Properties of Ca Currents Activated by T Cell Receptor Signaling

  • Brett A. Premack
  • Phyllis Gardner
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 365)


Influx of extracellular Ca is one of the early biochemical events associated with signaling through the T cell receptor (TCR) complex1–4. The influx of Ca is a critical component of the signaling pathway because it helps to drive the cytoplasmic Ca from resting levels of around 100 nM up to several μM, the concentration required for activation of many intracellular Ca binding proteins and enzymes5. Recently there has been a great deal of progress in understanding the molecular basis of the very earliest events in TCR signaling which precede Ca mobilization as well as those later Ca-dependent processes leading to transcription of the IL-2 gene6–9. Unfortunately, the molecules involved in initiation, maintenance, and termination of Ca influx remain elusive despite the combined efforts of researchers using molecular, biochemical and electrophysiological approaches. However, during the last year a number of important discoveries have generated an unprecedented interest in the nature of the Ca influx pathway10,11.


Inositol Phosphate Diffusible Messenger Cell Antigen Receptor Signal Transduction 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    R.Y. Tsien, R. Pozzan and T.J. Rink, T-cell mitogens cause early changes in cytoplasmic free Ca and membrane potential in lymphocytes, Nature 295: 68 (1982).PubMedCrossRefGoogle Scholar
  2. 2.
    T.R. Hesketh, G. A. Smith, J.P. Moore, M. V. Taylor and J.C. Metcalfe, Free cytoplasmic calcium concentration and the mitogenic stimulation of lymphocytes, J. Biol. Chem. 258: 4876 (1983).PubMedGoogle Scholar
  3. 3.
    J. Imboden and A. Weiss, The T-cell antigen receptor regulates sustained increases in cytoplasmic free Ca through extracellular Ca mobilization, Biochem. J. 247: 695 (1987).PubMedGoogle Scholar
  4. 4.
    E.W. Gelfand, R.K. Cheung, G.B. Mills and S. Grinstein, Uptake of extracellular Ca and not recruitment from internal stores is essential for T-lymphocyte proliferation, Eur. J. Immunol. 18: 917 (1988).PubMedCrossRefGoogle Scholar
  5. 5.
    B.A. Premack and P. Gardner, Signal transduction by T cell receptors: Mobilization of Ca and regulation of Ca-dependent effector molecules, Amer. J. Physiol. 263: C1119 (1992).PubMedGoogle Scholar
  6. 6.
    N.A. Clipstone and G.R. Crabtree, Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation, Nature 357: 695 (1992).PubMedCrossRefGoogle Scholar
  7. 7.
    J. Jain, P.G. McCaffrey, Z. Miner, T.K. Kerppola, J.N. Lambert, G.L. Verdine, T. Curran and A. Rao, The T cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun, Nature 365: 352 (1993).PubMedCrossRefGoogle Scholar
  8. 8.
    J. Liu, FK506 and cyclosporin, molecular probes for studying intracellular signal transduction, Immunol Today 14: 290 (1993).PubMedCrossRefGoogle Scholar
  9. 9.
    J.D. Fraser, D. Straus and A. Weiss, Signal transduction events leading to T-cell lymphokine gene expression, Immunol Today 14: 357 (1993).PubMedCrossRefGoogle Scholar
  10. 10.
    D.E. Clapham, A mysterious new influx factor?, Nature 364: 763 (1993).PubMedCrossRefGoogle Scholar
  11. 11.
    J.W. Putney Jr., Excitement about Ca signalling in nonexcitable cells, Science 262: 676 (1993).PubMedCrossRefGoogle Scholar
  12. 12.
    M.J. Berridge, Inositol trisphosphate and calcium signalling, Nature 361: 315 (1993).PubMedCrossRefGoogle Scholar
  13. 13.
    V. Von Tscharner, B. Prod’hom, M. Baggiolini and H. Reuter, Ion channels in human neutrophils are activated by a rise in the free cytosolic calcium concentration, Nature 324: 369 (1986).CrossRefGoogle Scholar
  14. 14.
    M. Kuno, J. Goronzy, C.M. Weyand and P. Gardner, Single-channel and whole-cell recordings of mitogen-regulated inward currents in human cloned helper T lymphocytes, Nature 323: 269 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Kuno and P. Gardner, Ion channels activated by inositol 1,4,5-trisphosphate in plasma membrane of human T lymphocytes, Nature 326: 301 (1987).PubMedCrossRefGoogle Scholar
  16. 16.
    R. Penner, G. Matthews and E. Neher, Regulation of calcium influx by second messengers in rat mast cells, Nature 334: 499 (1988).PubMedCrossRefGoogle Scholar
  17. 17.
    G. Matthews, E. Neher and R. Penner, Second messenger activated calcium influx in rat peritoneal mast cells, J. Physiol. 418: 105 (1989).PubMedGoogle Scholar
  18. 18.
    R.S. Lewis and M.D. Cahalan, Mitogen-induced oscillations of cytosolic Ca and transmembrane Ca current in human leukemic T cells, Cell Regul. 1: 99 (1989).PubMedGoogle Scholar
  19. 19.
    M. Hoth and R. Penner, Depletion of intracellular calcium stores activates a calcium current in mast cells, Nature 355: 353 (1992).PubMedCrossRefGoogle Scholar
  20. 20.
    A. Luckhoff and D.E. Clapham, Inositol 1,3,4,5-tetrakisphosphate activates an endothelial Ca-permeable channel, Nature 355: 356 (1992).PubMedCrossRefGoogle Scholar
  21. 21.
    J.W. Putney Jr., A model for receptor-regulated calcium entry, Cell Calcium 7: 1 (1986).PubMedCrossRefGoogle Scholar
  22. 22.
    J.W. Putney Jr., Capacitative calcium entry revisited, Cell Calcium 11: 611 (1990).PubMedCrossRefGoogle Scholar
  23. 23.
    J.W. Putney Jr., and G.S. Bird, The signal for capacitative Ca entry, Cell 75: 199 (1993).PubMedCrossRefGoogle Scholar
  24. 24.
    T.V. McDonald, B.A. Premack and P. Gardner, Flash photolysis of caged inositol 1,4,5-trisphosphate activates plasma membrane calcium current in Human T cells, J. Biol Chem. 268: 3889 (1993).PubMedGoogle Scholar
  25. 25.
    B.A. Premack, T.V. McDonald and P. Gardner, Activation of Ca currents in a Jurkat T cells following the depletion of Ca stores by microsomal Ca-ATPase inhibitors, In press: J. Immunol. (1994).Google Scholar
  26. 26.
    O.P. Hamill, A. Marty, E. Neher, B. Sakmann and F.J. Sigworth, Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches, Pflugers Arch. 391:85 (1981).PubMedCrossRefGoogle Scholar
  27. 27.
    T.R. Jackson, S.I. Patterson, O. Thastrup and M.R. Hanley, A novel tumour promoter, thapsigargin, transiently increases cytoplasmic free Ca without generation of inositol phosphates in NG115-401L neuronal cells, Biochem. J. 253: 81 (1988).PubMedGoogle Scholar
  28. 28.
    H. Takemura, A.R. Hughes, O. Thastrup and J.J. Putney, Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane, J. Biol. Chem. 264: 12266 (1989).PubMedGoogle Scholar
  29. 29.
    H. Gouy, D. Cefai, S.B. Christensen, P. Debre and G. Bismuth, Ca influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca stores. A study with the Ca endoplasmic reticulum-ATPase inhibitor thapsigargin, Eur. J. Immunol. 20: 2269 (1990).PubMedCrossRefGoogle Scholar
  30. 30.
    N. Demaurex, D.P. Lew and K.H. Krause, Cyclopiazonic acid depletes intracellular Ca stores and activates an influx pathway for divalent cations in HL-60 cells, J. Biol. Chem. 267: 2318 (1992).PubMedGoogle Scholar
  31. 31.
    M.J. Mason, S.M. Mahaut and S. Grinstein, The role of intracellular Ca in the regulation of the plasma membrane Ca permeability of unstimulated rat lymphocytes, J. Biol. Chem. 266: 10872 (1991).PubMedGoogle Scholar
  32. 32.
    B. Sarkadi, A. Tordai, L. Homolya, O. Scharffand G. Gardos, Calcium influx and intracellular calcium release in anti-CD3 antibody-stimulated and thapsigargin-treated human T lymphoblasts, J. Membr. Biol. 123: 9 (1991).PubMedCrossRefGoogle Scholar
  33. 33.
    J. Llopis, S.B. Chow, G.E. Kass, A. Gahm and S. Orrenius, Comparison between the effects of the microsomal Ca-translocase inhibitors thapsigargin and 2,5-di-(tert-butyl)-l,4-benzohydroquinone on cellular calcium fluxes Comparison between the effects of the microsomal Ca-translocase inhibitors thapsigargin and 2,5-di-(tert-butyl)-l,4-benzohydroquinone on cellular calcium fluxes, Biochem. J. 553 (1991).Google Scholar
  34. 34.
    M. Hoth and R. Penner, Calcium release-activated calcium current in mast cells, J. Physiol. 465: 359 (1993).PubMedGoogle Scholar
  35. 35.
    P. Hess and R.W. Tsien, Mechanism of ion permeation through calcium channels, Nature 309: 453 (1984).PubMedCrossRefGoogle Scholar
  36. 36.
    W. Aimers and E.W. McCleskey, Nonselective conductance in calcium channels of frog muscle: Calcium selectivity in a single-file pore, J. Physiol. 353: 585 (1984).Google Scholar
  37. 37.
    P. Hess, J.B. Lansman and R.W. Tsien, Calcium channel selectivity for monovalent and divalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells, J. Gen. Physiol. 88: 293 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    R.W. Tsien, P. Hess, E.W. McCleskey and R.L. Rosenberg, Calcium channels: mechanisms of selectivity, permeation and block, Ann. Rev. Biophys. Biophys. Chem. 16: 265 (1987).CrossRefGoogle Scholar
  39. 39.
    S. Tang, G. Mikala, A. Bahinski, A. Yatani, G. Varadi and A. Schwartz, Molecular localization of ion selectivity sites within the pore of a human L-type cardiac calcium channel, J. Biol. Chem. 268: 13026 (1993).PubMedGoogle Scholar
  40. 40.
    J. Yang, P.T. Ellinor, W.A. Sather, J.F. Zang and R.W. Tsien, Molecular determinants of Ca selectivity and ion permeation in L-type Ca channels, Nature 366: 158 (1993).PubMedCrossRefGoogle Scholar
  41. 41.
    M.A. Goldsmith, D.M. Desai, T. Schultz and A. Weiss, Function of a heterologous muscarinic receptor in T cell antigen receptor signal transduction mutants, J. Biol. Chem. 264: 17190 (1989).PubMedGoogle Scholar
  42. 42.
    D.M. Desai, M.E. Newton, T. Kadlecek and A. Weiss, Stimulation of the phosphatidylinositol pathway can induce T-cell activation, Nature 348: 66 (1990).PubMedCrossRefGoogle Scholar
  43. 43.
    A. Zweifach and R.S. Lewis, Mitogen-regulated Ca current of T lymphocytes is activated by depletion of intracellular stores, P.N.A.S 90: 6295 (1993).PubMedCrossRefGoogle Scholar
  44. 44.
    E. Neher, Controls on calcium influx, Nature 355: 298 (1992).PubMedCrossRefGoogle Scholar
  45. 45.
    T.D. Bahnson, S.J. Pandol and V.E. Dionne, Cyclic GMP mediates depletion-activated Ca entry in pancreatic acinar cells, J. Biol. Chem. 268: 10808 (1993).PubMedGoogle Scholar
  46. 46.
    C. Randriamampita and R.Y. Tsien, Emptying of intracellular Ca stores releases a novel small messenger that stimulates Ca influx, Nature 364: 809 (1993).PubMedCrossRefGoogle Scholar
  47. 47.
    C. Fasolato, M. Hoth and R. Penner, A GTP-dependent step in the activation of capacitative calcium influx, J. Biol. Chem. 268: 20737 (1993).PubMedGoogle Scholar
  48. 48.
    G.S. Bird and J.W. Putney, Inhibition of thapsigargin-induced Ca entry by microinjected Guanine nucleotide analogues, J. Biol. Chem. 268: 21486 (1993).PubMedGoogle Scholar
  49. 49.
    B.B. Niklinska, H. Yamada, J.J. O’Shea and J.D. Ashwell, Tyrosine kinase-regulated and inositol phosphate-independent Ca elevation and mobilization in T cells, J. Biol. Chem. 267: 7154 (1992).PubMedGoogle Scholar
  50. 50.
    K.M. Lee, K. Toscas and M.L. Villereal, Inhibition of bradykinin-and thapsigargin-induced Ca entry by tyrosine kinase inhibitors, J. Biol. Chem. 268: 9945 (1993).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Brett A. Premack
    • 1
  • Phyllis Gardner
    • 1
  1. 1.Departments of Molecular Pharmacology and MedicineStanford University Medical CenterStanfordUSA

Personalised recommendations