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Molecular and Cellular Biochemistry

, Volume 59, Issue 1–2, pp 11–32 | Cite as

Mechanism, regulation and physiological significance of the loop diuretic-sensitive NaCl/KCl symport system in animal cells

  • Milton H. SaierJr.
  • David A. Boyden
Review

Summary

Investigations in numerous laboratories have characterized a salt transport system, present in many animal cell types, which catalyzes the transmembrane transport of NaCl and KCI in a tightly coupled process. The system is inhibited by loop diuretics such as furosemide and bumetanide. This transport system has been designated the loop diuretic-sensitive NaCl/KCl symporter. It has been implicated in transepithelial salt secretion and absorption as well as in cell volume regulation, and it may be defective in patients suffering from essential hypertension. This review serves to evaluate research conducted to date regarding the mechanism, mode of regulation, and physiological significance of the transport system.

Ion binding specificities and absolute binding constants for all three naturally occurring ions have been determined in one cell system, the MDCK kidney epithelial cell line. In that same cell line, substrate binding was shown to exhibit apparent positive cooperativity. Although a few reports suggest unidirectional transport of ions via this system under certain conditions, the consensus of reports indicates fully reversible, bidirectional salt transport with the direction of net flux determined by the magnitudes of the gradients of the three transported ions. Growth of cells in media containing a low concentration of K+ (<0.25 mM) allows selection of mutants lacking or defective in the symporter.

Kinetic analyses with the MDCK cell line have shown that the symporter catalyzes accelerative exchange transport. However, exchange transport of one ion in the absence of one of the other two ionic substrates has not been documented. Comparison with other well-characterized transmembrane transport systems has shown that the characteristics of the NaCl/KCl symporter most resemble those of two-species facilitators (chemiosmotically-coupled symporters) found in prokaryotes and eukaryotes alike. These two-species facilitators consist of a single transmembrane protein and may function by a carrier-type mechanism as originally proposed by Peter Mitchell. A molecular model for the NaCl/KCl symporter is presented and discussed.

Activation of symport activity requires ATP and probably occurs by a protein kinase-catalyzed mechanism. In some cell types activation is cyclic AMP dependent. ATP hydrolysis is not stoichiometric with transport. Phosphorylation of an integral membrane protein with an apparent size of 240 000 daltons correlates with activation of transport. It is postulated that this protein is the loop diuretic-sensitive NaCl/KCl symporter.

Keywords

MDCK Cell Bumetanide Transmembrane Transport Kidney Epithelial Cell Salt Transport 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Rindler, M. J., McRoberts, J. A. and Saier, M. H., Jr., 1982. J. Biol. Chem. 257: 2254–2259.Google Scholar
  2. 2.
    McRoberts, J. A., Erlinger, S., Rindler, M. J. and Saier, M. H., Jr., 1982. J. Biol. Chem. 257: 2260–2266.Google Scholar
  3. 3.
    Geck, P., Pietrzyk, C., Burckhardt, B.-C., Pfeiffer, B. and Heinz, E., 1980. Biochim. Biophys. Acta 600: 432–447.Google Scholar
  4. 4.
    Haas, Mark, Schmidt, W. F. and McManus, T. J., 1982. J. Gen. Physiol. 80: 125–147.Google Scholar
  5. 5.
    Frizzell, R. A., Field, M. and Schultz, S. G., 1979. Am. J. Physiol. 236(1): F1-F8.Google Scholar
  6. 6.
    Musch, M. A., Orellana, S. A., Kimberg, L. S., Field, M., Halm, D. R., Krasny, E. J., Jr. and Frizzell, R. A., 1982. Nature 300: 351–353.Google Scholar
  7. 7.
    Dills, S. S., Apperson, A., Schmidt, M. R. and Saier, M. H., Jr., 1980. Microbiol. Rev. 44: 385–418.Google Scholar
  8. 8.
    Saier, M. H., Jr., 1980. J. Supramol. Struc. 14: 281–294.Google Scholar
  9. 9.
    Saier, M. H., Jr., 1982. Membranes and Transport, (Martonosi, A., ed.), Vol. 2, pp. 27–32, Plenum Press, New York.Google Scholar
  10. 10.
    Gargus, J. J., Miller, I. L., Slayman, C. W. and Adelberg, E. A., 1978. Proc. Natl. Acad. Sci. U.S.A. 75: 5589–5593.Google Scholar
  11. 11.
    Jayme, D. W., Adelberg, E. A. and Slayman, C. W., 1981. Proc. Natl. Acad. Sci. U.S.A. 78: 1057–1061.Google Scholar
  12. 12.
    Kregenow, F. M., 1981. Ann. Rev. Physiol. 43: 493–505.Google Scholar
  13. 13.
    Hoffmann. E. K., 1978. Osmotic and Volume Regulation (Jorgensen, C. B. and Rodhauge, E. S., eds.), pp. 397–412.Google Scholar
  14. 14.
    Adragna, N., Canessa, M., Bize, I., Garay, R. and Tosteson, D. C., 1980. Fed. Proc. 39: 1237.Google Scholar
  15. 15.
    Garay, R., Adragna, N., Canessa, M. and Tosteson, D., 1981. Membrane Biol. 62: 169–174.Google Scholar
  16. 16.
    Canessa, M., Bize, I., Adragna, N. and Tosteson, D., 1982. J. Gen. Physiol. 80: 149–168.Google Scholar
  17. 17.
    Lew, V. L., Mualiem, S. and Seymour, C. A., 1980. Nature 296: 742–744.Google Scholar
  18. 18.
    Ernst, M. and Adams, G., 1981. J. Membrane Biol. 61: 155–172.Google Scholar
  19. 19.
    Armstrong, C. M., Swenson, R. P., Jr. and Taylor, S. R., 19. J. Gen. Physiol. 80: 603–682.Google Scholar
  20. 20.
    Rindler, M. J., Taub, M. and Saier, M. H., Jr., 1979. J. Biol. Chem. 254: 11431–11439.Google Scholar
  21. 21.
    Taub, M. and Saier, M. H., Jr., 1979. J. Biol. Chem. 254: 11440–11444.Google Scholar
  22. 22.
    Rindler, M. J. and Saier, M. H., Jr., 1981. J. Biol. Chem. 256: 10820–10825.Google Scholar
  23. 23.
    Christensen, H. N., 1982. Physiol. Rev. 62: 1193–1233.Google Scholar
  24. 24.
    Gardner, J. D., Jow, N. and Kiino, D. R., 1975. J. Biol. Chem. 250: 1176–1185.Google Scholar
  25. 25.
    Gardner, J. D., Kiino, D. R., Jow, N. and Aurbach, G. D., 1975. J. Biol. Chem. 250: 1164–1175.Google Scholar
  26. 26.
    Gardner, J. D., Mensh, R. S., Kiino, D. R. and Aurbach, G. D., 1975. J. Biol. Chem. 250: 1155–1263.Google Scholar
  27. 27.
    Rudolph, S. A., Schafer, D. E. and Greengard, P., 1977. J. Biol. Chem. 252: 7132–7139.Google Scholar
  28. 28.
    Alper, S. L., Beam, K. G. and Greengard, P., 1980. J. Biol. Chem. 255: 4864–4871.Google Scholar
  29. 29.
    Alper, S. L., Palfrey, H. C., DeRiemer, S. A. and Greengard, P., 1980. J. Biol. Chem. 255: 11029–11039.Google Scholar
  30. 30.
    Rudolph, S. A. and Greengard, P., 1980. J. Biol. Chem. 255: 8534–8540.Google Scholar
  31. 31.
    Rindler, M. J., Chuman, L. M., Shaffer, L. and Saier, M. H., Jr., 1979. J. Cell Biol. 81: 635–648.Google Scholar
  32. 32.
    Erlinger, S. and Saier, M. H., Jr., 1982. In Vitro 18: 196–202.Google Scholar
  33. 33.
    Saier, M. H., Jr., Erlinger, S. and Boerner, Paula, 1982. Membranes in Growth and Development, pp. 569–597, Alan R. Liss, Inc., New York.Google Scholar
  34. 34.
    Boerner, P. and Saier, M. H., Jr., 1982. Cold Spring Harbor Conferences on Cell Proliferation (Sato, G. H., Pardee, A. B. and Sirbasku, D. A., eds.), 9: 555–565.Google Scholar
  35. 35.
    Boerner, P. and Saier, M. H., Jr., 1982. J. Cell. Physiol. 113: 240–246.Google Scholar
  36. 36.
    Anholt, R., Lindstrom, J. and Montal, M., 1983. The Enzymes of Biological Membranes (A. Martinosi, ed.), Vol. 7, Plenum Press, New York, in press.Google Scholar
  37. 37.
    Catterall, W. A., 1982. T.I.N.S. 9: 303–306.Google Scholar
  38. 38.
    Saier, M. H., Jr. and Stiles, C. D., 1975. Molecular Dynamics in Biological Membranes, Vol. 22, Springer-Verlag, New York.Google Scholar
  39. 39.
    Leonard, J. E., Lee, C., Apperson, A., Dills, S. S. and Saier, M. H., Jr., 1981. Organization of Prokaryotic Cell Membranes (Gosh, B. K., ed.), pp. 1–52, CRC Press.Google Scholar
  40. 40.
    Heller, K. B., Lin, E. C. C. and Wilson, T. H., 1980. J. Bacteriol. 144: 274–278.Google Scholar
  41. 41.
    Baldwin, S. A. and Lienhard, G. E., 1981. T.I.N.S. 6: 208–211.Google Scholar
  42. 42.
    Knauf, P. A., 1979. Curr. Top. Memb. Transp. 12: 249–363.Google Scholar
  43. 43.
    Aquila, H., Eiermann, W., Babel, W. and Klingenberg, M., 1978. Eur. J. Biochem. 85: 549–560.Google Scholar
  44. 44.
    Newman, M. J., Foster, D. L., Wilson, T. H. and Kaback, H. R., 1981. J. Biol. Chem. 256: 11804–11808.Google Scholar
  45. 45.
    Tsuchiya, T., Ottina, K., Moriyama, Y., Newman, M. J. and Wilson, T. H., 1982. J. Biol. Chem. 257: 5125–5128.Google Scholar
  46. 46.
    Booth, I. R. and Hamilton, W. A., 1980. Microorganisms and Nitrogen Sources (Payne. J. W., ed.), John Wiley and Sons.Google Scholar
  47. 47.
    Guidott, G. G., Borghetti, A. F. and Gazzola, G. C., 1978. Biochim. Biophys. Acta 515: 329–366.Google Scholar
  48. 48.
    Jorgensen, P. L., 1982. Biochim. Biophys. Acta 694: 27–68.Google Scholar
  49. 49.
    deMeis, L. and Vianna, A. L., 1979. Ann. Rev. Biochem. 48: 275–292.Google Scholar
  50. 50.
    Muñoz, E., 1982. Biochim. Biophys. Acta 650: 233–265.Google Scholar
  51. 51.
    Higgins, C. F., Haag, P. D., Nikaido, K., Ardeshir, F., Garcia, G. and Ames, G. F.-L., 1982. Nature 298: 723–727.Google Scholar
  52. 52.
    Stoeckenius, W., Lozier, R. H. and Bogomolni, R. A., 1978. Biochim. Biophys. Acta 505: 215–278.Google Scholar
  53. 53.
    Kadenbach, B. and Merle, P., 1981. FEBS Lett. 135: 1–11.Google Scholar
  54. 54.
    Lee, C. A. and Saier, M. H., Jr., 1983. J. Biol. Chem. 258: 10761–10767.Google Scholar
  55. 55.
    Erni, B., Trachsel, H., Postma, P. W. and Rosenbusch, J. P., 1982. J. Biol. Chem. 257: 13726–13730.Google Scholar
  56. 56.
    Saier, M. H., Jr., 1979. Microbiology, pp. 72–75. Am. Soc. Microbiol., Washington, D.C.Google Scholar
  57. 57.
    Kaczorowski, G. and Kaback, H. R., 1979. Biochemistry 18: 3691–3697.Google Scholar
  58. 58.
    West, I. C. and Wilson, T. H., 1973. Biochem. Biophys. Res. Commun. 50: 551–558.Google Scholar
  59. 59.
    Mitchell, P., 1981. Membrane Transport and Metabolism (Kleinzeller, A. and Kotzyk, A., eds.), Academic Press, New York.Google Scholar
  60. 60.
    Stein, W. D., 1968. The Movements of Molecules Across Cell Membranes, Academic Press, New York.Google Scholar
  61. 61.
    Pressman, B. and Haynes, D. H., 1969. The Molecular Basis of Membrane Function (Tosteson, D. C., ed.), pp. 221–248, Prentice Hall, Englewood Cliffs, New Jersey.Google Scholar
  62. 62.
    Nilsen-Hamilton, M. and Hamilton, R. T., 1979. Biochim. Biophys. Acta 588: 322–331.Google Scholar
  63. 63.
    Kregenow, F. M., 1977. Osmotic and Volume Regulation (Jorgensen, C. B. and Skadhauge, E., eds.), pp. 379–391, Academic Press, New York.Google Scholar
  64. 64.
    Spring, K. R. and Ericson, A-C., 1982. J. Membrane Biol. 69:167–176.Google Scholar
  65. 65.
    Garay, R. P., Dagher, G., Pernollet, M-G., Devynck, M-A. and Meyer, P., 1980. Nature 284: 281–283.Google Scholar
  66. 66.
    Hamlyn, J. M., Ringel, R., Schaeffer, J., Levinson, P. D., Hamilton, B. P., Kowarski, A. A. and Blaustein, M. P., 1982. Nature 300: 650–652.Google Scholar
  67. 67.
    Blaustein, M. P., 1977. Am. J. Physiol. 232: C165.Google Scholar
  68. 68.
    Davidson, J. S., Opie, L. H. and Keding, B., 1982. Br. Med. J. 284: 539–541.Google Scholar
  69. 69.
    Aiton, J. F., Brown, C. D. A., Ogden, P. and Simmons, N. L., 1982. J. Membrane Biol. 65: 99–109.Google Scholar
  70. 70.
    Simmons, N. L., 1981. Biochim. Biophys. Acta 646: 231–242.Google Scholar

Copyright information

© Martinus Nijhoff Publishers 1984

Authors and Affiliations

  • Milton H. SaierJr.
    • 1
  • David A. Boyden
    • 1
  1. 1.Department of Biology (C-016)The John Muir College, University of CaliforniaSan Diego, La JollaUSA

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