wong, A. R. Gosmanov, E. G. Schneider, and D. B. Thomason
Insulin-independent, MAPK-dependent stimulation of NKCC activity in skeletal muscle
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2001; 281(2): R561 - R571.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
N. Sevieux, J. Alam, and E. Songu-Mize
Effect of cyclic stretch on {alpha}-subunit mRNA expression of Na+-K+-ATPase in aortic smooth muscle cells
Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1555 - C1560.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
K. A. Dora and C. J. Garland
Properties of smooth muscle hyperpolarization and relaxation to K+ in the rat isolated mesenteric artery
Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2424 - H2429.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Aydemir-Koksoy and J. C. Allen
Regulation of Na+ pump expression by vascular smooth muscle cells
Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1869 - H1874.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
R. K. Wetzel and K. J. Sweadner
Immunocytochemical Localization of NaK-ATPase Isoforms in the Rat and Mouse Ocular Ciliary Epithelium
Invest. Ophthalmol. Vis. Sci., March 1, 2001; 42(3): 763 - 769.
[Abstract] [Full Text]

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 DiabetesHome page
S. Shen, A. Alt, E. Wertheimer, M. Gartsbein, T. Kuroki, M. Ohba, L. Braiman, S. R. Sampson, and T. Tennenbaum
PKC{delta} Activation: A Divergence Point in the Signaling of Insulin and IGF-1--Induced Proliferation of Skin Keratinocytes
Diabetes, February 1, 2001; 50(2): 255 - 264.
[Abstract] [Full Text]

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 Am. J. Physiol. Cell Physiol.Home page
D. R. Yingst, J. Davis, and R. Schiebinger
Effects of extracellular calcium and potassium on the sodium pump of rat adrenal glomerulosa cells
Am J Physiol Cell Physiol, January 1, 2001; 280(1): C119 - C125.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
A. G. Therien and R. Blostein
Mechanisms of sodium pump regulation
Am J Physiol Cell Physiol, September 1, 2000; 279(3): C541 - C566.
[Abstract] [Full Text] [PDF]

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 J. Histochem. Cytochem.Home page
G. Blanco, G. Sánchez, R. J. Melton, W. G. Tourtellotte, and R. W. Mercer
The {alpha}4 Isoform of the Na,K-ATPase Is Expressed in the Germ Cells of the Testes
J. Histochem. Cytochem., August 1, 2000; 48(8): 1023 - 1032.
[Abstract] [Full Text]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Arnon, J. M. Hamlyn, and M. P. Blaustein
Ouabain augments Ca2+ transients in arterial smooth muscle without raising cytosolic Na+
Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H679 - H691.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. P. Cutler, S. Brezillon, S. Bekir, I. L. Sanders, N. Hazon, and G. Cramb
Expression of a duplicate Na,K-ATPase beta 1-isoform in the European eel (Anguilla anguilla)
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2000; 279(1): R222 - R229.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Johansson, T. Jansson, and T. L. Powell
Na+-K+-ATPase is distributed to microvillous and basal membrane of the syncytiotrophoblast in human placenta
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2000; 279(1): R287 - R294.
[Abstract] [Full Text] [PDF]

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 Clin. Chem.Home page
A. M. Rose, H. M. Qazzaz, N. Zolotarjova, B. J. Mellett, A. W. Martin, and R. Valdes Jr
Sodium Pump Isoforms in Xenotransplantation: Importance of Biochemical Compatibility
Clin. Chem., February 1, 2000; 46(2): 234 - 241.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
G. Crambert, U. Hasler, A. T. Beggah, C. Yu, N. N. Modyanov, J.-D. Horisberger, L. Lelievre, and K. Geering
Transport and Pharmacological Properties of Nine Different Human Na,K-ATPase Isozymes
J. Biol. Chem., January 21, 2000; 275(3): 1976 - 1986.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
A. Arnon, J. M. Hamlyn, and M. P. Blaustein
Na+ entry via store-operated channels modulates Ca2+ signaling in arterial myocytes
Am J Physiol Cell Physiol, January 1, 2000; 278(1): C163 - C173.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
E. Arystarkhova, R. K. Wetzel, N. K. Asinovski, and K. J. Sweadner
The gamma Subunit Modulates Na+ and K+ Affinity of the Renal Na,K-ATPase
J. Biol. Chem., November 19, 1999; 274(47): 33183 - 33185.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
R. K. Wetzel, E. Arystarkhova, and K. J. Sweadner
Cellular and Subcellular Specification of Na,K-ATPase alpha and beta Isoforms in the Postnatal Development of Mouse Retina
J. Neurosci., November 15, 1999; 19(22): 9878 - 9889.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
A. G. Therien and R. Blostein
K+/Na+ antagonism at cytoplasmic sites of Na+-K+-ATPase: a tissue-specific mechanism of sodium pump regulation
Am J Physiol Cell Physiol, November 1, 1999; 277(5): C891 - C898.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
B. Sun, P. Xu, and P. M. Salvaterra
Dynamic visualization of nervous system in live Drosophila
PNAS, August 31, 1999; 96(18): 10438 - 10443.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. L. Woo, P. F. James, and J. B Lingrel
Sperm Motility Is Dependent on a Unique Isoform of the Na,K-ATPase
J. Biol. Chem., June 30, 2000; 275(27): 20693 - 20699.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. Segall, S. E. Daly, and R. Blostein
Mechanistic Basis for Kinetic Differences between the Rat alpha 1, alpha 2, and alpha 3 Isoforms of the Na,K-ATPase
J. Biol. Chem., August 17, 2001; 276(34): 31535 - 31541.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
W. Wang, D. J. Seward, L. Li, J. L. Boyer, and N. Ballatori
Expression cloning of two genes that together mediate organic solute and steroid transport in the liver of a marine vertebrate
PNAS, July 31, 2001; 98(16): 9431 - 9436.
[Abstract] [Full Text] [PDF]

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 Genome ResHome page
F. C. Serluca, A. Sidow, J. D. Mably, and M. C. Fishman
Partitioning of Tissue Expression Accompanies Multiple Duplications of the Na+/K+ ATPase alpha Subunit Gene
Genome Res., October 1, 2001; 11(10): 1625 - 1631.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
N. B. Pestov, T. V. Korneenko, G. Adams, M. Tillekeratne, M. I. Shakhparonov, and N. N. Modyanov
Nongastric H-K-ATPase in rodent prostate: lobe-specific expression and apical localization
Am J Physiol Cell Physiol, April 1, 2002; 282(4): C907 - C916.
[Abstract] [Full Text] [PDF]


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