Summary
Lymphocytes possess a plethora of distinct ion channels whose activities are important for controlling calcium homeostasis and signal transduction processes in these cells. Among those that have been identified by electrophysiological techniques are several different types of voltage-gated potassium channels, calcium-activated potassium channels, chloride channels and mitogen-regulated calcium channels. Functioning together, these ion channels regulate lymphocyte activation, mitogenesis and cell volume. The expression of the various potassium channels is species dependent. In human peripheral T cells, four types of potassium channels are found: a voltage-dependent channel, which is a member of theShaker family and the product of the Kv1.3 gene, and three distinct small conductance calcium-activated potassium channels. Inhibition of the Kv1.3 channel by selective peptidyl inhibitors (e.g., margatoxin) causes depolarization of human T cells, indicating that the activity of this channel controls the resting plasma membrane potential of lymphocytes. Depolarization of T cells specifically blocks calcium-dependent pathways controlling lymphokine production and cell proliferation, without having significant effects on calcium-independent T-cell responses. Therefore, it is expected that selective small-molecule inhibitors of Kv1.3 will function as novel immunosuppressant agents.
Similar content being viewed by others
References
Hamil, O.P., Marty, A., Neher, E., Sakmann, B. and Sigworth, F.J., Pflug. Arch. Eur. J. Physiol., 391 (1981) 85.
Neher, E. and Sakmann, B., Sci. Am., 266 (1992) 44.
Lewis, R.S. and Cahalan, M.D., Annu. Rev. Physiol., 52 (1990) 415.
Cahalan, M.D., Chandy, K.G. and Grissmer, S., Curr. Top. Membr., 39 (1991) 357.
Gallin, E.K., Physiol. Rev., 71 (1991) 775.
Soltoff, S.P. and Cantley, L.C., Annu. Rev. Physiol., 50 (1988) 207.
Grinstein, S. and Dixon, S.J., Physiol. Rev., 69 (1989) 417.
Grinstein, S. and Foskett, J.K., Annu. Rev. Physiol., 52 (1990) 399.
Imboden, J.B. and Stobo, J.D., J. Exp. Med., 161 (1985) 446.
Gelfand, E.W., Cheung, R.K. and Grinstein, S., J. Biol. Chem., 261 (1986) 11520.
Weiss, A., Koretzky, G., Schatzman, R.C. and Kadlecek, T., Proc. Natl. Acad. Sci. USA, 88 (1991) 5484.
Truneh, A., Albert, F., Golstein, P. and Schmitt-Verhulst, A.-M., Nature, 313 (1985) 318.
DeCoursey, T.E., Chandy, K.G., Gupta, S. and Cahalan, M.D., Nature, 307 (1984) 465.
Matteson, D.R. and Deutsch, C., Nature, 307 (1984) 468.
Cahalan, M.D., Chandy, K.G., DeCoursey, T.E. and Gupta, S., J. Physiol., 358 (1985) 197.
Lewis, R.S. and Cahalan, M.D., Science, 239 (1988) 771.
Bregestovski, P., Redkozubov, A. and Alexeev, A., Nature, 319 (1986) 776.
Sands, S.B., Lewis, R.S. and Cahalan, M.D., J. Gen. Physiol., 93 (1989) 1061.
Chandy, K.G., DeCoursey, T.E., Cahalan, M.D., McLaughlin, C. and Gupta, S., J. Exp. Med., 160 (1984) 369.
DeCoursey, T.E., Chandy, K.G., Gupta, S. and Cahalan, M.D., J. Neuroimmunol., 10 (1985) 71.
Deutsch, C. and Chen, L.-Q., Proc. Natl. Acad. Sci. USA, 90 (1993) 10036.
DeCoursey, T.E., Chandy, K.G., Gupta, S. and Cahalan, M.D., J. Gen. Physiol., 89 (1987) 379.
Chandy, K.G., DeCoursey, T.E., Fischbach, M., Talal, N., Cahalan, M.D. and Gupta, S., Science, 233 (1986) 1197.
Wilson, H.A. and Chused, T.M., J. Cell. Physiol., 125 (1985) 72.
Mahaut-Smith, M.P. and Schlichter, L.C., J. Physiol., 415 (1989) 69.
Grissmer, S., Lewis, R.S. and Cahalan, M.D., J. Gen. Physiol., 99 (1992) 63.
Leonard, R.J., Garcia, M.L., Slaughter, R.S. and Reuben, J.P., Proc. Natl. Acad. Sci. USA, 89 (1992) 10094.
Mahaut-Smith, M.P. and Mason, M.J., J. Physiol., 439 (1991) 513.
Attali, B., Romey, G., Honore, E., Schmid-Alliana, A., Mattei, M.G., Lesage, F., Ricard, P., Barhanin, J. and Lazdunski, M., J. Biol. Chem., 267 (1992) 8650.
Folander, K., Smith, J.S., Antanavage, J., Bennett, C., Stein, R.B. and Swanson, R., Proc. Natl. Acad. Sci. USA, 87 (1990) 2975.
Attali, B., Guillemare, E., Lesage, F., Honore, E., Romey, G., Lazdunski, M. and Barhanin, J., Nature, 365 (1993) 850.
Lewis, R.S., Ross, P.E. and Cahalan, M.D., J. Gen. Physiol., 101 (1993) 801.
Chen, J.H., Schulman, H. and Gardner, P., Science, 243 (1989) 657.
Pahapill, P.A. and Schlichter, L.C., J. Membr. Biol., 125 (1992) 171.
Lewis, R.S. and Cahalan, M.D., Cell Regul., 1 (1989) 99.
Kuno, M., Goronzy, J., Weyand, C.M. and Gardner, P., Nature, 323 (1986) 269.
Kuno, M. and Gardner, P., Nature, 326 (1987) 301.
Gardner, P., Alcover, A., Kuno, M., Moingeon, P., Weyand, C.M., Goronzy, J. and Reinherz, E.L., J. Biol. Chem., 264 (1989) 1068.
Pecht, I., Corcia, A., Liuzzi, M.P.T., Alcover, A. and Reinherz, E.L., EMBO J., 6 (1987) 1935.
Lytton, J., Westlin, M. and Hanley, M.R., J. Biol. Chem., 266 (1991) 17067.
Mason, M.J., Garcia-Rodriguez, C. and Grinstein, S., J. Biol. Chem., 266 (1991) 20856.
Zweifach, A. and Lewis, R.S., Proc. Natl. Acad. Sci. USA, 90 (1993) 6295.
Donnadieu, E., Bismuth, G. and Trautmann, A., J. Biol. Chem., 267 (1992) 25864.
Hess, S.D., Oortgiesen, M. and Cahalan, M.D., J. Immunol., 150 (1991) 2620.
Garcia, M.L., Galvez, A., Garcia-Calvo, M., King, V.F., Vazquez, J. and Kaczorowski, G.J., J. Bioeng. Biomembr., 23 (1991) 615.
Miller, C., Moczydlowski, E., Latorre, R. and Philips, M., Nature, 313 (1985) 316.
Bontems, F., Roumestand, C., Boyot, P., Gilquin, B., Doljansky, Y., Menez, A. and Toma, F., Eur. J. Biochem., 196 (1991) 19.
Gimenez-Gallego, G., Navia, M.A., Reuben, J.P., Katz, G.M., Kaczorowski, G.J. and Garcia, M.L., Proc. Natl. Acad. Sci. USA, 85 (1988) 3329.
Sugg, E.E., Garcia, M.L., Reuben, J.P., Patchett, A.A. and Kaczorowski, G.J., J. Biol. Chem., 265 (1990) 18745.
Park, C.S., Hausdorff, S.F. and Miller, C., Proc. Natl. Acad. Sci. USA, 88 (1991) 2046.
Giangiacomo, K., Sugg, E.E., Garcia-Calvo, M., Leonard, R.J., McManus, O.B., Kaczorowski, G.J. and Garcia, M.L., Biochemistry, 32 (1993) 2363.
Vazquez, J., Feigenbaum, P., Katz, G., King, V.F., Reuben, J.P., Roy-Contancin, L., Slaughter, R.S., Kaczorowski, G.J. and Garcia, M.L., J. Biol. Chem., 264 (1989) 20902.
Vazquez, J., Feigenbaum, P., King, V.F., Kaczorowski, G.J. and Garcia, M.L., J. Biol. Chem., 265 (1990) 15564.
Deutsch, C., Price, M., Lee, S., King, V.F. and Garcia, M.L., J. Biol. Chem., 266 (1991) 3668.
Galvez, A., Gimenez-Gallego, G., Reuben, J.P., Roy-Contancin, L., Feigenbaum, P., Kaczorowski, G. and Garcia, M.L., J. Biol. Chem., 265 (1990) 11083.
Lin, C., Boltz, R.C., Blake, T., Nguyen, M., Talento, A., Fischer, P., Springer, M., Sigal, N., Slaughter, R.S., Garcia, M., Kaczorowski, G.J. and Koo, G.C., J. Exp. Med., 177 (1993) 637.
Possani, L.D., Martin, B.M. and Svendsen, I.B., Carlsberg Res. Commun., 47 (1982) 285.
Harvey, A.L. and Anderson, A.J., Pharmacol. Ther., 31 (1985) 35.
Garcia-Calvo, M., Leonard, R.J., Novick, J., Stevens, S.P., Schmalhofer, W., Kaczorowski, G.J. and Garcia, M.L., J. Biol. Chem., 268 (1993) 18866.
Tempel, B.L., Papazian, D.M., Schwartz, T.L., Jan, Y.N. and Jan, L.Y., Science, 237 (1987) 770.
Baumann, A., Grupe, A., Ackermann, A. and Pongs, O., EMBO J., 7 (1988) 2457.
Douglass, J.O., Christie, M., Adelman, J.P. and North, R. A., NIDA Res. Monogr. Ser., 111 (1991) 54.
MacKinnon, R., Nature, 350 (1991) 232.
Chandy, K.G., Williams, C.B., Spencer, R.H., Aguilar, B.A., Ghanshani, S., Tempel, B.I. and Gutman, G.A., Science, 247 (1990) 973.
Grissmer, S., Dethlets, B., Wasmuth, J.J., Goldin, A.L., Gutman, G.A., Cahalan, M.D. and Chandy, K.G., Proc. Natl. Acad. Sci. USA, 87 (1990) 9411.
Stubmer, W.J., Ruppersberg, J.P., Schroter, K.H., Sakmann, B., Stocker, M., Giese, K.P., Perschke, A., Baumann, A. and Pongs, O., EMBO J., 8 (1989) 3235.
Douglass, J., Osborne, P.B., Cai, Y.-C., Wilkinson, M., Christie, M.J. and Adelman, J.P., J. Immunol., 144 (1990) 4841.
Swanson, R., Marshall, J., Smith, J.S., Williams, J.B., Boyle, M.B., Folander, K., Luneau, C.J., Antanavage, J., Oliva, C., Buhrow, S.A., Bennet, C., Stein, R.B. and Kaczmarek, L.K., Neuron, 4 (1990) 929.
Cai, Y.-C., Osborne, P.B., North, R.A., Dooley, D.C. and Douglass, J., DNA Cell Biol., 11 (1992) 163.
Grissmer, S., Ghanshani, S., Dethlefs, B., McPherson, J.D., Wasmuth, J.J., Gutman, G.A., Cahalan, M.D. and Chandy, K.G., J. Biol. Chem., 267 (1992) 20971.
Spencer, R.H., Chandy, K.G. and Gutman, G.A., Biochem. Biophys. Res. Commun., 191 (1993) 201.
DeCoursey, T.E., Chandy, K.G., Gupta, S. and Cahalan, M.D., J. Gen. Physiol., 89 (1987) 405.
Lee, S.C., Sabath, D.E., Deutsch, C. and Prystowsky, M.B., J. Cell. Biol., 102 (1986) 1200.
Lin, C.S., Nguyen, M., Blake, J.T., Sirotina, A., Koo, G.C., Felix, J. and Slaughter, R.S., J. Immunol., 150 (1993) 111A.
Garcia-Calvo, M., Knaus, H.G., McManus, O.B., Giangiacomo, K.M., Kaczorowski, G.J. and Garcia, M.L., J. Biol. Chem., 269 (1994) 676.
Rhem, H. and Lazdunski, M., Proc. Natl. Acad. Sci. USA, 85 (1988) 4919.
Knaus, H.G., Folander, K., Garcia-Calvo, M., Garcia, M.L., Kaczorowski, G.J., Smith, M. and Swanson, R., J. Biol. Chem., 269 (1994) 17274.
Trimmer, J.S., Proc. Natl. Acad. Sci. USA, 88 (1991) 10764.
Scott, V.E., Parcej, D.N., Keen, J.N., Findlay, J.B. and Dolly, J.O., J. Biol. Chem., 265 (1990) 20094.
Sabath, D.E., Monos, D.S., Lee, S.C., Deutsch, C. and Prystowsky, M.B., Proc. Natl. Acad. Sci. USA, 83 (1986) 4739.
Randriamampita, C., Bismuth, G., Debre, P. and Trautmann, A., Cell Calcium, 12 (1991) 313.
Price, M., Lee, S.C. and Deutsch, C., Proc. Natl. Acad. Sci. USA, 86 (1989) 10171.
Gelfand, E.W. and Or, R., J. Immunol., 147 (1991) 3452.
Bono, M.R., Simon, V. and Rosenblatt, M.S., Cell Biochem. Funct., 7 (1989) 219.
Lin, C.S., Boltz, R.C., Siekierka, J.J. and Sigal, N.H., Cell. Immunol., 133 (1991) 269.
Liu, J., Farmer Jr., J.D., Lane, W.S., Freidman, J., Weissman, I. and Schreiber, S.L., Cell, 66 (1991) 807.
Freedman, B.D., Price, M.A. and Deutsch, C.J., J. Immunol., 149 (1992) 3784.
June, C., Ledbetter, J.A., Rabinovitch, P.S., Martin, P.J., Beatty, P.G. and Hansen, J.A., J. Clin. Invest., 77 (1986) 1224.
Durell, S.R. and Guy, H.R., Biophys. J., 62 (1992) 238.
Nichols, C.G., Trends Pharmacol. Sci., 14 (1993) 320.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kaczorowski, G.J., Koo, G.C. Lymphocyte ion channels as a target for immunosuppression. Perspectives in Drug Discovery and Design 2, 233–248 (1994). https://doi.org/10.1007/BF02171746
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02171746