Potassium channels as targets for modulating cell growth and differentiation

Abstract

Potassium channels, especially small and intermediate conductance KCa channels, have important roles in controlling cell proliferation and differentiation. Thus far regulation of these channels is reported to be primarily at the level of expression, in response to activation of the central growth regulatory signaling pathway (i.e., growth factor receptor tyrosine kinase/Ras/Raf/MEK/ERK). Therefore, the function and regulation of these cell growth-associated channels must be viewed differently from that of channels which govern electrical signaling in excitable cells, and which are typically studied in terms of their transient modulation by G-protein coupled receptors. Although there are suggestions that potassium channels also contribute to growth regulation in excitable cells, a coherent picture of this role in these systems is still emerging. For fibroblasts and T-lymphocytes, it is clear that growth factor and oncogenic upregulation of a unique KCa channel (or possibly KCa channel class) is stimulatory for cell proliferation and activation, respectively. This mitogenic channel has a single channel conductance in the range of 33–39 pS, it is charybdotoxin-sensitive and apamin-insensitive, and its gating is voltage-independent. Recent cloning data suggest that the KCa channel (or channel class) described for fibroblasts and T-cells has a widespread distribution in other mitogenically active (non-neuronal) tissues. A number of studies are now underway to understand the physiology, pharmacology and regulation of this channel. Further, it is now critical to determine how KCa activity integrates into the signaling pathways which convey growth regulatory information from the cell membrane, to the nucleus, and then to the ultimate effectors for cell proliferation or differentiation. It has also become apparent that these growth regulatory signaling systems interact with other channel types, affecting channel densities at the level of expression, and channel activities at the level of gating modulation. Therefore, it seems most appropriate to view ion channel function in the context of how it contributes to and is affected by both cell growth activity, and the biochemical signaling systems linked to growth control.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Johnson, G.L. and Vaillancourt, R.R., Curr. Opin. Cell Biol., 6 (1994) 230.

    Google Scholar 

  2. 2.

    Jones, S.M. and Ribera, A.B., J. Neurosci., 14 (1994) 2789.

    Google Scholar 

  3. 3.

    Hardingham, G.E., Chawla, S., Johnson, C.M. and Bading, H., Nature, 385 (1997) 260.

    Google Scholar 

  4. 4.

    Spitzer, N.C., Gu, X. and Olson, E., Curr. Opin. Neurobiol., 4 (1994) 70.

    Google Scholar 

  5. 5.

    Wilson, G.F. and Chiu, S.Y., J. Physiol., 470 (1993) 501.

    Google Scholar 

  6. 6.

    Gallo, V., Zhou, J.M., Mcbain, C.J., Wright, P., Knutson, P.L. and Armstrong, R.C., J. Neurosci., 16 (1996) 2659.

    Google Scholar 

  7. 7.

    Patil, N., Cox, D.R., Bhat, D., Faham, M., Myers, R.M. and Peterson, A.S., Nature Genet., 11 (1995) 126.

    Google Scholar 

  8. 8.

    Slesinger, P.A., Patil, N., Liao, Y.J., Jan, Y.N., Jan, L.Y. and Cox, D.R., Neuron, 16 (1996) 321.

    Google Scholar 

  9. 9.

    Kofuji, P., Hofer, M., Millen, K.J., Millonig, J.H., Davidson, N., Lester, H.A. and Hatten, M.E., Neuron, 16 (1996) 941.

    Google Scholar 

  10. 10.

    Yu, S.P., Yeh, C.H., Sensi, S.L., Gwag, B.J., Canzoniero, L.M.T., Farhangrazi, Z.S., Ying, H.S., Tian, M., Dugan, L.L. and Choi, D.W., Science, 278 (1997) 114.

    Google Scholar 

  11. 11.

    Rane, S.G., Am. J. Physiol., 260 (1991) C104.

    Google Scholar 

  12. 12.

    Huang, Y. and Rane, S.G., J. Biol. Chem., 269 (1994) 31183.

    Google Scholar 

  13. 13.

    Repp, H., Draheim, H., Ruland, J., Seidel, G., Beise, J., Presek, P. and Dreyer, F., Proc. Natl. Acad. Sci. USA, 90 (1993) 3403.

    Google Scholar 

  14. 14.

    Draheim, H.J., Repp, H. and Dreyer, F., Biochim. Biophys. Acta, 1269 (1995) 57.

    Google Scholar 

  15. 15.

    Yatani, A., Okabe, K., Polakis, P., Halenbeck, R., McCormick, F. and Brown, A.M., Cell, 61 (1990) 769.

    Google Scholar 

  16. 16.

    Fitzgerald, E.M. and Dolphin, A.C., Eur. J. Neurosci., 9 (1997) 1252.

    Google Scholar 

  17. 17.

    Huang, Y. and Rane, S.G., J. Physiol., 461 (1993) 601.

    Google Scholar 

  18. 18.

    Grissmer, S., Nguyen, A.N. and Cahalan, M.D., J. Gen. Physiol., 102 (1993) 601.

    Google Scholar 

  19. 19.

    Mahaut-Smith, M.P. and Schlichter, L.C., J. Physiol., 415 (1989) 69.

    Google Scholar 

  20. 20.

    Partiseti, M., Choquet, D., Diu, A. and Korn, H., J. Immunol., 148 (1992) 3361.

    Google Scholar 

  21. 21.

    Sauvé, R., Simoneau, C., Monette, R. and Roy, G., J. Membr. Biol., 92 (1986) 269.

    Google Scholar 

  22. 22.

    Enomoto, K., Furuya, K., Maeno, T., Edwards, C. and Oka, T., J. Membr. Biol., 119 (1991) 133.

    Google Scholar 

  23. 23.

    Ishii, T.M., Silvia, C., Hirschberg, B., Bond, C.T., Adelman, J.P. and Maylie, J., Proc. Natl. Acad. Sci. USA, 94 (1997) 11651.

    Google Scholar 

  24. 24.

    Kohler, M., Hirschberg, B., Bond, C.T., Kinzie, J.M., Marrion, N.V., Maylie, J. and Adelman, J.P., Science, 273 (1996) 1709.

    Google Scholar 

  25. 25.

    Joiner, W.J., Wang, L.Y., Tang, M.D. and Kaczmarek, L.K., Proc. Natl. Acad. Sci. USA, 94 (1997) 11013.

    Google Scholar 

  26. 26.

    Lovisolo, D., Munaron, L., Baccino, F.M. and Bonelli, G., Biochim. Biophys. Acta, 1112 (1992) 241.

    Google Scholar 

  27. 27.

    Lovisolo, D., Bonelli, G., Baccino, F.M., Peres, A., Alonzo, F. and Munaron, L., Biochim. Biophys. Acta, 1104 (1992) 73.

    Google Scholar 

  28. 28.

    Lewis, R.S. and Cahalan, M.D., Annu. Rev. Immunol., 13 (1995) 623.

    Google Scholar 

  29. 29.

    DeCoursey, T.E., Chandy, K.G., Gupta, S. and Cahalan, M.D., J. Gen. Physiol., 89 (1987) 405.

    Google Scholar 

  30. 30.

    Lee, S.C., Sabath, D.E., Deutsch, C. and Prystowsky, M.B., J. Cell Biol., 102 (1986) 1200.

    Google Scholar 

  31. 31.

    Partiseti, M., Korn, H. and Choquet, D., J. Immunol., 151 (1993) 2462.

    Google Scholar 

  32. 32.

    DeCoursey, T.E., Chandy, K.G., Gupta, S. and Cahalan, M.D., Nature, 307 (1984) 465.

    Google Scholar 

  33. 33.

    Deutsch, C., Krause, D. and Lee, S.C., J. Physiol., 372 (1986) 405.

    Google Scholar 

  34. 34.

    Price, M., Lee, S.C. and Deutsch, C., Proc. Natl. Acad. Sci. USA, 86 (1989) 10171.

    Google Scholar 

  35. 35.

    Lin, C.S., Boltz, R.C., Blake, J.T., Nguyen, M., Talento, A., Fischer, P.A., Springer, M.S., Sigal, N.H., Slaughter, R.S., Garcia, M.L., Kaczorowski, G.J. and Koo, G.C., J. Exp. Med., 177 (1993) 637.

    Google Scholar 

  36. 36.

    Rader, R.K., Kahn, L.E., Anderson, G.D., Martin, C.L., Chinn, K.S. and Gregory, S.A., J. Immunol., 156 (1996) 1425.

    Google Scholar 

  37. 37.

    Kerschbaum, H.H., Negulescu, P.A. and Cahalan, M.D., J. Immunol., 159 (1997) 1628.

    Google Scholar 

  38. 38.

    Kaczorowski, G.J. and Koo, G.C., Perspect. Drug Discov. Des., 2 (1994) 233.

    Google Scholar 

  39. 39.

    Verheugen, J.A.H., Le Deist, F., Devignot, V. and Korn, H., Cell Calcium, 21 (1997) 1.

    Google Scholar 

  40. 40.

    Dubois, J.M. and Rouzaire-Dubois, B., Prog. Biophys. Mol. Biol., 59 (1993) 1.

    Google Scholar 

  41. 41.

    Logsdon, N.J., Kang, J.S., Togo, J.A., Christian, E.P. and Aiyar, J., J. Biol. Chem., 272 (1997) 32723.

    Google Scholar 

  42. 42.

    Verheugen, J.A.H. and Korn, H., J. Physiol., 503 (1997) 317.

    Google Scholar 

  43. 43.

    Cattaneo, M.G., Gullo, M. and Vicentini, L.M., Eur. J. Pharmacol., 247 (1993) 325.

    Google Scholar 

  44. 44.

    Corsini, A., Bonfatti, M., Quarato, P., Accomazzo, M.R., Raiteri, M., Sartani, A., Testa, R., Nicosia, S., Paoletti, R. and Fumagalli, R., J. Cardiovasc. Pharmacol., 28 (1996) 687.

    Google Scholar 

  45. 45.

    Holland, M., Langton, P.D., Standen, N.B. and Boyle, J.P., Br. J. Pharmacol., 117 (1996) 119.

    Google Scholar 

  46. 46.

    Wonderlin, W.F. and Strobl, J.S., J. Membr. Biol., 154 (1996) 91.

    Google Scholar 

  47. 47.

    Wonderlin, W.F., Woodfork, K.A. and Strobl, J.S., J. Cell. Physiol., 165 (1995) 177.

    Google Scholar 

  48. 48.

    Woodfork, K.A., Wonderlin, W.F., Peterson, V.A. and Strobl, J.S., J. Cell. Physiol., 162 (1995) 163.

    Google Scholar 

  49. 49.

    Day, M.L., Pickering, S.J., Johnson, M.H. and Cook, D.I., Nature, 365 (1993) 560.

    Google Scholar 

  50. 50.

    Blumer, K.J. and Johnson, G.L., Trends Biochem. Sci., 19 (1994) 236.

    Google Scholar 

  51. 51.

    Marshall, C.J., Cell, 80 (1995) 179.

    Google Scholar 

  52. 52.

    D'Arcangelo, G., Paradiso, K., Shepherd, D., Brehm, P., Halegoua, S. and Mandel, G., J. Cell Biol., 122 (1993) 915.

    Google Scholar 

  53. 53.

    Fanger, G.R., Erhardt, P., Cooper, G.M. and Maue, R., J. Neurochem., 61 (1993) 1977.

    Google Scholar 

  54. 54.

    Fanger, G.R., Vaillancourt, R.R., Heasley, L.E., Montmayeur, J.P.R., Johnson, G.L. and Maue, R.A., Mol. Cell. Biol., 17 (1997) 89.

    Google Scholar 

  55. 55.

    Lewis, D.L., Deaizpurua, H. J. and Rausch, D.M., J. Physiol., 465 (1993) 325.

    Google Scholar 

  56. 56.

    Rane, S.G. and Pollock, J.D., J. Neurosci. Res., 38 (1994) 590.

    Google Scholar 

  57. 57.

    Pollock, J.D. and Rane, S.G., J. Biol. Chem., 271 (1996) 8008.

    Google Scholar 

  58. 58.

    Cole, K. and Kohn, E., Cancer Metastasis Rev., 13 (1994) 31.

    Google Scholar 

  59. 59.

    Olson, E.N., Dev. Biol., 154 (1992) 261.

    Google Scholar 

  60. 60.

    Rhodes, S.J. and Konieczny, S.F., Genes Devel., 3 (1989) 2050.

    Google Scholar 

  61. 61.

    Peña, T.L. and Rane, S.G., J. Biol. Chem., 272 (1997) 21909.

    Google Scholar 

  62. 62.

    Hamann, M., Widmer, H., Baroffio, A., Aubry, J.-P., Krause, R.M., Kaelin, A. and Bader, C.R., J. Physiol., 475 (1994) 305.

    Google Scholar 

  63. 63.

    Kang, H. and Schuman, E.M., Science, 267 (1995) 1658.

    Google Scholar 

  64. 64.

    Figurov, A., Pozzo-Miller, L.D., Olafsson, P., Wang, T. and Lu, B., Nature, 381 (1996) 706.

    Google Scholar 

  65. 65.

    Lohof, A.M., Ip, N.Y. and Poo, M.M., Nature, 363 (1993) 350.

    Google Scholar 

  66. 66.

    Stoop, R. and Poo, M.M., J. Neurosci., 16 (1996) 3256.

    Google Scholar 

  67. 67.

    Wildering, W.C., Lodder, J.C., Kits, K.S. and Bulloch, A.G., J. Neurophysiol., 74 (1995) 2778.

    Google Scholar 

  68. 68.

    Holm, N.R., Christophersen, P., Olesen, S.P. and Gammeltoft, S., Proc. Natl. Acad. Sci. USA, 94 (1997) 1002.

    Google Scholar 

  69. 69.

    Huang, X.Y., Morielli, A.D. and Peralta, E.G., Cell, 75 (1993) 1145.

    Google Scholar 

  70. 70.

    Lev, S., Moreno, H., Martinez, R., Canoll, P., Peles, E., Musacchio, J.M., Plowman, G.D., Rudy, B. and Schlessinger, J., Nature, 376 (1995) 737.

    Google Scholar 

  71. 71.

    Dikic, I., Tokiwa, G., Lev, S., Courtneidge, S.A. and Schlessinger, J., Nature, 383 (1996) 547.

    Google Scholar 

  72. 72.

    Diversepierluissi, M., Remmers, A.E., Neubig, R.R. and Dunlap, K., Proc. Natl. Acad. Sci. USA, 94 (1997) 5417.

    Google Scholar 

  73. 73.

    Wang, Y.T. and Salter, M.W., Nature, 369 (1994) 233.

    Google Scholar 

  74. 74.

    Yu, X.M., Askalan, R., Keil, G.J. and Salter, M.W., Science, 275 (1997) 674.

    Google Scholar 

  75. 75.

    Holmes, T.C., Berman, K., Swartz, J.E., Dagan, D. and Levitan, I.B., J. Neurosci., 17 (1997) 8964.

    Google Scholar 

  76. 76.

    Hilborn, M.D., Vaillancourt, R.R. and Rane, S.G., J. Neurosci., 18 (1998) 590.

    Google Scholar 

  77. 77.

    Dahring, T.K., Lu, G.H., Hamby, J.M., Batley, B.L., Kraker, A.J. and Panek, R.L., J. Pharmacol. Exp. Ther., 281 (1997) 1446.

    Google Scholar 

  78. 78.

    Lynch, B.A., Loiacono, K.A., Tiong, C.L., Adams, S.E. and MacNeil, I.A., Anal. Biochem., 247 (1997) 77.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rane, S.G. Potassium channels as targets for modulating cell growth and differentiation. Perspectives in Drug Discovery and Design 15, 295–311 (1999). https://doi.org/10.1023/A:1017053215745

Download citation

  • mitogenic signaling
  • proliferation
  • Ras
  • receptor tyrosine kinase
  • Src