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The versatility and universality of calcium signalling

Abstract

The universality of calcium as an intracellular messenger depends on its enormous versatility. Cells have a calcium signalling toolkit with many components that can be mixed and matched to create a wide range of spatial and temporal signals. This versatility is exploited to control processes as diverse as fertilization, proliferation, development, learning and memory, contraction and secretion, and must be accomplished within the context of calcium being highly toxic. Exceeding its normal spatial and temporal boundaries can result in cell death through both necrosis and apoptosis.

Key Points

  • Versatility in Ca2+ signalling is provided by a toolkit that can be divided into four types of tool:

    • Ca2+-mobilizing signals include the four intracellular messengers inositol-1,4,5-trisphosphate, cyclic ADP ribose, nicotinic acid dinucleotide phosphate and sphingosine-1-phosphate. Membrane depolarization increases Ca2+ in excitable cells.

    • ON mechanisms largely depend on channels in the plasma membrane or the endoplasmic/sarcoplasmic reticulum membrane. In both cases the result is an increase in the cytoplasmic Ca2+ concentration.

    • Ca2+ sensors, including the ubiquitous Ca2+-binding protein calmodulin and a wide variety of Ca2+?calmodulin-activated proteins, translate the ON mechanisms into physiological responses.

    • OFF mechanisms reduce the free cytoplasmic Ca2+ concentration by either sequestering it (Ca2+ buffers) or pumping it out of the cytoplasm.

  • Ca2+ can be mobilized as different types of elementary events: blips and quarks are caused by the opening of a single inositol-1,4,5-trisphosphate receptor or ryanodine receptor; puffs and sparks represent the opening of a group of such receptors. These can be built up into more complex intra- and intercellular Ca2+ signals such as waves.

  • The frequency of Ca2+ waves can vary among different cell types, and according to the intensity of the Ca2+-mobilizing signal.

  • Ca2+ signalling is used throughout the life cycle of an organism.

  • Processes that depend on Ca2+ signals include fertilization, axis formation, cell differentiation, proliferation, transcriptional activation and apoptosis.

  • An important challenge for the future will be understanding how individual cell types select their own unique Ca2+ signalling toolkit.

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Figure 1: The four units of the Ca2+ signalling network.
Figure 2: Elements of the Ca2+ signalling toolkit.
Figure 3: Ca2+ signalling by conformational coupling using macromolecular complexes.
Figure 4: Application of the Ca2+ signalling toolkit to regulate different cellular processes.
Figure 5: The spatial organization of Ca2+ release from internal stores.
Figure 6: Ca2+ function during lymphocyte proliferation.

References

  1. Berridge, M. J. Inositol trisphosphate and calcium signalling. Nature 361, 315?325 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Clapham, D. E. Calcium signaling. Cell 80, 259? 268 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Clapper, D. L., Walseth, T. F., Dargei, P. J. & Lee, H. C. Pyridine nucleotide metabolites stimulate calcium release from sea urchin egg microsomes desensitized to inositol trisphosphate. J. Biol. Chem. 262, 9561?9568 ( 1987).

    CAS  PubMed  Google Scholar 

  4. Genazzini, A. A. & Galione, A. A. Ca2+ release mechanism gated by the novel pyridine nucleotide, NAADP. Trends Pharmacol. Sci. 18, 108?110 (1997).

    Article  Google Scholar 

  5. Mao, C. G. et al. Molecular cloning and characterization of SCaMPER, a sphingolipid Ca2+ release-mediating protein from endoplasmic reticulum. Proc. Natl Acad. Sci. USA 93, 1993? 1996 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cancela, J. M. & Petersen, O. H. The cyclic ADP ribose antagonist 8-NH2-cADP-ribose blocks cholecystokinin-evoked cytosolic Ca2+ spiking in pancreatic acinar cells. Pfluger's Arch. 435, 746?748 (1998).

    Article  CAS  Google Scholar 

  7. Young, K. W., Challiss, R. A. J., Nahorski, S. R., & Mackrill, J. J. Lysophosphatidic acid-mediated Ca2+ mobilization in human SH-SY5Y neuroblastoma cells is independent of phosphoinositide signalling, but dependent on sphingosine kinase activation. Biochem. J. 343, 45?52 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Putney, J. W. Jr. A model for receptor-regulated calcium entry. Cell Calcium 7, 1?12 ( 1986).

    Article  CAS  PubMed  Google Scholar 

  9. Hofmann, T. et al. Direct activation of human TRP6 and TRPC3 channels by diacylglycerol . Nature 397, 259?263 (1999).The mammalian homologues of the Drosophila transient receptor potential (TRP) proteins function as Ca2+ channels but their control is still largely unknown. This paper suggests that some may be regulated by diacylglycerol.

    Article  CAS  PubMed  Google Scholar 

  10. Broad, L. M., Cannon, T. R. & Taylor, C. W. A non-capacitative pathway activated by arachidonic acid is the major Ca2+ entry mechanism in rat A7r5 smooth muscle cells stimulated with low concentrations of vasopressin. J. Physiol. 517, 121?134 ( 1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mignen, O. & Shuttleworth, T. J. IARC, a novel arachidonate-regulated, noncapacitative Ca2+ entry channel . J. Biol. Chem. 275, 9114? 9119 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Kiselyov, K. et al. Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396, 478?482 (1998).Some of the first evidence to indicate that inositol-1,4,5-trisphosphate receptors might be directly linked to Ca2+ channels in the plasma membrane.

    Article  CAS  PubMed  Google Scholar 

  13. Boulay, G. et al. Modulation of Ca2+ entry by polypeptides of the inositol 1,4,5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): Evidence for roles of TRP and IP3R in store depletion-activated Ca2+ entry. Proc. Natl Acad. Sci. USA 96, 14955?14960 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Berridge, M. J. Capacitative calcium entry. Biochem. J. 312, 1?11 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bootman, M. D. & Lipp, P. Calcium signalling: Ringing changes to the ?bell-shaped curve?. Curr. Biol. 9, R876?R878 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  16. Mermelstein, P. G., Bito, H., Deisseroth, K. & Tsien, R. W. Critical dependence of cAMP response element-binding protein phosphorylation on L-type calcium channels support a selective response to EPSPs in preference to action potentials . J. Neurosci. 20, 266? 273 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Berridge, M. J. Neuronal calcium signaling. Neuron 21, 13?26 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Nakamura, T., Barbara, J. G., Nakamura, K. & Ross, W. N. Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials. Neuron 24, 727? 737 (1999).Direct evidence that the inositol-1,4,5-trisphosphate receptor may act as a coincident detector, integrating a Ca2+ signal coming from an action potential and inositol-1,4,5-trisphosphate generated by a metabotropic receptor.

    Article  CAS  PubMed  Google Scholar 

  19. Cancela, J. M., Churchill, G. C. & Galione, A. Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells. Nature 398, 74?76 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Fierro, L. & Llano, I. High endogenous calcium buffering in Purkinje cells from rat cerebellar slices. J. Physiol. 496, 617?625 (1996).

    Article  Google Scholar 

  21. Pozzan, T., Rizzuto, R., Volpe, P. & Meldolesi, J. Molecular and cellular physiology of intracellular calcium stores. Physiol. Rev. 74, 595?636 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  22. Blaustein, M. P. & Lederer, W. J. Sodium/calcium exchange: Its physiological implications. Physiol. Rev. 79, 763?854 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Budd, S. L. & Nicholls, D. G. A reevaluation of the role of mitochondria in neuronal Ca2+ homeostasis. J. Neurochem. 66, 403?411 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  24. Jouaville, L. S., Ichas, F., Holmuhamedor, E. L., Camacho, P. & Lechleiter, J. D. Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature 377, 438?441 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  25. Collins, T. J., Lipp, P., Berridge, M. J., Li, W. & Bootman, M. D. Inositol 1,4,5-trisphosphate-induced Ca2+ release is inhibited by mitochondrial depolarization. Biochem. J. 347, 593?600 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Duchen, M. R. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death. J. Physiol. 516 , 1?17 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rizzuto, R., Brini, M., Murgia, M. & Pozzan, T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262, 744?747 (1993).The first demonstration that mitochondria sense the high concentrations of Ca2+ that build up in the vicinity of intracellular channels such as the inositol-1,4,5-trisphosphate receptor.

    Article  CAS  PubMed  Google Scholar 

  28. Csordas, G., Thomas, A. P. & Hajnoczky, G. Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J. 18, 96?108 (1999).

    Article  Google Scholar 

  29. Leissring, M. A. et al. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793?797 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bernadi, P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127? 1155 (1999).

    Article  Google Scholar 

  31. Ichas, F., Jouaville, L. S. & Mazat, J. P. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89, 1145?1153 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Berridge, M. J. Elementary and global aspects of calcium signalling. J. Physiol. 499, 291?306 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lipp, P. & Niggli, E. A hierarchical concept of cellular and subcellular Ca2+ signaling. Prog. Biophys. Mol. Biol. 65, 265?296 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  34. Lipp, P. & Niggli, E. Fundamental calcium release events revealed by two-photon excitation photolysis of caged calcium in guinea-pig cardiac myocytes. J. Physiol. 508, 801? 809 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bootman, M., Niggli, E., Berridge, M. J. & Lipp, P. Imaging the hierarchical Ca2+ signalling system in HeLa cells. J. Physiol. 499, 307?314 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cheng, H., Lederer, W. J. & Cannell, M. B. Calcium sparks ? elementary events underlying excitation-contraction coupling in heart-muscle. Science 262, 740?744 (1993). One of the first visualizations of the localized Ca2+ signal emerging from small groups of ryanodine receptors. Such elementary events are the basic building blocks of Ca2+ signals.

    Article  CAS  PubMed  Google Scholar 

  37. Yao, Y., Coi, J. & Parker, I. Quantal puffs of intracellular Ca2+ evoked by inositol trisphosphate in Xenopus oocytes. J. Physiol. 482, 533?553 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sun, X. -P., Callamaras, N., Marchant, J. S. & Parker, I. A continuum of InsP3-mediated elementary Ca2+ signalling events in Xenopus oocytes. J. Physiol. 509, 67?80 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thomas, D. Lipp, P., Berridge, M. J. & Bootman, M. D. Hormone-evoked elementary Ca2+ signals are not stereotypic, but reflect activation of different size channel clusters and variable recruitment of channels within a cluster. J. Biol. Chem. 273, 27130?27136 (1998).

    Article  Google Scholar 

  40. Lansley, A. B. & Sanderson, M. J. Regulation of airway ciliary activity by Ca2+: Simultaneous measurement of beat frequency and intracellular Ca2+. Biophys. J. 77, 629?638 ( 1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Robb-Gaspers, L. D. & Thomas, A. P. Coordination of Ca2+ signaling by intercellular propogation of Ca2+ waves in the intact liver. J. Biol. Chem. 270, 8102?8107 (1995). The first demonstration of intercellular Ca2+ waves travelling through large numbers of cells in an intact organ.

    Article  CAS  PubMed  Google Scholar 

  42. Zimmermann, B. & Walz, B. The mechanism mediating regenerative intercellular Ca2+ waves in the blowfly salivary gland. EMBO J. 18, 3222? 3231 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tse, F. W. & Tse, A. Regulation of exocytosis via release of Ca2+ from intracellular stores. BioEssays 21, 861?865 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Maturana, A. D. et al. Angiotensin II negatively modulates L-type calcium channels through a pertussis toxin-sensitive G protein in adrenal glomerulosa cells . J. Biol. Chem. 274, 19943? 19948 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Lipp, P., Thomas, D., Berridge, M. J. & Bootman, M. D. Nuclear calcium signalling by individual cytoplasmic calcium puffs. EMBO J. 16, 7166?7173 ( 1997).A demonstration that Ca2+ puffs are concentrated around the nucleus and are therefore able to feed Ca2+ directly into the nucleoplasm.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. DeKoninck, P. & Schulman, H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279, 227?230 (1998).

    Article  CAS  Google Scholar 

  47. Oancea, E. & Meyer, T. Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals. Cell 95, 307?318 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Li, W. H., Llopis, J., Whitney, M., Zlokarnik, G. & Tsien, R. Y. Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression. Nature 392, 936?941 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  49. Dolmetsch, R. E., Xu, K. L. & Lewis, R. S. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933? 936 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Ding, J. M. et al. A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock. Nature 394, 381?384 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Hamada, T. et al. The role of inositol trisphosphate-induced Ca2+ release from IP3-receptor in the rat suprachiasmatic nucleus on circadian entrainment mechanism. Neurosci. Lett. 263 , 125?128 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Miyazaki, S. et al. Essential role of the inositol 1,4,5-trisphosphate receptor/Ca2+ release channel in Ca2+ waves and Ca2+ oscillations at fertilization of mammalian eggs. Dev. Biol. 158, 62?78 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Jones, K. T., Matsuda, M., Parrington, J., Katan, M. & Swann, K. Different Ca2+-releasing abilities of sperm extracts compared with tissue extracts and phospholipase C isoforms in sea urchin egg homogenate, and mouse eggs. Biochem. J. 346, 743?749 ( 2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Swanson, C. A., Arkin, A. P. & Ross, J. An endogenous calcium oscillator may control early embryonic division. Proc. Natl Acad. Sci. USA 94, 1194?119 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kono, T., Jones, K. T., BosMikich, A., Whittingham, D. G. & Carroll, J. A cell cycle-associated change in Ca2+ releasing activity leads to the generation of Ca2+ transients in mouse embryos during the first mitotic division . J. Cell Biol. 132, 915? 923(1996).

    Article  CAS  PubMed  Google Scholar 

  56. Chang, D. C. & Meng, C. L A localized elevation of cytosolic-free calcium is associated with cytokinesis in the zebrafish embryo. J. Cell Biol. 131, 1539?1545 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Keating, T. J., Cork, R. J. & Robinson, K. R. Intracellular free calcium oscillations in normal and cleavage-blocked embryos and artificially activated eggs of Xenopus-laevis . J. Cell Sci. 107, 2229? 2237 (1994).

    CAS  PubMed  Google Scholar 

  58. Kubota, H. Y., Yoshimoto, Y. & Hiramoto, Y. Oscillation of intracellular free calcium in cleaving and cleavage-arrested embryos of Xenopus-laevis. Dev. Biol. 160, 512?518 ( 1993).

    Article  Google Scholar 

  59. Stith, B. J., Goalstone, M., Silva, S. & Jaynes, C. Inositol 1,4,5-trisphosphate mass changes from fertilization through 1st-cleavage in Xenopus laevis . Mol. Biol. Cell 4, 435? 443 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Han, J. K. Oscillation of inositol polyphosphates in the embryonic cleavage cycle of the Xenopus laevis. Biochem. Biophys. Res. Commun. 206, 775?780 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Ciapa, B., Pesando, D., Wilding, M. & Whitaker, M. Cell-cycle calcium transients driven by cyclic changes in inositol trisphosphate levels. Nature 368, 875?878 ( 1994).Some of the first evidence that cyclic changes in inositol-1,4,5-trisphosphate and Ca2+ are responsible for controlling certain cell-cycle events, especially those occurring at mitosis.

    Article  CAS  PubMed  Google Scholar 

  62. Gilland, E., Miller, A. L., Karplus, E., Baker, R. & Webb, S. E. Imaging of multicellular large-scale rhythmic calcium waves during zebrafish gastrulation. Proc. Natl Acad. Sci. USA 96, 157?161(1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Webb, S. E. & Miller, A. L. Calcium signalling during zebrafish embryonic development. Bioessays 22, 113 ?123 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Creton, R., Speksnijder, J. E. & Jaffe, L. F. Patterns of free calcium in zebrafish embryos. J. Cell Sci. 111, 1613?1622 (1998).

    CAS  PubMed  Google Scholar 

  65. Maslanski, J. A, Leshko, L. & Busa, W. B. Lithium-sensitive production of inositol phosphates during amphibian embryonic mesoderm induction. Science 256, 243?245(1992).

    Article  CAS  PubMed  Google Scholar 

  66. Kume, S., Muto, A., Okano, H. & Mikoshiba, K. Developmental expression of the inositol 1,4,5-trisphosphate receptor and localization of inositol 1,4,5-trisphosphate during early embryogenesis in Xenopus laevis . Mech. Dev. 66, 157?168 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Reinhard, E. et al. Localized calcium signals in early zebrafish development. Dev. Biol. 170, 50?71( 1995).

    Article  CAS  PubMed  Google Scholar 

  68. Creton, R., Kreiling, J. A. & Jaffe, L. F. Presence and roles of calcium gradients along the dorsal-ventral axis in Drosophila embryos. Dev. Biol. 217, 375?385 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. K¨hl, M., Sheldahl, L. C., Malbon, C. C. & Moon, R. T. Ca2+/calmodulin-dependent protein kinase II is stimulated by Wnt and frizzled homologs and promotes ventral cell fates in Xenopus. J. Biol. Chem. 275, 12701?12711 (2000).

    Article  Google Scholar 

  70. Kume, S. et al. Role of inositol 1,4,5-trisphosphate receptor in ventral signaling in Xenopus embryos. Science 278, 1940?1943 (1997). A role for Ca2+ in setting up the dorsoventral axis in Xenopus oocytes was demonstrated by showing that the axis was modified by inhibiting the activity of the inositol-1,4,5-trisphosphate receptor.

    Article  CAS  PubMed  Google Scholar 

  71. Buonanno, A. & Fields, R. D. Gene regulation by patterned electrical activity during neural and skeletal muscle development. Curr. Opin. Neurobiol. 9, 110?120 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  72. Ferrari, M. B., Ribbeck, K., Hagler, D. J. & Spitzer, N. C. A calcium signaling cascade essential for myosin thick filament assembly in Xenopus myocytes. J. Cell Biol. 141, 1349 ?1356 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gu, X. N. & Spitzer, N. C. Breaking the code: Regulation of neuronal differentiation by spontaneous calcium transients. Dev. Neurosci. 19, 33?41(1997).

    Article  CAS  PubMed  Google Scholar 

  74. Carey, M. B. & Matsumoto, S. G. Spontaneous calcium transients are required for neuronal differentiation of murine neural crest. Dev. Biol. 215, 298?313 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Gomez, T. M. & Spitzer, N. C. In vivo regulation of axon extension and pathfinding by growth-cone calcium transients. Nature 397, 350?355( 1999).By studying Ca2+ signals in individual neurons growing in vivo , it was possible to show that brief Ca2+ transients function both in the extension of the axon and in its ability to locate its target.

    Article  CAS  PubMed  Google Scholar 

  76. Wong, R. O. L. Retinal waves and visual system development. Annu. Rev. Neurosci. 22, 29?47 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  77. Lu, K. P. & Means, A. R. Regulation of the cell-cycle by calcium and calmodulin. Endocrine Rev. 14, 40?58 (1993).

    Article  CAS  Google Scholar 

  78. Berridge, M. J. Calcium signalling and cell-proliferation. Bioessays 17, 491?500 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Monks, C. R. F., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82?86 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Akagi, K., Nagao, T. & Urushidani, T. Correlation between Ca2+ oscillation and cell proliferation via CCKB/gastrin receptor. Biochim. Biophys. Acta 1452, 243?253 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Scharenberg, A. M. & Kinet, J. P. Ptdlns-3,4,5-P 3: A regulatory nexus between tyrosine kinases and sustained calcium signals. Cell 94, 5?8 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Lewis, R. S. & Cahalan, M. D. Potassium and calcium channels in lymphocytes. Annu. Rev. Immunol. 13, 623?653 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Hoth, M., Fanger, C. M. & Lewis, R. S. Mitochondrial regulation of store-operated calcium signalling in T lymphocytes. J. Cell Biol. 137, 633?648 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Crabtree, G. R. Generic signals and specific outcomes: Signaling through Ca2+, calcineurin, and NF-AT. Cell 96, 611? 614 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Timmerman, L. A., Clipstone, N. A., Ho, S. N., Northrop, J. P. & Crabtree, G. R. Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression. Nature 383, 837?840 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  86. Chawla, S., Hardingham, G. E., Quinn, D. R. & Bading, H. CBP: A signal-regulated transcriptional coactivator controlled by nuclear calcium and CaM kinase IV. Science 281, 1505?1509 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Hardingham, G. E., Chawla, S., Cruzalegui, F. H. & Bading, H. Control of recruitment and transcription?activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22, 789?798 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  88. Wang, J. H., Moreira, K. M., Campos, B., Kaetzel, M. A. & Dedman, J. R. Targeted neutralization of calmodulin in the nucleus blocks DNA synthesis and cell cycle progression. Biochim. Biophys. Acta 1313, 223?228 (1996).

    Article  PubMed  Google Scholar 

  89. Yang, H., Shen, F., Herenyiova, M. & Weber, G. Phospholipase C (EC 3. 1. 4. 11): A malignancy linked signal transduction enzyme. Anticancer Res. 18, 1399?1404 (1998).

    CAS  PubMed  Google Scholar 

  90. Smith, M. R. et al. Overexpression of phosphoinositide-specific phospholipase C γ in NIH 3T3 cells promotes transformation and tumorigenicity. Carcinogenesis 19, 177?185 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Rizzo, M. T. & Weber, G. L. Phosphatidylinositol 4-kinase ? an enzyme linked with proliferation and malignancy. Cancer Res. 54, 2611?2614 ( 1994).

    CAS  PubMed  Google Scholar 

  92. Benzaquen, L. R., Brugnara, C., Byers, H. R., Gattoni-Celli, S. & Halperin, J. A. Clotrimazole inhibits cell proliferation in vitro and in vivo. Nature Med. 1, 534?540 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Nie, L., Mogami, H., Kanzaki, M., Shibata, H. & Kojima, I. Blockade of DNA synthesis induced by platelet-derived growth factor by tranilast, an inhibitor of Ca2+ entry, in vascular smooth muscle cells. Mol. Pharm. 50, 763?769 (1996).

    Google Scholar 

  94. Haverstick, D. M., Heady, T. N., Macdonald, T. L. & Gray, L. S. Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block Ca2+ entry. Cancer Res. 60, 1002?1008 (2000).

    CAS  PubMed  Google Scholar 

  95. Kohn, E. C. et al. Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers. Cancer Res. 56 , 569?573 (1996).

    CAS  PubMed  Google Scholar 

  96. Gao, B. et al. Functional properties of a new voltage-dependent calcium channel α 2δ auxiliary subunit gene (CACNA2D2). J. Biol. Chem. 275, 12237?12242 ( 2000).One of the first indications that malignancy might be linked to an alteration in Ca2+ signalling.

    Article  CAS  PubMed  Google Scholar 

  97. Kass, G. E. N. & Orrenius, S. Calcium signaling and cytotoxicity. Environ. Health Perspect. 107, 25?35 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Szalai, G., Krishnamurthy, R. & Hajnoczky, G. Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J. 18, 6349? 6361 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shimizu, S., Narita, M. & Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399, 483?487 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Barr, P. J. & Tomei, L. D. Apoptosis and its role in human disease. Biotechnology 12, 487? 493 (1994).

    Article  CAS  PubMed  Google Scholar 

  101. Reed, J. C. Bcl-2 and the regulation of programmed cell-death. J. Cell Biol. 124, 1?6 (1994 ).

    Article  CAS  PubMed  Google Scholar 

  102. Murphy, A., Bredesen, D. E., Cortopassi, G., Wang, E. & Fiskum, G. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc. Natl Acad. Sci. USA 93, 9893?9898 ( 1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Vander Heiden, M., Chandel, N. S., Williamson, E. K., Schumacker, P. T. & Thompson, C. B. Bcl-x L regulates the membrane potential and volume homeostasis of mitochondria . Cell 91, 627?637 (1997).

    Article  Google Scholar 

  104. Zhu, L. P. et al. Modulation of mitochondrial Ca2+ homeostasis by Bcl-2. J. Biol. Chem. 274, 33267? 33273 (1999).Evidence that mitochondrial metabolism can be modulated by the anti-apoptotic modulator Bcl-2.

    Article  CAS  PubMed  Google Scholar 

  105. Kuo, T. H. et al. Modulation of endoplasmic reticulum calcium pump by Bcl-2 . Oncogene 17, 1903?1910 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. Foyouzi-Youssefi, R. et al. Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 97, 5723?5728 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pinton, P. et al. Reduced loading on intracellular Ca2+ stores and downregulation of capacitative Ca2+ influx in Bcl-2-overexpressing cells. J. Biol. Chem. 275, 857? 862 (2000).

    Google Scholar 

  108. Schlossmann, J. et al. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Iβ. Nature 404, 197?201 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  109. Morimoto, A. M. et al. The MMAC1 tumor suppressor phosphatase inhibits phospholipase C and integrin-linked kinase-activity. Oncogene 19, 200?209 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Lev, S. et al. Protein-tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion-channel and map kinase functions. Nature 376, 737?745 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Brinson, A. E. et al. Regulation of a calcium-dependent tyrosine kinase in vascular smooth muscle cells by angiotensin II and platelet-derived growth factor. Dependence on calcium and the actin cytoskeleton. J. Biol. Chem. 273, 1711?1718 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  112. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinases of proHB?EGF. Nature 402, 884?888 (1999).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Michael J. Berridge.

Supplementary information

Related links

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DATABASE LINKS

α1S

α1C

α2δ

Bad

Bak1

β-amyloid precursor protein

Bax

Bcl-2

Bcl-XL

calbindin-D28K

Calcineurin

calmodulin

calretinin

CAMKII

CAMKIV

CBP

cholecystokinin receptors

CREB

Cytochrome c

EF hands

FAS

FAS ligand

gastrin

IκB

Inositol-1,4,5-trisphosphate receptors

interleukin-2

MAPK

muscarinic acetylcholine receptors

muscarinic M3 receptors

Na+/Ca2+ exchanger

NF-AT

NF-κB

parvalbumin

phosphorylase kinase

PKC

presenilins

PI(3)K

PLCγ1

Phosphatidylinositol-4-OH kinase

ryanodine receptors

synaptotagmin

troponin C

FURTHER INFORMATION

Inositol signalling

M. J. Sanderson's lab page

ELS LINKS

Calcium signalling and regulation of cell function

Calcium and neurotransmitter release

Calcium channel diversity

Glossary

Ca2+-INDUCED Ca2+ RELEASE

An autocatalytic mechanism by which cytoplasmic Ca2+ activates the release of Ca2+ from internal stores through channels such as inositol-1,4,5-trisphosphate receptors or ryanodine receptors.

VOLTAGE-OPERATED CHANNELS

Plasma-membrane ion channels that are activated by membrane depolarization.

RECEPTOR-OPERATED CHANNELS

Plasma membrane ion channels that open in response to binding of an extracellular ligand.

STORE-OPERATED CHANNELS

Plasma membrane ion channels, of uncertain identity, that open in response to depletion of internal Ca2+ stores.

CDC25

A dual-specificity threonine/tyrosine phosphatase required for progression of the cell cycle. It dephosphorylates and activates cyclin?CDK complexes.

SOMITES

A series of paired blocks of cells that form during early vertebrate development and give rise to the backbone and body muscle.

SPHINGOMYELIN SIGNALLING

Several metabolites of sphingomyelin affect apoptosis through poorly undertood mechanisms: ceramide and sphingomyelin are generally proapoptotic whereas sphingosine 1-phosphate is generally antiapoptotic.

STRESS-ACTIVATED PROTEIN KINASES

Members of the mitogen-activated protein kinase (MAPK) family that are activated by stress, including c-Jun N-terminal kinase (JNK) and p38 MAPK.

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Berridge, M., Lipp, P. & Bootman, M. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1, 11–21 (2000). https://doi.org/10.1038/35036035

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