Pflügers Archiv

, Volume 447, Issue 5, pp 549–565 | Cite as

Diversity of the mammalian sodium/proton exchanger SLC9 gene family

  • John OrlowskiEmail author
  • Sergio Grinstein
The ABC of Solute carriers Guest Editor: Matthias A. Hediger


Sodium/proton antiporters or exchangers (NHE) are integral membrane proteins present in most, if not all, living organisms. In mammals, these transporters chiefly catalyze the electroneutral exchange of Na+ and H+ down their respective concentration gradients and are crucial for numerous physiological processes, ranging from the fine control of intracellular pH and cell volume to systemic electrolyte, acid-base and fluid volume homeostasis. NHE activity also facilitates the progression of other cellular events such as adhesion, migration, and proliferation. Thus far, eight distinct NHE genes (NHE1/SLC9A1–NHE8/SLC9A8) and several pseudogenes have been identified in the human genome. The functional genes encode proteins of varying primary sequence identity (25–70%), but share a common predicted secondary structure comprising 12 conserved membrane-spanning segments at the amino-terminus and a more divergent, cytoplasmically-oriented, carboxy-terminus. They show considerable heterogeneity in their patterns of tissue/cell expression and membrane localization. Functional studies have revealed further differences in their kinetic properties, sensitivity to pharmacological antagonists, and regulation by diverse hormonal and mechanical stimuli. Altered NHE activity has been linked to the pathogenesis of several diseases, including essential hypertension, congenital secretory diarrhea, diabetes, and tissue damage caused by ischemia/reperfusion. Further characterization of their functional properties should lead to a better understanding of their unique contributions to human health and disease.


Na+/H+ exchanger Genetic diversity Acid-base homeostasis Na+ absorption Organellar function 



This study was supported by the Canadian Institutes of Health Research and the Kidney Foundation of Canada. J. O. is a supported by an Investigator Award from the Canadian Institutes of Health Research and is a current holder of a James McGill Professorship. S.G. is cross-appointed to the Department of Biochemistry of the University of Toronto and is the current holder of the Pitblado Chair in Cell Biology.


  1. 1.
    Aharonovitz O, Zaun HC, Balla T, York JD, Orlowski J, Grinstein S (2000) Intracellular pH regulation by Na+/H+ exchange requires phosphatidylinositol 4,5-bisphosphate. J Cell Biol 150:213–224CrossRefPubMedGoogle Scholar
  2. 2.
    Akhter S, Kovbasnjuk O, Li X, Cavet M, Noël J, Arpin M, Hubbard AL, Donowitz M (2002) Na+/H+ exchanger 3 is in large complexes in the center of the apical surface of proximal tubule-derived OK cells. Am J Physiol 283:C927–C940Google Scholar
  3. 3.
    Amemiya M, Loffing J, Lötscher M, Kaissling B, Alpern RJ, Moe OW (1995) Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney Int 48:1206–1215PubMedGoogle Scholar
  4. 4.
    Andreeva N, Khodorov B, Stelmashook E, Sokolova S, Cragoe EJ Jr, Victorov I (1992) 5-(N-ethyl-N-isopropyl)amiloride and mild acidosis protect cultured cerebellar granule cells against glutamate-induced delayed neuronal death. Neuroscience 49:175–181CrossRefPubMedGoogle Scholar
  5. 5.
    Apse MP, Aharon GS, Snedden WA, Blumwald E (1999) Salt tolerance conferred by overexpression of a vacuolar Na+/H+ antiport in Arabidopsis. Science 285:1256–1258PubMedGoogle Scholar
  6. 6.
    Aronson PS (1985) Kinetic properties of the plasma membrane Na-H exchanger. Annu Rev Physiol 47:545–560CrossRefPubMedGoogle Scholar
  7. 7.
    Attaphitaya S, Nehrke K, Melvin JE (2001) Acute inhibition of brain-specific Na+/H+ exchanger isoform 5 by protein kinases A and C and cell shrinkage. Am J Physiol 281:C1146–C1157Google Scholar
  8. 8.
    Attaphitaya S, Park K, Melvin JE (1999) Molecular cloning and functional expression of a rat Na+/H+ exchanger (NHE5) highly expressed in brain. J Biol Chem 274:4383–4388PubMedGoogle Scholar
  9. 9.
    Baird NR, Orlowski J, Szabó EZ, Zaun HC, Schultheis PJ, Menon AG, Shull GE (1999) Molecular cloning, genomic organization, and functional expression of Na+/H+ exchanger isoform 5 (NHE5) from human brain. J Biol Chem 274:4377–4382CrossRefPubMedGoogle Scholar
  10. 10.
    Beliveau R, Demeule M, Potier M (1988) Molecular size of the Na+/H+ antiport in renal brush border membranes, as estimated by radiation inactivation. Biochem Biophys Res Commun 152:484–489PubMedGoogle Scholar
  11. 11.
    Bell SM, Schreiner CM, Schultheis PJ, Miller ML, Evans RL, Vorhees CV, Shull GE, Scott WJ (1999) Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Am J Physiol 276:C788–C795PubMedGoogle Scholar
  12. 12.
    Biemesderfer D, Reilly RF, Exner M, Igarashi P, Aronson PS (1992) Immunocytochemical characterization of Na+-H+ exchanger isoform NHE-1 in rabbit kidney. Am J Physiol 263:F833–F840PubMedGoogle Scholar
  13. 13.
    Biemesderfer D, Pizzonia J, Abu-Alfa A, Exner M, Reilly R, Igarashi P, Aronson PS (1993) NHE3: A Na+/H+ exchanger isoform of renal brush border. Am J Physiol 265:F736–F742PubMedGoogle Scholar
  14. 14.
    Biemesderfer D, Rutherford PA, Nagy T, Pizzonia JH, Abu-Alfa AK, Aronson PS (1997) Monoclonal antibodies for high-resolution localization of NHE3 in adult and neonatal kidney. Am J Physiol 273:F289–F299PubMedGoogle Scholar
  15. 15.
    Biemesderfer D, DeGray B, Aronson PS (1998) Membrane topology of NHE3. Epitopes within the carboxyl-terminal hydrophilic domain are exoplasmic. J Biol Chem 273:12391–12396CrossRefPubMedGoogle Scholar
  16. 16.
    Biemesderfer D, Nagy T, DeGray B, Aronson PS (1999) Specific association of megalin and the Na+/H+ exchanger isoform NHE3 in the proximal tubule. J Biol Chem 274:17518–17524CrossRefPubMedGoogle Scholar
  17. 17.
    Biemesderfer D, DeGray B, Aronson PS (2001) Active (9.6 S) and inactive (21 S) oligomers of NHE3 in microdomains of the renal brush border. J Biol Chem 276:10161–10167CrossRefPubMedGoogle Scholar
  18. 18.
    Bookstein C, Musch MW, DePaoli A, Xie Y, Rabenau K, Villereal M, Rao MC, Chang EB (1996) Characterization of the rat Na+/H+ exchanger isoform NHE4 and localization in rat hippocampus. Am J Physiol 271:C1629–C1638PubMedGoogle Scholar
  19. 19.
    Booth IW, Stange G, Murer H, Fenton TR, Milla PJ (1985) Defective jejunal brush-border Na+/H+ exchange: a cause of congenital secretory diarrhoea. Lancet1066–1069Google Scholar
  20. 20.
    Bowers K, Levi BP, Patel FI, Stevens TH (2000) The sodium/proton exchanger Nhx1p is required for endosomal protein trafficking in the yeast Saccharomyces cerevisiae. Mol Biol Cell 11:4277–4294PubMedGoogle Scholar
  21. 21.
    Brant SR, Yun CHC, Donowitz M, Tse C-M (1995) Cloning, tissue distribution, and functional analysis of the human Na+/H+ exchanger isoform, NHE3. Am J Physiol 269:C198–C206PubMedGoogle Scholar
  22. 22.
    Brett CL, Wei Y, Donowitz M, Rao R (2002) Human Na+/H+ exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am J Physiol 282:C1031–C1041Google Scholar
  23. 23.
    Buerke M, Ruprecht HJ, vom Dahl J, Terres W, Seyfarth M, Schultheiss HP, Richardt G, Sheehan FH, Drexler H (1999) Sodium-hydrogen exchange inhibition: novel strategy to prevent myocardial injury following ischemia and reperfusion. Am J Cardiol 83:19G–22GCrossRefPubMedGoogle Scholar
  24. 24.
    Cabado AG, Yu FH, Kapus A, Gergely L, Grinstein S, Orlowski J (1996) Distinct structural domains confer cAMP sensitivity and ATP dependence to the Na+/H+ exchanger NHE3 isoform. J Biol Chem 271:3590–3599CrossRefPubMedGoogle Scholar
  25. 25.
    Chambrey R, Achard JM, Warnock DG (1997) Heterologous expression of rat NHE4: A highly amiloride-resistant Na+/H+ exchanger isoform. Am J Physiol 272:C90–C98PubMedGoogle Scholar
  26. 26.
    Chambrey R, Warnock DG, Podevin RA, Bruneval P, Mandet C, Bélair MF, Bariéty J, Paillard M (1998) Immunolocalization of the Na+/H+ exchanger isoform NHE2 in rat kidney. Am J Physiol 275:F379–F386PubMedGoogle Scholar
  27. 27.
    Chambrey R, St John PL, Eladari D, Quentin F, Warnock DG, Abrahamson DR, Podevin RA, Paillard M (2001) Localization and functional characterization of Na+/H+ exchanger isoform NHE4 in rat thick ascending limbs. Am J Physiol 281:F707–F717Google Scholar
  28. 28.
    Chow CW, Khurana S, Woodside M, Grinstein S, Orlowski J (1999) The epithelial Na+/H+ exchanger, NHE3, is internalized through a clathrin-mediated pathway. J Biol Chem 274:37551–37558CrossRefPubMedGoogle Scholar
  29. 29.
    Chow CW, Woodside M, Demaurex N, Yu FH, Plant P, Rotin D, Grinstein S, Orlowski J (1999) Proline-rich motifs of the Na+/H+ exchanger 2 isoform—binding of Src homology domain 3 and role in apical targeting in epithelia. J Biol Chem 274:10481–10488CrossRefPubMedGoogle Scholar
  30. 30.
    Counillon L, Franchi A, Pouysségur J (1993) A point mutation of the Na+/H+ exchanger gene (NHE1) and amplification of the mutated allele confer amiloride resistance upon chronic acidosis. Proc Natl Acad Sci USA 90:4508–4512PubMedGoogle Scholar
  31. 31.
    Counillon L, Scholz W, Lang HJ, Pouysségur J (1993) Pharmacological characterization of stably transfected Na+/H+ antiporter isoforms using amiloride analogs and a new inhibitor exhibiting anti-ischemic properties. Mol Pharmacol 44:1041–1045PubMedGoogle Scholar
  32. 32.
    Counillon L, Pouysségur J, Reithmeier RAF (1994) The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain. Biochemistry 33:10463–10469PubMedGoogle Scholar
  33. 33.
    Counillon L, Noël J, Reithmeier RA, Pouysségur J (1997) Random mutagenesis reveals a novel site involved in inhibitor interaction within the fourth transmembrane segment of the Na+/H+ exchanger-1. Biochemistry 36:2951–2959CrossRefPubMedGoogle Scholar
  34. 34.
    Cox GA, Lutz CM, Yang CL, Biemesderfer D, Bronson RT, Fu A, Aronson PS, Noebels JL, Frankel WN (1997) Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91:139–148CrossRefPubMedGoogle Scholar
  35. 35.
    D'Souza S, Garcia-Cabado A, Yu F, Teter K, Lukacs G, Skorecki K, Moore HP, Orlowski J, Grinstein S (1998) The epithelial sodium-hydrogen antiporter Na+/H+ exchanger 3 accumulates and is functional in recycling endosomes. J Biol Chem 273:2035–2043CrossRefPubMedGoogle Scholar
  36. 36.
    Demaurex N, Furuya W, D'Souza S, Bonifacino JS, Grinstein S (1998) Mechanism of acidification of the trans-Golgi network (TGN): in situ measurements of pH using retrieval of TGN38 and furin from the cell surface. J Biol Chem 273:2044–2051CrossRefPubMedGoogle Scholar
  37. 37.
    Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL (2000) Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H+ translocation. Mol Cell 6:1425–1436PubMedGoogle Scholar
  38. 38.
    Denker SP, Barber DL (2002) Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol 159:1087–1096CrossRefPubMedGoogle Scholar
  39. 39.
    Dransfield DT, Bradford AJ, Smith J, Martin M, Roy C, Mangeat PH, Goldenring JR (1997) Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. EMBO J 16:35–43CrossRefPubMedGoogle Scholar
  40. 40.
    Fafournoux P, Noël J, Pouysségur J (1994) Evidence that Na+/H+ exchanger isoforms NHE1 and NHE3 exist as stable dimers in membranes with a high degree of specificity for homodimers. J Biol Chem 269:2589–2596PubMedGoogle Scholar
  41. 41.
    Fan LZ, Wiederkehr MR, Collazo R, Wang HM, Crowder LA, Moe OW (1999) Dual mechanisms of regulation of Na/H exchanger NHE-3 by parathyroid hormone in rat kidney. J Biol Chem 274:11289–11295CrossRefPubMedGoogle Scholar
  42. 42.
    Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (1998) 14-3-3 proteins interact with specific MEK kinases. J Biol Chem 273:3476–3483CrossRefPubMedGoogle Scholar
  43. 43.
    Firek L, Weingart R (1995) Modification of gap junction conductance by divalent cations and protons in neonatal rat heart cells. J Mol Cell Cardiol 27:1633–1643PubMedGoogle Scholar
  44. 44.
    Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, Kaplan C, Ptacek LJ (1996) Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 59:392–399PubMedGoogle Scholar
  45. 45.
    Forgac M (1999) Structure and properties of the vacuolar (H+)-ATPases. J Biol Chem 274:12951–12954CrossRefPubMedGoogle Scholar
  46. 46.
    Franchi A, Cragoe EJ Jr, Pouysségur J (1986) Isolation and properties of fibroblast mutants overexpressing an altered Na+/H+ antiporter. J Biol Chem 261:14614–14620PubMedGoogle Scholar
  47. 47.
    Garlid KD, Sun X, Paucek P, Woldegiorgis G (1995) Mitochondrial cation transport systems. Methods Enzymol 260:331–348PubMedGoogle Scholar
  48. 48.
    Gekle M, Freudinger R, Mildenberger S (2001) Inhibition of Na+-H+ exchanger-3 interferes with apical receptor-mediated endocytosis via vesicle fusion. J Physiol (Lond) 531:619–629Google Scholar
  49. 49.
    Girardi ACC, Degray BC, Nagy T, Biemesderfer D, Aronson PS (2001) Association of Na+-H+ exchanger isoform NHE3 and dipeptidyl peptidase IV in the renal proximal tubule. J Biol Chem 276:46671–46677CrossRefPubMedGoogle Scholar
  50. 50.
    Goss GG, Woodside M, Wakabayashi S, Pouysségur J, Waddell T, Downey GP, Grinstein S (1994) ATP dependence of NHE-1, the ubiquitous isoform of the Na+/H+ antiporter. Analysis of phosphorylation and subcellular localization. J Biol Chem 269:8741–8748PubMedGoogle Scholar
  51. 51.
    Goyal S, Vanden Heuvel G, Aronson PS (2003) Renal Expression of Novel Na+-H+ Exchanger Isoform NHE8. Am J Physiol 284:F467–F473Google Scholar
  52. 52.
    Grinstein S, Woodside M, Waddell TK, Downey GP, Orlowski J, Pouysségur J, Wong DCP, Foskett JK (1993) Focal localization of the NHE-1 isoform of the Na+/H+ antiport: assessment of effects on intracellular pH. EMBO J 12:5209–5218PubMedGoogle Scholar
  53. 53.
    Gu XQ, Yao H, Haddad GG (2001) Increased neuronal excitability and seizures in the Na+/H+ exchanger null mutant mouse. Am J Physiol 281:C496–C503Google Scholar
  54. 54.
    Harris RC, Brenner BM, Seifter JL (1986) Sodium-hydrogen exchange and glucose transport in renal microvillus membrane vesicles from rats with diabetes mellitus. J Clin Invest 77:724–733PubMedGoogle Scholar
  55. 55.
    Hilgemann DW, Ball R (1996) Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. Science 273:956–959PubMedGoogle Scholar
  56. 56.
    Hoogerwerf WA, Tsao SC, Devuyst O, Levine SA, Yun CHC, Yip JW, Cohen ME, Wilson PD, Lazenby AJ, Tse CM, Donowitz M (1996) NHE2 and NHE3 are human and rabbit intestinal brush-border proteins. Am J Physiol 270:G29–G41PubMedGoogle Scholar
  57. 57.
    Horikawa N, Nishioka M, Itoh N, Kuribayashi Y, Matsui K, Ohashi N (2001) The Na+/H+ exchanger SM-20220 attenuates ischemic injury in in vitro and in vivo models. Pharmacology 63:76–81CrossRefPubMedGoogle Scholar
  58. 58.
    Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002) Molecular structure and physiological function of chloride channels. Physiol Rev 82:503–568PubMedGoogle Scholar
  59. 59.
    Kapus A, Grinstein S, Wasan S, Kandasamy RA, Orlowski J (1994) Functional characterization of three isoforms of the Na+/H+ exchanger stably expressed in Chinese hamster ovary cells: ATP dependence, osmotic sensitivity and role in cell proliferation. J Biol Chem 269:23544–23552PubMedGoogle Scholar
  60. 60.
    Karmazyn M (2001) Role of sodium-hydrogen exchange in cardiac hypertrophy and heart failure: a novel and promising therapeutic target. Basic Res Cardiol 96:325–328CrossRefPubMedGoogle Scholar
  61. 61.
    Karmazyn M, Gan XHT, Humphreys RA, Yoshida H, Kusumoto K (1999) The myocardial Na+-H+ exchange—structure, regulation, and its role in heart disease. Circ Res 85:777–786PubMedGoogle Scholar
  62. 62.
    Kelly MP, Quinn PA, Davies JE, Ng LL (1997) Activity and expression of Na+-H+ exchanger isoforms 1 and 3 in kidney proximal tubules of hypertensive rats. Circ Res 80:853–860PubMedGoogle Scholar
  63. 63.
    Khadilkar A, Iannuzzi P, Orlowski J (2001) 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 276:43792–43800CrossRefPubMedGoogle Scholar
  64. 64.
    Khan I (2001) Topology of the C-terminus of sodium hydrogen exchanger isoform-1: Presence of an extracellular epitope. Arch Biochem Biophys 391:25–29CrossRefPubMedGoogle Scholar
  65. 65.
    Klanke CA, Su YR, Callen DF, Wang Z, Meneton P, Baird N, Kandasamy RA, Orlowski J, Otterud BE, Leppert M, Shull GE, Menon AG (1995) Molecular-cloning and physical and genetic-mapping of a novel human Na+/H+ exchanger (NHE5/Slc9A5) to chromosome 16q22.1. Genomics 25:615–622CrossRefPubMedGoogle Scholar
  66. 66.
    Kokke FTM, Elsawy T, Bengtsson U, Wasmuth JJ, Jabs EW, Tse C-M, Donowitz M, Brant SR (1996) A NHE3-related pseudogene is on chromosome 10; the functional gene maps to 5p15.3. Mamm Genome 7:235–236CrossRefPubMedGoogle Scholar
  67. 67.
    Kummerow D, Hamann J, Browning JA, Wilkins R, Ellory JC, Bernhardt I (2000) Variations of intracellular pH in human erythrocytes via K+(Na+)/H+ exchange under low ionic strength conditions. J Membr Biol 176:207–216CrossRefPubMedGoogle Scholar
  68. 68.
    Kurashima K, Yu FH, Cabado AG, Szabó EZ, Grinstein S, Orlowski J (1997) Identification of sites required for down-regulation of Na+/H+ exchanger NHE3 activity by cAMP-dependent protein kinase. Phosphorylation-dependent and -independent mechanisms. J Biol Chem 272:28672–28679CrossRefPubMedGoogle Scholar
  69. 69.
    Kurashima K, Szabó EZ, Lukacs G, Orlowski J, Grinstein S (1998) Endosomal recycling of the Na+/H+ exchanger NHE3 isoform is regulated by the phosphatidylinositol 3-kinase pathway. J Biol Chem 273:20828–20836CrossRefPubMedGoogle Scholar
  70. 70.
    Kurashima K, D'Souza S, Szászi K, Ramjeesingh R, Orlowski J, Grinstein S (1999) The apical Na+/H+ exchanger isoform NHE3 is regulated by the actin cytoskeleton. J Biol Chem 274:29843–29849CrossRefPubMedGoogle Scholar
  71. 71.
    Lagana A, Vadnais J, Le PU, Nguyen TN, Laprade R, Nabi IR, Noël J (2000) Regulation of the formation of tumor cell pseudopodia by the Na+/H+ exchanger NHE1. J Cell Sci 113:3649–3662PubMedGoogle Scholar
  72. 72.
    Lang P, Gesbert F, Delespine-Carmagnat M, Stancou R, Pouchelet M, Bertoglio J (1996) Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J 15:510–519PubMedGoogle Scholar
  73. 73.
    Ledoussal C, Lorenz JN, Nieman ML, Soleimani M, Schultheis PJ, Shull GE (2001) Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2. Am J Physiol 281:F718–F727Google Scholar
  74. 74.
    Lehoux S, Abe J, Florian JA, Berk BC (2001) 14-3-3 binding to Na+/H+ exchanger isoform-1 is associated with serum-dependent activation of Na+/H+ exchange. J Biol Chem 276:15794–15800CrossRefPubMedGoogle Scholar
  75. 75.
    Levine SA, Nath SK, Yun CHC, Yip JW, Montrose M, Donowitz M, Tse CM (1995) Separate C-terminal domains of the epithelial specific brush border Na+/H+ exchanger isoform NHE3 are involved in stimulation and inhibition by protein kinases/growth factors. J Biol Chem 270:13716–13725CrossRefPubMedGoogle Scholar
  76. 76.
    Li X, Alvarez B, Casey JR, Reithmeier RA, Fliegel L (2002) Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger. J Biol Chem 277:36085–36091CrossRefPubMedGoogle Scholar
  77. 77.
    Lifton RP, Hunt SC, Williams RR, Pouysségur J, Lalouel J-M (1991) Exclusion of the Na+-H+ antiporter as a candidate gene in human essential hypertension. Hypertension 17:8–14PubMedGoogle Scholar
  78. 78.
    Lin X, Barber DL (1996) A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange. Proc Natl Acad Sci USA 93:12631–12636CrossRefPubMedGoogle Scholar
  79. 79.
    Liu Y, Edwards RH (1997) The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu Rev Neurosci 20:125–156CrossRefPubMedGoogle Scholar
  80. 80.
    Llopis J, McCaffery JM, Miyawaki A, Farquhar MG, Tsien RY (1998) Measurement of cytosolic, mitochondrial, and Golgi pH in single living cells with green fluorescent proteins. Proc Natl Acad Sci USA 95:6803–6808CrossRefPubMedGoogle Scholar
  81. 81.
    Maher MM, Gontarek JD, Jimenez RE, Donowitz M, Yeo CJ (1996) Role of brush border Na+/H+ exchange in canine ileal absorption. Dig Dis Sci 41:651–659PubMedGoogle Scholar
  82. 82.
    Maher MM, Gontarek JD, Bess RS, Donowitz M, Yeo CJ (1997) The Na+/H+ exchange isoform NHE3 regulates basal canine ileal Na+ absorption in vivo. Gastroenterology 112:174–183Google Scholar
  83. 83.
    Mahnensmith RL, Aronson PS (1985) Interrelationships among quinidine, amiloride, and lithium as inhibitors of the renal Na+-H+ exchanger. J Biol Chem 260:12586–12592PubMedGoogle Scholar
  84. 84.
    Mahnensmith RL, Aronson PS (1985) The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res 56:773–788PubMedGoogle Scholar
  85. 85.
    Mailander J, Muller-Esterl W, Dedio J (2001) Human homolog of mouse tescalcin associates with Na+/H+ exchanger type-1. FEBS Lett 507:331–335CrossRefPubMedGoogle Scholar
  86. 86.
    Malakooti J, Dahdal RY, Schmidt L, Layden TJ, Dudeja PK, Ramaswamy K (1999) Molecular cloning, tissue distribution, and functional expression of the human Na+/H+ exchanger NHE2. Am J Physiol 277:G383–G390PubMedGoogle Scholar
  87. 87.
    Mellman I (1992) The importance of being acid: the role of acidification in intracellular membrane traffic. J Exp Biol 172:39–45PubMedGoogle Scholar
  88. 88.
    Miller RT, Pollock AS (1987) Modification of the internal pH sensitivity of the Na+/H+ antiporter by parathyroid hormone in a cultured renal cell line. J Biol Chem 262:9115–9120PubMedGoogle Scholar
  89. 89.
    Miyazaki E, Sakaguchi M, Wakabayashi S, Shigekawa M, Mihara K (2001) NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell. J Biol Chem 276:49221–49227CrossRefPubMedGoogle Scholar
  90. 90.
    Nehrke K, Melvin JE (2002) The NHX family of Na+-H+ exchangers in Caenorhabditis elegans. J Biol Chem 277:29036–29044CrossRefPubMedGoogle Scholar
  91. 91.
    Nguyen HV, Shull GE, Melvin JE (2000) Muscarinic receptor-induced acidification in sublingual mucous acinar cells: loss of pH recovery in Na+-H+ exchanger-1 deficient mice. J Physiol (Lond) 523:139–146Google Scholar
  92. 92.
    Numata M, Orlowski J (2001) Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem 276:17387–17394CrossRefPubMedGoogle Scholar
  93. 93.
    Numata M, Petrecca K, Lake N, Orlowski J (1998) Identification of a mitochondrial Na+/H+ exchanger. J Biol Chem 273:6951–6959CrossRefPubMedGoogle Scholar
  94. 94.
    Orlov SN, Adragna NC, Adarichev VA, Hamet P (1999) Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension. Am J Physiol 276:C511–C536PubMedGoogle Scholar
  95. 95.
    Orlowski J (1993) Heterologous expression and functional properties of the amiloride high affinity (NHE-1) and low affinity (NHE-3) isoforms of the rat Na/H exchanger. J Biol Chem 268:16369–16377PubMedGoogle Scholar
  96. 96.
    Orlowski J, Grinstein S (1997) Na+/H+ exchangers in mammalian cells. J Biol Chem 272:22373–22376CrossRefPubMedGoogle Scholar
  97. 97.
    Orlowski J, Kandasamy RA (1996) Delineation of transmembrane domains of the Na+/H+ exchanger that confer sensitivity to pharmacological antagonists. J Biol Chem 271:19922–19927CrossRefPubMedGoogle Scholar
  98. 98.
    Orlowski J, Kandasamy RA, Shull GE (1992) Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins. J Biol Chem 267:9331–9339PubMedGoogle Scholar
  99. 99.
    Otsu K, Kinsella JL, Koh E, Froehlich JP (1992) Proton dependence of the partial reactions of the sodium-proton exchanger in renal brush border membranes. J Biol Chem 267:8089–8096PubMedGoogle Scholar
  100. 100.
    Otsu K, Kinsella JL, Heller P, Froehlich JP (1993) Sodium dependence of the Na+-H+ exchanger in the pre-steady state. Implications for the exchange mechanism. J Biol Chem 268:3184–3193PubMedGoogle Scholar
  101. 101.
    Padan E, Venturi M, Gerchman Y, Dover N (2001) Na+/H+ antiporters. Biochim Biophys Acta 1505:144–157CrossRefPubMedGoogle Scholar
  102. 102.
    Page RDM (1996) TREEVIEW: an application to display phylogenetic trees on personal computers. Computer Applications in the Biosciences 12:357–358PubMedGoogle Scholar
  103. 103.
    Pang T, Su XH, Wakabayashi S, Shigekawa R (2001) Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers. J Biol Chem 276:17367–17372CrossRefPubMedGoogle Scholar
  104. 104.
    Pang T, Wakabayashi S, Shigekawa M (2002) Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger. J Biol Chem 277:43771–43777CrossRefPubMedGoogle Scholar
  105. 105.
    Park K, Evans RL, Watson GE, Nehrke K, Richardson L, Bell SM, Schultheis PJ, Hand AR, Shull GE, Melvin JE (2001) Defective fluid secretion and NaCl absorption in the parotid glands of Na+/H+ exchanger-deficient mice. J Biol Chem 276:27042–27050CrossRefPubMedGoogle Scholar
  106. 106.
    Peti-Peterdi J, Chambrey R, Bebok Z, Biemesderfer D, St John PL, Abrahamson DR, Warnock DG, Bell PD (2000) Macula densa Na+/H+ exchange activities mediated by apical NHE2 and basolateral NHE4 isoforms. Am J Physiol 278:F452–F463Google Scholar
  107. 107.
    Petrecca K, Atanasiu R, Grinstein S, Orlowski J, Shrier A (1999) Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium. Am J Physiol 276:H709–H717PubMedGoogle Scholar
  108. 108.
    Phan VN, Kusuhara M, Lucchesi PA, Berk BC (1997) A 90-kD Na+-H+ exchanger kinase has increased activity in spontaneously hypertensive rat vascular smooth muscle cells. Hypertension 29:1265–1272PubMedGoogle Scholar
  109. 109.
    Pizzonia JH, Biemesderfer D, Abu-Alfa AK, Wu MS, Exner M, Isenring P, Igarashi P, Aronson PS (1998) Immunochemical characterization of Na+/H+ exchanger isoform NHE4. Am J Physiol 275:F510–F517PubMedGoogle Scholar
  110. 110.
    Pouysségur J, Sardet C, Franchi A, L'Allemain G, Paris S (1984) A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc Natl Acad Sci USA 81:4833–4837PubMedGoogle Scholar
  111. 111.
    Pulsinelli W (1992) Pathophysiology of acute ischaemic stroke. Lancet 339:533–536PubMedGoogle Scholar
  112. 112.
    Putney LK, Denker SP, Barber DL (2002) The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annu Rev Pharmacol Toxicol 42:527–552CrossRefPubMedGoogle Scholar
  113. 113.
    Reczek D, Berryman M, Bretscher A (1997) Identification of EBP50: a PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J Cell Biol 139:169–179PubMedGoogle Scholar
  114. 114.
    Rockwell NC, Fuller RS (2002) Specific modulation of Kex2/furin family proteases by potassium. J Biol Chem 277:17531–17537CrossRefPubMedGoogle Scholar
  115. 115.
    Rotin D, Grinstein S (1989) Impaired cell volume regulation in Na+-H+ exchange-deficient mutants. Am J Physiol 257:C1158–C1165PubMedGoogle Scholar
  116. 116.
    Sangan P, Rajendran VM, Geibel JP, Binder HJ (2002) Cloning and expression of a chloride-dependent Na+-H+ exchanger. J Biol Chem 277:9668–9675CrossRefPubMedGoogle Scholar
  117. 117.
    Sardet C, Franchi A, Pouysségur J (1989) Molecular cloning, primary structure, and expression of the human growth factor-activatable Na/H antiporter. Cell 56:271–280PubMedGoogle Scholar
  118. 118.
    Schapiro FB, Grinstein S (2000) Determinants of the pH of the Golgi complex. J Biol Chem 275:21025–21032CrossRefPubMedGoogle Scholar
  119. 119.
    Schneider H, Scheiner-Bobis G (1997) Involvement of the M7/M8 extracellular loop of the sodium pump alpha subunit in ion transport. Structural and functional homology to P-loops of ion channels. J Biol Chem 272:16158–16165CrossRefPubMedGoogle Scholar
  120. 120.
    Scholz W, Albus U, Counillon L, Gögelein H, Lang H-J, Linz W, Weichert A, Schölkens BA (1995) Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 29:260–268PubMedGoogle Scholar
  121. 121.
    Schultheis PJ, Clarke LL, Meneton P, Harline M, Boivin GP, Stemmermann G, Duffy JJ, Doetschman T, Miller ML, Shull GE (1998) Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J Clin Invest 101:1243–1253PubMedGoogle Scholar
  122. 122.
    Schultheis PJ, Clarke LL, Meneton P, Miller ML, Soleimani M, Gawenis LR, Riddle TM, Duffy JJ, Doetschman T, Wang T, Giebisch G, Aronson PS, Lorenz JN, Shull GE (1998) Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nature Genet 19:282–285CrossRefPubMedGoogle Scholar
  123. 123.
    Schwark JR, Jansen HW, Lang H-J, Krick W, Burckhardt G, Hropot M (1998) S3226, a novel inhibitor of Na+/H+ exchanger subtype 3 in various cell types. Pflugers Arch 436:797–800CrossRefPubMedGoogle Scholar
  124. 124.
    Shi H, Quintero FJ, Pardo JM, Zhu JK (2002) The putative plasma membrane Na+/H+ antiporter SOS1 controls long-distance Na+ transport in plants. Plant Cell 14:465–477CrossRefPubMedGoogle Scholar
  125. 125.
    Shrode LD, Gan BS, D'Souza SJ, Orlowski J, Grinstein S (1998) Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage. Am J Physiol 275:C431–C439PubMedGoogle Scholar
  126. 126.
    Sweeney FP, Quinn PA, Ng LL (1997) Enhanced mitogen-activated protein kinase activity and phosphorylation of the Na+/H+ exchanger isoform-1 of human lymphoblasts in hypertension. Metabolism 46:297–302PubMedGoogle Scholar
  127. 127.
    Szabó EZ, Numata M, Shull GE, Orlowski J (2000) Kinetic and pharmacological properties of human brain Na+/H+ exchanger isoform 5 stably expressed in Chinese hamster ovary cells. J Biol Chem 275:6302–6307CrossRefPubMedGoogle Scholar
  128. 128.
    Szászi K, Grinstein S, Orlowski J, Kapus A (2000) Regulation of the epithelial Na+/H+ exchanger isoform by the cytoskeleton. Cell Physiol Biochem 10:265–272PubMedGoogle Scholar
  129. 129.
    Szászi K, Kurashima K, Kapus A, Paulsen A, Kaibuchi K, Grinstein S, Orlowski J (2000) RhoA and Rho kinase regulate the epithelial Na+/H+ exchanger NHE3—role of myosin light chain phosphorylation. J Biol Chem 275:28599–28606CrossRefPubMedGoogle Scholar
  130. 130.
    Szászi K, Kurashima K, Kaibuchi K, Grinstein S, Orlowski J (2001) Role of the cytoskeleton in mediating cAMP-dependent protein kinase inhibition of the epithelial Na+/H+ exchanger NHE3. J Biol Chem 276:40761–40768PubMedGoogle Scholar
  131. 131.
    Szászi K, Paulsen A, Szabó EZ, Numata M, Grinstein S, Orlowski J (2002) Clathrin-mediated endocytosis and recycling of the neural Na+/H+ exchanger NHE5 isoform: regulation by phosphatidylinositol 3′-kinase and the actin cytoskeleton. J Biol Chem 277:42623–42632CrossRefPubMedGoogle Scholar
  132. 132.
    Takahashi E, Abe J, Gallis B, Aebersold R, Spring DJ, Krebs EG, Berk BC (1999) p90RSK is a serum-stimulated Na+/H+ exchanger isoform-1 kinase—regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1. J Biol Chem 274:20206–20214CrossRefPubMedGoogle Scholar
  133. 133.
    Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, positions-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedGoogle Scholar
  134. 134.
    Tominaga T, Ishizaki T, Narumiya S, Barber DL (1998) p160ROCK mediates RhoA activation of Na-H exchange. EMBO J 17:4712–4722CrossRefPubMedGoogle Scholar
  135. 135.
    Touret N, Poujeol P, Counillon L (2001) Second-site revertants of a low-sodium-affinity mutant of the Na+/H+ exchanger reveal the participation of TM4 into a highly constrained sodium-binding site. Biochemistry 40:5095–5101CrossRefPubMedGoogle Scholar
  136. 136.
    Tse C-M, Ma AI, Yang VW, Watson AJM, Levine S, Montrose MH, Potter J, Sardet C, Pouysségur J, Donowitz M (1991) Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H+ exchanger. EMBO J 10:1957–1967PubMedGoogle Scholar
  137. 137.
    Tse C-M, Brant SR, Walker MS, Pouysségur J, Donowitz M (1992) Cloning and sequencing of a rabbit cDNA encoding an intestinal and kidney-specific Na+/H+ exchanger isoform (NHE-3). J Biol Chem 267:9340–9346PubMedGoogle Scholar
  138. 138.
    Tse C-M, Levine SA, Yun CHC, Montrose MH, Little PJ, Pouysségur J, Donowitz M (1993) Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropylamiloride-resistant epithelial Na+/H+ exchanger isoform (NHE-2). J Biol Chem 268:11917–11924PubMedGoogle Scholar
  139. 139.
    Tse C-M, Levine SA, Yun CHC, Khurana S, Donowitz M (1994) Na+/H+ exchanger-2 is an O-linked but not an N-linked sialoglycoprotein. Biochemistry 33:12954–12961PubMedGoogle Scholar
  140. 140.
    Vallon V, Schwark JR, Richter K, Hropot M (2000) Role of Na+/H+ exchanger NHE3 in nephron function: micropuncture studies with S3226, an inhibitor of NHE3. Am J Physiol 278:F375–F379Google Scholar
  141. 141.
    Vázquez CM, Coleto R, Zanetti R, Ruiz-Gutierrez V (1997) Increased Na+-H+ exchanger activity in the ileal brush-border membrane of spontaneously hypertensive rats. Cell Mol Life Sci 53:442–446CrossRefPubMedGoogle Scholar
  142. 142.
    Wakabayashi S, Fafournoux P, Sardet C, Pouysségur J (1992) The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls "H+-sensing". Proc Natl Acad Sci USA 89:2424–2428PubMedGoogle Scholar
  143. 143.
    Wakabayashi S, Bertrand B, Ikeda T, Pouysségur J, Shigekawa M (1994) Mutation of calmodulin-binding site renders the Na+/H+ exchanger (NHE1) highly H+-sensitive and Ca2+ regulation-defective. J Biol Chem 269:13710–13715PubMedGoogle Scholar
  144. 144.
    Wakabayashi S, Ikeda T, Iwamoto T, Pouysségur J, Shigekawa M (1997) Calmodulin-binding autoinhibitory domain controls "pH-sensing" in the Na+/H+ exchanger NHE1 through sequence-specific interaction. Biochemistry 36:12854–12861CrossRefPubMedGoogle Scholar
  145. 145.
    Wakabayashi S, Shigekawa M, Pouysségur J (1997) Molecular physiology of vertebrate Na+/H+ exchangers. Physiol Rev 77:51–74PubMedGoogle Scholar
  146. 146.
    Wakabayashi S, Pang T, Su X, Shigekawa M (2000) A novel topology model of the human Na+/H+ exchanger isoform 1. J Biol Chem 275:7942–7949CrossRefPubMedGoogle Scholar
  147. 147.
    Wakabayashi S, Hisamitsu T, Pang T, Shigekawa M (2003) Mutations of Arg440 and Gly455/Gly456 oppositely change pH sensing of Na+/H+ exchanger 1. J Biol Chem 278:11828–11835CrossRefPubMedGoogle Scholar
  148. 148.
    Wang D, Balkovetz DF, Warnock DG (1995) Mutational analysis of transmembrane histidines in the amiloride-sensitive Na+/H+ exchanger. Am J Physiol 269:C392–C402PubMedGoogle Scholar
  149. 149.
    Wang T, Hropot M, Aronson PS, Giebisch G (2001) Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron. Am J Physiol 281:F1117–F1122Google Scholar
  150. 150.
    Wang Z, Orlowski J, Shull GE (1993) Primary structure and functional expression of a novel gastrointestinal isoform of the rat Na/H exchanger. J Biol Chem 268:11925–11928PubMedGoogle Scholar
  151. 151.
    Wang ZH, Rabb H, Craig T, Burnham C, Shull GE, Soleimani M (1997) Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Kidney Int 51:1106–1115PubMedGoogle Scholar
  152. 152.
    Warnock DG, Yang W-C, Huang Z-Q, Cragoe EJ, Jr. (1988) Interactions of chloride and amiloride with the renal Na+/H+ antiporter. J Biol Chem 263:7216–7221PubMedGoogle Scholar
  153. 153.
    Watts BA III, Good DW (1994) Apical membrane Na+/H+ exchange in rat medullary thick ascending limb. pHi-dependence and inhibition by hyperosmolality. J Biol Chem 269:20250–20255PubMedGoogle Scholar
  154. 154.
    Watts BA, Good DW (1999) Hyposmolality stimulates apical membrane Na+/H+ exchange and HCO3 absorption in renal thick ascending limb. J Clin Invest 104:1593–1602PubMedGoogle Scholar
  155. 155.
    Weiner ID, Hamm LL (1990) Regulation of intracellular pH in the rabbit cortical collecting tubule. J Clin Invest 85:274–281PubMedGoogle Scholar
  156. 156.
    Weinman EJ, Steplock D, Wang Y, Shenolikar S (1995) Characterization of a protein cofactor that mediates protein kinase A regulation of the renal brush border membrane Na+-H+ exchanger. J Clin Invest 95:2143–2149PubMedGoogle Scholar
  157. 157.
    Weinman EJ, Steplock D, Shenolikar S (2001) Acute regulation of NHE3 by protein kinase A requires a multiprotein signal complex. Kidney Int 60:450–454CrossRefPubMedGoogle Scholar
  158. 158.
    Weisz OA (2003) Organelle acidification and disease. Traffic 4:57–64CrossRefPubMedGoogle Scholar
  159. 159.
    White BC, Sullivan JM, DeGracia DJ, O'Neil BJ, Neumar RW, Grossman LI, Rafols JA, Krause GS (2000) Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 179:1–33CrossRefPubMedGoogle Scholar
  160. 160.
    White RL, Doeller JE, Verselis VK, Wittenberg BA (1990) Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca++. J Gen Physiol 95:1061–1075PubMedGoogle Scholar
  161. 161.
    Williams KA (2000) Three-dimensional structure of the ion-coupled transport protein NhaA. Nature 403:112–115CrossRefPubMedGoogle Scholar
  162. 162.
    Winkel GK, Sardet C, Pouysségur J, Ives HE (1993) Role of cytoplasmic domain of the Na+/H+ exchanger in hormonal activation. J Biol Chem 268:3396–3400PubMedGoogle Scholar
  163. 163.
    Xu L, Mann G, Meissner G (1996) Regulation of cardiac Ca2+ release channel (ryanodine receptor) by Ca2+, H+, Mg2+, and adenine nucleotides under normal and simulated ischemic conditions. Circ Res 79:1100–1109PubMedGoogle Scholar
  164. 164.
    Yan WH, Nehrke K, Choi J, Barber DL (2001) The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor. J Biol Chem 276:31349–31356CrossRefPubMedGoogle Scholar
  165. 165.
    Yao H, Ma EB, Gu XQ, Haddad GG (1999) Intracellular pH regulation of CA1 neurons in Na+/H+ isoform 1 mutant mice. J Clin Invest 104:637–645PubMedGoogle Scholar
  166. 166.
    Yeo CJ, Barry MK, Gontarek JD, Donowitz M (1994) Na+/H+ exchange mediates meal-stimulated ileal absorption. Surgery 116:388–395PubMedGoogle Scholar
  167. 167.
    Yip KP, Tse CM, McDonough AA, Marsh DJ (1998) Redistribution of Na+/H+ exchanger isoform NHE3 in proximal tubules induced by acute and chronic hypertension. Am J Physiol 275:F565–F575PubMedGoogle Scholar
  168. 168.
    Yokoi S, Quintero FJ, Cubero B, Ruiz MT, Bressan RA, Hasegawa PM, Pardo JM (2002) Differential expression and function of Arabidopsis thaliana NHX Na+/H+ antiporters in the salt stress response. Plant J 30:529–539CrossRefPubMedGoogle Scholar
  169. 169.
    Yonemura S, Tsukita S (1999) Direct involvement of ezrin/radixin/moesin (ERM)-binding membrane proteins in the organization of microvilli in collaboration with activated ERM proteins. J Cell Biol 145:1497–1509CrossRefPubMedGoogle Scholar
  170. 170.
    Yu FH, Shull GE, Orlowski J (1993) Functional properties of the rat Na/H exchanger NHE-2 isoform expressed in Na/H exchanger-deficient Chinese hamster ovary cells. J Biol Chem 268:25536–25541PubMedGoogle Scholar
  171. 171.
    Yun CH, Oh S, Zizak M, Steplock D, Tsao S, Tse CM, Weinman EJ, Donowitz M (1997) cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci USA 94:3010–3015CrossRefPubMedGoogle Scholar
  172. 172.
    Yun CHC, Lamprecht G, Forster DV, Siebens AW (1998) NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeleton protein ezrin. J Biol Chem 273:25856–25863CrossRefPubMedGoogle Scholar
  173. 173.
    Zhang YB, Norian JM, Magyar CE, Holstein-Rathlou NH, Mircheff AK, McDonough AA (1999) In vivo PTH provokes apical NHE3 and NaPi2 redistribution and Na-K-ATPase inhibition. Am J Physiol 276:F711–F719PubMedGoogle Scholar
  174. 174.
    Zhao H, Wiederkehr MR, Fan LZ, Collazo RL, Crowder LA, Moe OW (1999) Acute inhibition of Na/H exchanger NHE-3 by cAMP—role of protein kinase A and NHE-3 phosphoserines 552 and 605. J Biol Chem 274:3978–3987CrossRefPubMedGoogle Scholar
  175. 175.
    Zizak M, Cavet ME, Bayle D, Tse CM, Hallen S, Sachs G, Donowitz M (2000) Na+/H+ exchanger NHE3 has 11 membrane spanning domains and a cleaved signal peptide: topology analysis using in vitro transcription/translation. Biochemistry 39:8102–8112CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  1. 1.Department of PhysiologyMcGill UniversityMontrealCanada
  2. 2.Programme in Cell BiologyThe Hospital for Sick Children Research InstituteTorontoCanada

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