Skip to main content
SpringerLink
Log in

Structure/function studies of the epithelial isoforms of the mammalian Na+/H+ exchanger gene family

  • Topical Review
  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Ahearn, G.A., Franco, P. 1990. Sodium and calcium share the electrogenic 2Na+-1H+ antiporter in crustacean antennal glands. Am. J. Physiol. 259:F758-F767

    Google Scholar 

  2. Alpers, R.J. 1990. Cell mechanisms of proximal tubule acidification. Physiol. Rev. 70:79–114

    Google Scholar 

  3. Aronson, P.S., Nee, J., Suhm, N.A. 1982. Modifer role of internal H+ inactivating the Na+/H+ exchange in renal microvillus membrane vesicles. Nature 299:161–163

    Google Scholar 

  4. Benos, D.J. 1988. Amiloride: chemistry, kinetics, and structure-activity relationships. In: Na+/H+ Exchange. S. Grinstein, editor. pp. 121–136. CRC, Boca Raton, FL

    Google Scholar 

  5. Berger, H. A., Travis, S. M., Welsh, M. J. 1993. Regulation of the cystic fibrosis transmembrane conductance regulator Cl− channel by specific protein kinases and protein phosphatases. J. Biol. Chem. 268:2037–2047

    Google Scholar 

  6. Biemesderfer, D., Reilly, R., Exner, M., Igarashi, P., Aronson, P. 1992. Immunocytochemical characterization of Na+/H+ exchanger isoform NHE1 in rabbit kidney. Am. J. Physiol. 263:F833-F840

    Google Scholar 

  7. Borgese, F., Sardet, C., Cappadoro, M., Pouyssegur, J., Motais, R. 1992. Cloning and expressing a cAMP-activated Na+/H+ exchanger: evidence that the cytoplasmic domain mediates hormonal regulation. Proc. Natl. Acad. Sci. USA 89:6768–6769

    Google Scholar 

  8. Boron, W.F. 1983. Transport of H+ and ionic weak acids and bases. J. Membrane Biol. 72:1–16

    Google Scholar 

  9. Brant, S.R., Bernstein, M., Wasmuth, J.J., Taylor, E.W., McPherson, J.D., Li, X., Walker, S.A., Pouyssegur, J., Donowitz, M., Tse, C.M., Jabs, E.W. 1993. Physical and genetic mapping of a human apical epithelial Na+/H+ exchanger (NHE-3) isoform to chromosome 5p15.3. Genomics 15:668–672

    Google Scholar 

  10. Casavola, V., Guerra, L., Helmle-Kolb, C., Reshkin, S., Murer, H. 1992. Na+/H+ exchange in A6 cells: polarity and vasopressin regulation. J. Membrane Biol. 130:105–114

    Google Scholar 

  11. Casavola, V., Helmle-Kolb, C., Montrose, M.H., Murer, H. 1991. Polarized expression of Na+/H+ exchange activities in clonal LLC-PK1 cells (Clone4 and PKE20) cells. I. Basic characterization. Pfluegers Arch. 418:276–283

    Google Scholar 

  12. Casavola, V., Helmle-Kolb, C., Murer, H. 1989. Separate regulatory control of apical and basolateral Na+/H+ exchange in renal epithelial cells. Biochem. Biophys. Res. Commun. 165:833–837

    Google Scholar 

  13. Casavola, V., Reshkin, S.J., Murer, H., Helmle-Kolb, C. 1992. Polarized expression of Na+/H+ exchange activity in clonal LLC-PK1 cells (Clone4 and PKE20) cells: Hormonal regulation. Pfluegers Arch. 420:282–289

    Google Scholar 

  14. Chambard, J.C., Paris, S., L'Allemain, G., Pouyssegur, J. 1987. Two growth factor signaling pathways in fibroblasts distinguished by pertussis toxin. Nature 326:800–803

    Google Scholar 

  15. Charney, A.N., Kinsey, M.D., Meyers, L., Giannella, R.A., Gots, R. 1978. Na-K activated adenosine triphosphatase and intestinal electrolyte transport—effect of adrenal steroids. J. Clin. Invest. 56:653–660

    Google Scholar 

  16. Clark, J.D., Limbird, L.L. 1991. Na+/H+ exchanger subtypes: a predictive review. Am. J. Physiol. 261:G945-G953

    Google Scholar 

  17. Cohen, M.E., Reinlib, L., Gorelick, F., Rys-Sikora, K., Tse, M., Rood, R.P., Czernik, A.S., Sharp, C.W.G., Donowitz, M. 1990. Rabbit ileal villus cell brush border Na+/H+ exchange is regulated by Ca2+/calmodulin dependent protein kinase II, a brush border membrane protein. Proc. Natl. Acad. Sci. USA 87:8990–8994

    Google Scholar 

  18. Cohen, M.E., Wesolek, J., McCullen, J., Pandol, S., Rood, R.P., Sharp, C.W.G., Donowitz, M. 1991. Carbachol and elevated Ca2+-induced translocation of functionally active protein kinase C to the brush border of ileal Na+ absorbing cells. J. Clin. Invest. 88:855–863

    Google Scholar 

  19. Counillon, L., Franchi, A., Pouyssegur, J. 1993. A point mutation of the Na+/H+ exchanger gene (NHE-1) and amplification of the mutated allele confer amiloride-resistance upon chronic acidosis. Proc. Natl. Acad. Sci. USA 90:4508–4512

    Google Scholar 

  20. Donowitz, M., Cheng, H.Y., Sharp, G.W.G. 1986. Effects of phorbol esters on Na and Cl transport in rat colon. Am. J. Physiol. 251:509–517

    Google Scholar 

  21. Donowitz, M., Cohen, M.E., Gould, M., Sharp, G.W.G. 1989. Elevated intracellular Ca2+ acts through protein kinase C to regulate rabbit ileal NaCl absorption: Evidence for sequential control by Ca2+/calmodulin and protein kinase C. J. Clin. Invest. 83:1953–1962

    Google Scholar 

  22. Donowitz, M., Welsh, M.J. 1987. Regulation of mammalian small intestinal electrolyte transport. In: Physiology of the Gastrointestinal Tract. L.R. Johnson, editor. pp. 1351–1388. Raven, New York

    Google Scholar 

  23. Donowitz, M., Wicks, J., Madara, J.L., Sharp, G.W.G. 1985. Studies on the role of calmodulin in Ca2+ regulation of rabbit ileal Na+ and Cl− transport. Am. J. Physiol. 248:726–740

    Google Scholar 

  24. Emmer, E., Rood, R.P., Wesokel, J.H., Cohen, M.E., Braithwaite, R.S., Sharp, G.W.G., Murer, H., Donowitz, M. 1989. The role of calcium and calmodulin in the regulation of the rabbit ileal brush border membrane Na+/H+ antiporter. J. Membrane Biol. 108:207–215

    Google Scholar 

  25. Engelman, D.M., Goldman, A., Steitz, T.A. 1982. The identification of helical segments in the polypeptide chain of Bacteriorhodopsin. Methods Enzymol. 88:81–89

    Google Scholar 

  26. Fliegel, L., Haworth, R.S., Dyck, J.R.B. 1993. Characterization of the placental brush border membrane Na+/H+ exchanger: Identification of thio-dependent transition in apparent molecular size. Biochem. J. 289:101–107

    Google Scholar 

  27. Fliegel, L., Sardet, C., Pouyssegur, J., Barr, A. 1991. Identification of the protein and cDNA of the cardiac Na+/H+ exchanger. FEBS Lett. 279:25–29

    Google Scholar 

  28. Franchi, A., Cragoe, E., Pouyssegur, J. 1986. Isolation and properties of fibroblast mutants overexpressing an altered Na+/H+ antiporter. J. Biol. Chem. 261:14614–14620

    Google Scholar 

  29. Franchi, A., Perucca-Lostanten, D., Pouyssegur, J. 1986. Functional expression of a human Na+/H+ antiporter gene transfected into antiporter-deficient mouse L cells. Proc. Natl. Acad. Sci. USA 83:9388–9392

    Google Scholar 

  30. Freiberg, J.M., Kinsella, J., Sacktor, B. 1982. Glucocorticoids increase the Na+/H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles. Proc. Natl. Acad. Sci. USA 9:4932–4936

    Google Scholar 

  31. Grinstein, S., Rotin, D., Marson, M.J. 1989. Na+/H+ exchanger and growth factor-induced cytosolic pH change. Role in cellular proliferation. Biochim. Biophys. Acta 988:73–91

    Google Scholar 

  32. Grinstein, S., Smith, I.D. 1987. Asymmetry of the Na+/H+ antiport of dog red cell ghosts, sidedness of inhibition by amiloride. J. Biol. Chem. 262:9088–9092

    Google Scholar 

  33. Grinstein, S., Woodside, M., Sardet, C., Pouyssegur, J., Rotin, D. 1992. Activation of the Na+/H+ antiporter during cell volume regulation. Evidence for a phosphorylation-independent mechanism. J. Biol. Chem. 267:23823–23828

    Google Scholar 

  34. Hanley, R.M., Shenolikar, S., Pollack, J., Steplock, D., Weinman, E.J. 1990. Identification of calcium/calmodulin multifunctional protein kinase II in rabbit kidney. Kidney Int. 38:63–66

    Google Scholar 

  35. Helme-Kolb, C., Montrose, M.H., Murer, H. 1990. Parathyroid hormone regulation of Na+/H+ exchange in opossum kidney cells. Polarity and mechanisms. Pfluegers Arch. 416:615–623

    Google Scholar 

  36. Hildebrandt, F., Pizzona, J.H., Reilly, R.F., Rebouc, N.A., Sardet, C., Pouyssegur, J., Slayman, C.N., Aronson, P.S., Igarashi, P. 1991. Cloning of cDNA encoding a rabbit renal Na+/H+ exchanger—tissue distribution and comparison to the human sequence. Biochim. Biophys. Acta 1129:105–108

    Google Scholar 

  37. Jia, Z.P., McCullough, N., Martel, R., Hemmingsen, S.K., Young, P.G. 1992. Gene amplification at a locus encoding a putative Na+/H+ antiporter confers sodium and lithium tolerance in fission yeast. EMBO. J. 11:1631–1640

    Google Scholar 

  38. Karpel, R., Alon, T., Glaser, G., Schuldiner, S., Padan, E. 1991. Expression of sodium proton antiporter (NhaA) in Escherichia coli as induced by Na+ and Li+ ions. J. Biol. Chem. 265:20297–20302

    Google Scholar 

  39. Knickelbein, R.G., Aronson, P.S., Dobbins, J.W. 1990. Characterization of Na+/H+ exchangers on villus cells in rabbit ileum. Am. J. Physiol. 259:G802-G806

    Google Scholar 

  40. Kopito, R., Lodish, H.F. 1985. Primary structure and transmembrane orientation of the murine anion exchange protein. Nature 316:234–238

    Google Scholar 

  41. Krapf, R., Alpern, R.J. 1993. Cell pH and transepithelial H/HCO3 transport in renal proximal tubule. J. Membrane Biol. 131:1–10

    Google Scholar 

  42. Krapf, G., Solioz, M. 1991. Na+/H+ antiporter in RNA expression in single nephron segments of rat kidney cortex. J. Clin. Invest. 88:783–788

    Google Scholar 

  43. Kyte, J., Doolittle, R.F. 1992. A simple method for displaying the hydrophobic character of a protein. J. Mol. Biol. 157:103–132

    Google Scholar 

  44. L'Allemain, G., Paris, S., Pouyssegur, J. 1984. Growth factors action and intracellular pH regulation in fibroblasts. Evidence for a major role of the Na+/H+ antiporter. J. Biol. Chem. 259:5809–5815

    Google Scholar 

  45. L'Allemain, G., Seuwen, K., Velu, T., Pouyssegur, J. 1989. Signal transduction in hamster fibroblasts overexpressing the human EGF receptor. Growth Factors 1:311–321

    Google Scholar 

  46. Levine, S., Yun, C., Montrose M, Tse C.M., Donowitz, M. Detailed characterization of three cloned mammalian Na+/H+ exchangers stably expressed in a fibroblast cell line. (in preparation)

  47. Levine, S., Yun, C., Montrose, M., Tse, C.M., Donowitz, M. 1993. Plasma membrane sorting and C kinase regulation of three cloned Na+/H+ exchangers expressed in an epithelial cell line, Caco-2. Gastroenterology 104:259A

  48. Little, P.J., Weissberg, P.L., Cragoe, E.J., Bobik, A. 1988. Dependence of Na+/H+ antiporter in cultured rat aortic smooth muscle on calmodulin, calcium, and ATP. Evidence for the involvement of calmodulin-dependent kinases. J. Biol. Chem. 263:16780–16786

    Google Scholar 

  49. Marra, M.A., Prasad, S.S., Baillie, D.L. 1993. Molecular analysis of two genes between let-56 in the unc-22(IV) region of Caenorhabditis elegans. Mol. Gen. Genet. (in press).

  50. Mattei, M.G., Sardet, C., Franchi, A., Pouyssegur, J. 1988. The human amiloride-sensitive Na+/H+ antiporters: localization to chromosome 1 by in situ hybridization. Cytogenet. Cell. Censt. 48:6–8

    Google Scholar 

  51. Miller, R.T., Pollock, A.S. 1987. Modification of the internal pH sensitivity of the Na+/H+ antiporter by parathyroid hormone in a cultured renal cell line. J. Biol. Chem. 262:9115–9210

    Google Scholar 

  52. Montrose, M.H., Murer, H. 1990. Polarity and kinetics of Na+/H+ exchange in cultured opossum kidney cells. Am. J. Physiol. 259:C121-C133

    Google Scholar 

  53. Morell, G., Steplock, D., Shenolikar, S., Weinman, E.J. 1990. Identification of a putative Na+/H+ exchanger regulatory co-factor in rabbit renal BBM. Am. J. Physiol. 259:F867-F871

    Google Scholar 

  54. Mrkic, B., Forgo, J., Murer, H., Helmle-Kolb, C. 1992. Apical and basolateral Na/H exchange in cultured murine proximal tubule cells (MCT): Effect of parathyroid hormone (PTH). J. Membrane Biol. 130:205–217

    Google Scholar 

  55. Mrkic, B., Tse, C.M., Forgo, J., Helmle-Kolb, C., Donowitz, M. Murer, H. 1993. Identification of PTH-responsive Na+/H+ exchanger—isoforms in a rabbit proximal tubule cell line (RKPC-2). Pfluegers Arch. (in press)

  56. Murer, H., Hopfer, U., Kinne, R. 1976. Sodium, proton antiport in brush border membranes isolated from rat small intestine and kidney. Biochem. J. 154:597–602

    Google Scholar 

  57. Nicholl, D.A., Longoni, S., Philipson, K.D. 1990. Molecular cloning and functional expression of the cardiac sarcolemmal Na-Ca exchanger. Science 250:562–565

    Google Scholar 

  58. Opleta-Madsen, K., Hardin, J., Gall, D.G. 1991. Epidermal growth factor up regulates intestinal electrolyte and nutrient transport. Am. J. Physiol. 260:G807-G814

    Google Scholar 

  59. Orlowski, J., Kandasamy, R.A., Shull, G.E. 1992. Molecular cloning of putative members of the Na+/H+ exchanger gene family. J. Biol. Chem. 267:9332–9339

    Google Scholar 

  60. Pinner, E., Kotler, Y., Padan, E., Schuldiner, S. 1993. Physiological role of NhaB, specific Na+/H+ antiporter Escherichia coli. J. Biol. Chem. 268:1729–1734

    Google Scholar 

  61. Pouyssegur, 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 81:4833–4837

    Google Scholar 

  62. Rajendran, V.M., Binder, H.J. 1990. Characterization of Na+/H+ exchanger in apical membrane vesicles of rat colon. J. Biol. Chem. 265:8408–8414

    Google Scholar 

  63. Raley-Susman, K.M., Cragoe, E.J., Jr., Sapolsky, R.M., Kopito, R.R. 1991. Regulation of intracellular pH in cultured hippocampal neurons by an amiloride-insensitive Na+/H+ exchanger. J. Biol. Chem. 266:2739–2745

    Google Scholar 

  64. Reidel, B.D., Kikuchi, K., Ghisan, F.K. 1989. Ileal brush border Na+/H+ exchange: the effect of epidermal growth factor and mechanism of action. Gastroenterology 96:415A

    Google Scholar 

  65. Reilly, R.F., Hildebrandt, F., Biemesderfer, D., Sardet, C., Pouyssegur, J., Aronson, P.S., Slayman, C.N., Igarashi, P. 1991. cDNA cloning and immunolocalization of a Na+/H+ exchange in LLC-PK1 renal epithelial cells. Am. J. Physiol. 261:F1088-F1094

    Google Scholar 

  66. Reuss, L., Petersen, K.U. 1985. Cyclic AMP inhibits Na+/H+ exchange at the apical membrane of Necturus gallbladder epithelium. J. Gen. Physiol. 85:409–429

    Google Scholar 

  67. Sardet, C., Counillon, L., Franchi, A., Pouyssegur, J. 1990. Growth factors induce phosphorylation of the Na+/H+ antiporter, a glycoprotein of 110 kD. Science 247:723–726

    Google Scholar 

  68. Sardet, C., Fafournox, P., Pouyssegur, J. 1991. Thrombin epidermal growth factor, and okadaic acid activate the Na+/H+ exchanger, NHE1, by phosphorylating a set of common sites. J. Biol. Chem. 266:19166–19171

    Google Scholar 

  69. Sardet, C., Franchi, A., Pouyssegur, J. 1989. Molecular cloning, primary structure and expression of the human growth factor—activatable Na+/H+ antiporter. Cell 56:271–280

    Google Scholar 

  70. Sellin, J.H., Field, M. 1981. Physiologic and pharmacologic effects of glucocorticoids on ion transport across rabbit ileal mucosa in vitro. J. Clin. Invest. 67:770–778

    Google Scholar 

  71. Takaichi, K., Wang, D., Blakovets, D.F., Warnock, D.G. 1992. Cloning, sequencing, and expression of Na+/H+ antiporter cDNAs from human tissues. Am. J. Physiol. 262:C1069-C1076

    Google Scholar 

  72. Tse, C.M., Brant, S.R., Walker, S., Pouyssegur, J., Donowitz, M. 1992. Cloning and sequencing a rabbit cDNA encoding an intestinal and kidney-specific Na+/H+ exchanger isoform (NHE-3). J. Biol. Chem. 267:9340–9346

    Google Scholar 

  73. Tse, C.M., Levine, S.A., Yun, C.H., Brant, S.R., Pouyssegur, J., Montrose, M.H., Donowitz, M. 1993. Functional characteristics of a cloned epithelial Na+/H+ exchanger (NHE3): resistance to amiloride and inhibition of protein kinase C. Proc. Natl. Acad. Sci. USA (in press)

  74. Tse, C.M., Levine, S.A., Yun, C.H.C., Montrose, M.H., Little, P.J., Pouyssegur, J., Donowitz, M. 1993. Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropyl amiloride resistant epithelial Na+/H+ exchanger isoform (NHE-2). J. Biol. Chem. 268: 11917–11924

    Google Scholar 

  75. Tse, C.M., Ma, A.I., Yang, V.W., Watson, A.J.M., Potter, J., Sardet, C., Pouyssegur, J., Donowitz, M. 1991. Molecular cloning of cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H+ exchanger. EMBO. J. 10:1957–1967

    Google Scholar 

  76. Vigne, P., Frelin, C., Lazdunski, M. 1985. The Na+/H+ antiporter is activated by serum and phorbol ester in proliferating myoblasts but not in differentiated myotubes. Properties of the activation process. J. Biol. Chem. 260:8008–8013

    Google Scholar 

  77. Wakabayashi, S., Fafournoux, P., Sardet, C., Pouyssegur, J. 1992. The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls H+ sensing. Proc. Natl. Acad. Sci. USA 89:2424–2428

    Google Scholar 

  78. Wakabayashi, S., Sardet, C., Fafournoux, P., Counillon, L., Meloche, S., Pages, G., Pouyssegur, J. 1992. Structure function of the growth factor-activatable Na+/H+ exchange (NHE-1). Rev. Physiol. Biochem. Pharmacol. 119:157–186

    Google Scholar 

  79. Watson, A.J.M., Levine, S., Donowitz, M., Montrose, M.H. 1991. Kinetics and regulation of polarized Na+/H+ exchanger from Caco-2 cells, a human intestinal cell line. Am. J. Physiol. 261:G229-G238

    Google Scholar 

  80. Watson, A.J.M., Levine, S., Donowitz, M., Montrose, M.H. 1992. Serum regulates Na+/H+ exchange in Caco-2 cells by a mechanism which is dependent on F-actin. J. Biol. Chem. 267:956–962

    Google Scholar 

  81. Weinman, E.J., Dubinsky, W.P., Dinh, Q., Steplock, D., Shenolikar, S. 1989. Effect of limited trypsin digestion on the renal Na+/H+ exchanger and its regulation by cAMPdependent protein kinase. J. Membrane Biol. 109:233–241

    Google Scholar 

  82. Weinman, E.J., Dubinsky, W., Shenolikar, S. 1989. Regulation of the renal Na+/H+ exchanger by protein phosphorylation. Kidney Int. 36:519–525

    Google Scholar 

  83. Weinman, E.J., Steplock, D., Bui, G., Yuan, N., Shenolikar, S. 1990. Regulation of renal Na+/H+ exchanger by cAMPdependent protein kinase. Am. J. Physiol. 258:F1254-F1258

    Google Scholar 

  84. Yun, C.H.C., Little, P.J., Tse, C.M., Pouyssegur, J., Donowitz, M. 1993. Amino acid 143 in membrane spanning domain 4 determines the sensitivity to amiloride in a cloned epithelial Na+/H+ exchanger, NHE-2. Biochem. Biophys. Res. Comm. (in press)

  85. Yun, C.H., Gurubhagavatula, S., Levine, S.A., Montgomery, J.M., Brant, S.R., Cohen, M.E., Pouyssegur, J., Tse, C.M., Donowitz, M. 1993. Glucocorticoid stimulation of ileal Na+ absorptive cell brush border Na+/H+ exchange and association with an increase in message for NHE-3, an epithelial isoform Na+/H+ exchanger. J. Biol. Chem. 268:206–211

    Google Scholar 

  86. Yusufi, A.N.K., Szczeparska-Konkel, M., Dousa, T.P. 1988. Role of N-linked oligosaccharides in the transport activity of the Na+/H+ antiporter in rat renal brush border membrane. J. Biol. Chem. 263:13683–13691

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and Physiology, GI Unit, The Johns Hopkins University School of Medicine, 21205, Baltimore, Maryland

    Ming Tse, Sue Levine, Chris Yun, Steve Brant & Mark Donowitz

  2. Department of Biochemistry, University of Nice, Nice, France

    Laurent T. Counillon & Jacques Pouyssegur

Authors
  1. Ming Tse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sue Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chris Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steve Brant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laurent T. Counillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jacques Pouyssegur
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Donowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tse, M., Levine, S., Yun, C. et al. Structure/function studies of the epithelial isoforms of the mammalian Na+/H+ exchanger gene family. J. Membarin Biol. 135, 93–108 (1993). https://doi.org/10.1007/BF00231435

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00231435

Key words

Search

Navigation