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Physiol. Rev. 77: 51-74, 1997;
0031-9333/97 $15.00
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Physiological Reviews, Vol 77, 51-74, Copyright © 1997 by American Physiological Society

JOURNAL ARTICLE

Molecular physiology of vertebrate Na+/H+ exchangers

S. Wakabayashi, M. Shigekawa and J. Pouyssegur
Department of Molecular Physiology, National Cardiovascular Center Research Institute, Osaka, Japan.

This review describes recent progress concerning the molecular aspects of the Na+/H+ exchanger. The Na+/H+ exchanger is an important regulator for intracellular pH, cell volume, and transepithelial Na+ transport. It exists in virtually all cells with cell type-dependent pattern of isoform expression, and it is regulated in response to a variety of extracellular stimuli, among them not only agonists such as growth factors and hormones but also mechanical stimuli such as osmotic stress and cell spreading. Thus this transporter is also an excellent model to study the signal transduction. Since the first molecular cloning of the Na+/H+ exchanger, detailed studies revealed many interesting features of this transporter. At present, at least five different isoforms of the Na+/H+ exchanger are known. These isoforms differ in tissue localization, sensitivity of inhibitors, and mode of transcriptional and posttranscriptional regulation, allowing them to participate in different physiological processes. We have only started to understand an intriguing mechanism underlying these functional differences among the exchanger isoforms. Because the Na+/H+ exchanger is relatively simple in terms of its kinetic features, e.g., a simple 1:1 stoichiometry of Na+ and H+ and no input of metabolic energy such as ATP hydrolysis, the study of its structural and mechanistic aspects would also serve as a good model to understand the general mechanism of various ion transporters.


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M. H. Montrose
The Future of GI and Liver Research: Editorial Perspectives: I. Visions of epithelial research
Am J Physiol Gastrointest Liver Physiol, April 1, 2003; 284(4): G547 - G550.
[Abstract] [Full Text] [PDF]

Home page
 JGPHome page
T. M. Kang, V. S. Markin, and D. W. Hilgemann
Ion Fluxes in Giant Excised Cardiac Membrane Patches Detected and Quantified with Ion-selective Microelectrodes
J. Gen. Physiol., March 31, 2003; 121(4): 325 - 348.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. Wakabayashi, T. Hisamitsu, T. Pang, and M. Shigekawa
Mutations of Arg440 and Gly455/Gly456 Oppositely Change pH Sensing of Na+/H+ Exchanger 1
J. Biol. Chem., March 28, 2003; 278(14): 11828 - 11835.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
D. G Allen and X.-H. Xiao
Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion
Cardiovasc Res, March 15, 2003; 57(4): 934 - 941.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
M. Avkiran and R. S Haworth
Regulatory effects of G protein-coupled receptors on cardiac sarcolemmal Na+/H+ exchanger activity: signalling and significance
Cardiovasc Res, March 15, 2003; 57(4): 942 - 952.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
M. I Bak and J. S Ingwall
Contribution of Na+/H+ exchange to Na+ overload in the ischemic hypertrophied hyperthyroid rat heart
Cardiovasc Res, March 15, 2003; 57(4): 1004 - 1014.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
S. Goyal, G. Vanden Heuvel, and P. S. Aronson
Renal expression of novel Na+/H+ exchanger isoform NHE8
Am J Physiol Renal Physiol, March 1, 2003; 284(3): F467 - F473.
[Abstract] [Full Text] [PDF]

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 Ann. Thorac. Surg.Home page
R. M. Mentzer Jr, R. D. Lasley, A. Jessel, and M. Karmazyn
Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection
Ann. Thorac. Surg., February 1, 2003; 75(2): S700 - 708.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
C. L Brett, T. Kelly, C. Sheldon, and J. Church
Regulation of Cl--HCO3- exchangers by cAMP-dependent protein kinase in adult rat hippocampal CA1 neurons
J. Physiol., December 15, 2002; 545(3): 837 - 853.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
M. Johansson, J. D. Glazier, C. P. Sibley, T. Jansson, and T. L. Powell
Activity and Protein Expression of the Na+/H+ Exchanger Is Reduced in Syncytiotrophoblast Microvillous Plasma Membranes Isolated from Preterm Intrauterine Growth Restriction Pregnancies
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5686 - 5694.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. Pang, S. Wakabayashi, and M. Shigekawa
Expression of Calcineurin B Homologous Protein 2 Protects Serum Deprivation-induced Cell Death by Serum-independent Activation of Na+/H+ Exchanger
J. Biol. Chem., November 8, 2002; 277(46): 43771 - 43777.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
S. Akhter, O. Kovbasnjuk, X. Li, M. Cavet, J. Noel, M. Arpin, A. L. Hubbard, and M. Donowitz
Na+/H+ exchanger 3 is in large complexes in the center of the apical surface of proximal tubule-derived OK cells
Am J Physiol Cell Physiol, September 1, 2002; 283(3): C927 - C940.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
K. Nehrke and J. E. Melvin
The NHX Family of Na+-H+ Exchangers in Caenorhabditis elegans
J. Biol. Chem., August 2, 2002; 277(32): 29036 - 29044.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
T. Igarashi, T. Sekine, J. Inatomi, and G. Seki
Unraveling the Molecular Pathogenesis of Isolated Proximal Renal Tubular Acidosis
J. Am. Soc. Nephrol., August 1, 2002; 13(8): 2171 - 2177.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
J. Chu, S. Chu, and M. H. Montrose
Apical Na+/H+ exchange near the base of mouse colonic crypts
Am J Physiol Cell Physiol, July 1, 2002; 283(1): C358 - C372.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. Lucioni, C. Womack, M. W. Musch, F. L. Rocha, C. Bookstein, and E. B. Chang
Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function
Am J Physiol Gastrointest Liver Physiol, July 1, 2002; 283(1): G51 - G56.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
B. A. Watts III and D. W. Good
ERK mediates inhibition of Na+/H+ exchange and HCO3- absorption by nerve growth factor in MTAL
Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1056 - F1063.
[Abstract] [Full Text] [PDF]

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 J. Neurophysiol.Home page
C. Sheldon and J. Church
Intracellular pH Response to Anoxia in Acutely Dissociated Adult Rat Hippocampal CA1 Neurons
J Neurophysiol, May 1, 2002; 87(5): 2209 - 2224.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. Incerpi, P. De Vito, P. Luly, S. Spagnuolo, and S. Leoni
Short-Term Effects of Thyroid Hormones and 3,5-Diiodothyronine on Membrane Transport Systems in Chick Embryo Hepatocytes
Endocrinology, May 1, 2002; 143(5): 1660 - 1668.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
S. Engelhardt, L. Hein, U. Keller, K. Klambt, and M. J. Lohse
Inhibition of Na+-H+ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in {beta}1-Adrenergic Receptor Transgenic Mice
Circ. Res., April 19, 2002; 90(7): 814 - 819.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
H. Hayashi, K. Szaszi, N. Coady-Osberg, J. Orlowski, J. L. Kinsella, and S. Grinstein
A Slow pH-dependent Conformational Transition Underlies a Novel Mode of Activation of the Epithelial Na+/H+ Exchanger-3 Isoform
J. Biol. Chem., March 22, 2002; 277(13): 11090 - 11096.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. Malakooti, V. C. Memark, P. K. Dudeja, and K. Ramaswamy
Molecular cloning and functional analysis of the human Na+/H+ exchanger NHE3 promoter
Am J Physiol Gastrointest Liver Physiol, March 1, 2002; 282(3): G491 - G500.
[Abstract] [Full Text] [PDF]

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 J. Exp. Biol.Home page
W. Zeiske, H. Meyer, and H. Wieczorek
Insect midgut K+ secretion: concerted run-down of apical/basolateral transporters with extra-/intracellular acidity
J. Exp. Biol., February 15, 2002; 205(4): 463 - 474.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
M Inoue, N Fujishiro, I Imanaga, and Y Sakamoto
Role of ATP decrease in secretion induced by mitochondrial dysfunction in guinea-pig adrenal chromaffin cells
J. Physiol., February 15, 2002; 539(1): 145 - 155.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
E. W. Yeung, J.-P. Bourreau, D. G. Allen, and H. J. Ballard
Effect of eccentric contraction-induced injury on force and intracellular pH in rat skeletal muscles
J Appl Physiol, January 1, 2002; 92(1): 93 - 99.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
X. Li, T. Galli, S. Leu, J. B Wade, E. J Weinman, G. Leung, A. Cheong, D. Louvard, and M. Donowitz
Na+-H+ exchanger 3 (NHE3) is present in lipid rafts in the rabbit ileal brush border: a role for rafts in trafficking and rapid stimulation of NHE3
J. Physiol., December 1, 2001; 537(2): 537 - 552.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
M. E. Cavet, S. Akhter, R. Murtazina, F. Sanchez de Medina, C.-M. Tse, and M. Donowitz
Half-lives of plasma membrane Na+/H+ exchangers NHE1-3: plasma membrane NHE2 has a rapid rate of degradation
Am J Physiol Cell Physiol, December 1, 2001; 281(6): C2039 - C2048.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Khadilkar, P. Iannuzzi, and J. Orlowski
Identification of Sites in the Second Exomembrane Loop and Ninth Transmembrane Helix of the Mammalian Na+/H+ Exchanger Important for Drug Recognition and Cation Translocation
J. Biol. Chem., November 16, 2001; 276(47): 43792 - 43800.
[Abstract] [Full Text] [PDF]

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 MicrobiologyHome page
M. L. Verkhovskaya, B. Barquera, and M. Wikstrom
Deletion of one of two Escherichia coli genes encoding putative Na+/H+ exchangers (ycgO) perturbs cytoplasmic alkali cation balance at low osmolarity
Microbiology, November 1, 2001; 147(11): 3005 - 3013.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
S. Wei, E. C. Rothstein, L. Fliegel, L. J. Dell'Italia, and P. A. Lucchesi
Differential MAP kinase activation and Na+/H+ exchanger phosphorylation by H2O2 in rat cardiac myocytes
Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1542 - C1550.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. Santhanagopal, P. Chidiac, W. C. Horne, R. Baron, and S. J. Dixon
Calcitonin (CT) Rapidly Increases Na+/H+ Exchange and Metabolic Acid Production: Effects Mediated Selectively by the C1a CT Receptor Isoform
Endocrinology, October 1, 2001; 142(10): 4401 - 4413.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
S. Attaphitaya, K. Nehrke, and J. E. Melvin
Acute inhibition of brain-specific Na+/H+ exchanger isoform 5 by protein kinases A and C and cell shrinkage
Am J Physiol Cell Physiol, October 1, 2001; 281(4): C1146 - C1157.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
H. Yao, X.-Q. Gu, R. M. Douglas, and G. G. Haddad
Role of Na+/H+ exchanger during O2 deprivation in mouse CA1 neurons
Am J Physiol Cell Physiol, October 1, 2001; 281(4): C1205 - C1210.
[Abstract] [Full Text] [PDF]


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