Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Calcium

Calcium signalling: dynamics, homeostasis and remodelling

Key Points

  • Ca2+ is a highly versatile intracellular signal that operates over a wide temporal range to regulate many different cellular processes. This signalling system uses 'on' reactions that introduce Ca2+ into the cell and 'off' reactions that remove it from the cytoplasm.

  • An extensive Ca2+-signalling toolkit is used to assemble cell-specific signalling systems that have very different spatial and temporal dynamics. Channels in the plasma membrane and endoplasmic/sarcoplasmic reticulum are responsible for the on reactions, whereas pumps and exchangers carry out the off reactions.

  • Many of these Ca2+-signalling components are organized into macromolecular complexes in which Ca2+-signalling functions are carried out within highly localized environments. These complexes can operate as autonomous units that can be multiplied or mixed and matched to create larger, more diverse signalling systems, as illustrated by cardiac Ca2+ signalling.

  • Rapid highly localized Ca2+ spikes regulate fast responses, whereas repetitive global transients or intracellular Ca2+ waves control slower responses. Cells respond to such oscillations using sophisticated mechanisms including an ability to interpret changes in frequency, and such frequency-modulated signalling can regulate specific responses such as exocytosis, mitochondrial redox state and differential gene transcription.

  • The operation of Ca2+-signalling systems is constantly under review by an internal quality-assessment mechanism that can respond to changes in the properties of its output signal. We propose the hypothesis that Ca2+ itself has an important function in this internal assessment mechanism by remodelling its own signalling pathway.

  • Several important disease states (hypertension, heart disease, diabetes, manic depression, Alzheimer's disease) might result from abnormal remodelling of Ca2+ signalling. For example, Ca2+ has a prominent role in the remodelling that occurs during both cardiac hypertrophy and congestive heart failure.

Abstract

Ca2+ is a highly versatile intracellular signal that operates over a wide temporal range to regulate many different cellular processes. An extensive Ca2+-signalling toolkit is used to assemble signalling systems with very different spatial and temporal dynamics. Rapid highly localized Ca2+ spikes regulate fast responses, whereas slower responses are controlled by repetitive global Ca2+ transients or intracellular Ca2+ waves. Ca2+ has a direct role in controlling the expression patterns of its signalling systems that are constantly being remodelled in both health and disease.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Calcium-signalling dynamics and homeostasis.
Figure 2: Calcium-mobilizing messengers and modulators.
Figure 3: Cardiac calcium-signalling module.
Figure 4: A calcium-induced calcium-signalling remodelling hypothesis.
Figure 5: Signalling pathways that participate in the control of compensatory hypertrophy.

Similar content being viewed by others

References

  1. Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).

    CAS  Google Scholar 

  2. Carafoli, E., Santella, L., Brance, D. & Brisi, M. Generation, control, and processing of cellular calcium signals. Crit. Rev. Biochem. Mol. Biol. 36, 107–260 (2001).

    CAS  PubMed  Google Scholar 

  3. Bootman, M. D., Berridge, M. J. & Roderick, H. L. Calcium signalling: more messengers, more channels, more complexity. Curr. Biol. 12, R563–R565 (2002).

    CAS  PubMed  Google Scholar 

  4. Kelley, G. G., Reks, S. E., Ondrako, J. M. & Smrcka, A. V. Phospholipase Cε: a novel Ras effector. EMBO J. 20, 743–754 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Saunders, C. M. et al. PLCζ: a sperm-specific trigger of Ca2+ oscillations in eggs and embryo development. Development 129, 3533–3544 (2002). The mystery of how mammalian eggs are activated seems to have been solved by the discovery that the sperm injects a new PLC, PLCζ, into the egg to stimulate the production of Ins(1,4,5)P 3.

    CAS  PubMed  Google Scholar 

  6. Van der Wal, J., Habets, R., Várnai, P., Balla, T. & Jalink, K. Monitoring agonist-induced phospholipase C activation in live cells by fluorescence resonance energy transfer. J. Biol. Chem. 276, 15337–15344 (2001).

    CAS  PubMed  Google Scholar 

  7. Kim, D. et al. Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389, 290–293 (1997).

    CAS  PubMed  Google Scholar 

  8. Tanaka, J. et al. Gq protein α-subunits Gαq and Gα11 are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells. Eur. J. Neurosci. 12, 781–792 (2000).

    CAS  PubMed  Google Scholar 

  9. Kawabate, S. et al. Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature 383, 89–92 (1996).

    Google Scholar 

  10. Luo, X., Popov, S., Bera, A. K., Wilkie, T. M. & Muallem, S. RGS proteins provide biochemical control of agonist-evoked [Ca2+]I oscillations. Mol. Cell 7, 651–660 (2001).

    CAS  PubMed  Google Scholar 

  11. 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).

    CAS  PubMed  Google Scholar 

  12. Patel, S., Churchill, G. C. & Galione, A. Coordination of Ca2+ signalling by NAADP. Trends Biochem. Sci. 26, 482–489 (2001).

    CAS  PubMed  Google Scholar 

  13. Cancela, J. M., Van Coppenolle, F., Galione, A., Tepikin, A. V. & Petersen, O. H. Transformation of local Ca2+ spikes to global Ca2+ transients: the combinatorial roles of multiple Ca2+ releasing messengers. EMBO J. 21, 909–919 (2002). This paper describes the complex interactions among the different intracellular Ca2+-mobilizing messengers such as Ins(1,4,5)P 3 , cADPR and NAADP.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee, H. C. Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP. Physiol. Rev. 77, 1133–1164 (1997).

    CAS  PubMed  Google Scholar 

  15. Tohgo, A. et al. Lysine 129 of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) participates in the binding of ATP to inhibit the cyclic ADP-ribose hydrolase. J. Biol. Chem. 272, 3879–3882 (1997).

    CAS  PubMed  Google Scholar 

  16. Wilson, H. L. et al. ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor: a primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction. J. Biol. Chem. 276, 11180–11188 (2001).

    CAS  PubMed  Google Scholar 

  17. Churchill, G. C. et al. NAADP mobilizes Ca2+ from reserve granules, lysosome-related organelles, in sea urchin eggs. Cell 111, 703–708 (2002).

    CAS  PubMed  Google Scholar 

  18. Hua, S. -Y. et al. Cyclic ADP-ribose modulates Ca2+ release channels for activation by physiological Ca2+ entry in bullfrog sympathetic neurons. Neuron 12, 1073–1079 (1994).

    CAS  PubMed  Google Scholar 

  19. Hashii, M., Minabe, Y. & Higashida, H. cADP-ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L-type voltage-activated Ca2+ channels in NG108–15 neuronal cells. Biochem. J. 345, 207–215 (2000).

    PubMed  PubMed Central  Google Scholar 

  20. Currie, K. P. M., Swann, K., Galione, A. & Scott, R. H. Activation of Ca2+-dependent currents in cultured rat dorsal root ganglion neurones by a sperm factor and cyclic ADP-ribose. Mol. Biol. Cell 3, 1415–1425 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cui, Y., Galione, A. & Terrar, D. A. Effects of photoreleased cADP-ribose on calcium transients and calcium sparks in myocytes isolated from guinea-pig and rat ventricle. Biochem. J. 342, 269–273 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Empson, R. M. & Galione, A. Cyclic ADP-ribose enhances coupling between voltage-gated Ca2+ entry and intracellular Ca2+ release. J. Biol. Chem. 272, 20967–20970 (1997).

    CAS  PubMed  Google Scholar 

  23. Lukyanenko, V., Györke, I., Wiesner, T. F. & Györke, S. Potentiation of Ca2+ release by cADP-ribose in the heart is mediated by enhanced SR Ca2+ uptake into the sarcoplasmic reticulum. Circ. Res. 89, 614–622 (2001). This paper indicates that cADPR might function to enhance Ca2+ signalling by stimulating the SERCA pump to increase the luminal level of Ca2+.

    CAS  PubMed  Google Scholar 

  24. Rakovic, S. et al. An antagonist of cADP-ribose inhibits arrhythmogenic oscillations of intracellular Ca2+ in heart cells. J. Biol. Chem. 274, 17820–17827 (1999).

    CAS  PubMed  Google Scholar 

  25. Noguchi, N. et al. Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca2+ from islet microsomes. J. Biol. Chem. 272, 3133–3136 (1997).

    CAS  PubMed  Google Scholar 

  26. Koizumi. S., Lipp, P., Berridge, M. J. & Bootman, M. D. Regulation of ryanodine receptor opening by lumenal Ca2+ underlies quantal Ca2+ release in PC12 cells. J. Biol. Chem. 274, 33327–33333 (1999).

    CAS  PubMed  Google Scholar 

  27. Young, K. W. et al. Lysophosphatidic acid-induced Ca2+ mobilisation requires intracellular sphingosine 1-phosphate production: potential involvement of endogenous Edg-4 receptors. J. Biol. Chem. 275, 38532–38539 (2000). Evidence of Ca2+ mobilization by distinct pathways using Ins(1,4,5)P 3 or S1P within the same cell.

    CAS  PubMed  Google Scholar 

  28. Melendez, A. J. & Khaw, A. A. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J. Biol. Chem. 277, 17255–17262 (2002).

    CAS  PubMed  Google Scholar 

  29. Schnurbus, R., De Pietri Tonelli, D., Grohovaz, F. & Zacchetti, D. Re-evaluation of primary structure, topology, and localization of Scamper, a putative intracellular Ca2+ channel activated by sphingosylphosphocholine. Biochem. J. 362, 183–189 (2002). SCaMPER has been widely cited as a receptor for Ca2+-mobilizing sphingolipids. This paper presents a detailed characterization of the SCaMPER protein, which indicates that it is unlikely to function as a conventional Ca2+ channel.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mignen, O. & Shuttleworth, T. J. IARC, a novel arachidonate-regulated, noncapacitative Ca2+ entry channel. J. Biol. Chem. 275, 9114–9119 (2000). The principal route for hormone-stimulated Ca2+ entry into cells was believed to be by a store-operated mechanism. Emerging evidence indicates that many cells express a distinct Ca2+-entry pathway that is activated by arachidonic acid.

    CAS  PubMed  Google Scholar 

  31. Clapham, D. E., Runnels, L. W. & Strübing, C. The TRP ion channel family. Nature Rev. Neurosci. 2, 387–396 (2001).

    CAS  Google Scholar 

  32. Minke, B. & Cook, B. TRP channel proteins and signal transduction. Physiol. Rev. 82, 429–472 (2002).

    CAS  PubMed  Google Scholar 

  33. Montell, C., Birnbaumer, L. & Flockerzi, V. The TRP channels, a remarkably functional family. Cell 108, 595–598 (2002).

    CAS  PubMed  Google Scholar 

  34. Vennekens, R., Voets, T., Bindels, R. J. M., Droogmans, G. & Nilius, B. Current understanding of mammalian TRP homologues. Cell Calcium 31, 253–264 (2002).

    CAS  PubMed  Google Scholar 

  35. Nadif Kasri, N. et al. The role of calmodulin for inositol 1,4,5-trisphosphate receptor function. Biochim. Biophys. Acta 1600, 19–31 (2002).

    CAS  PubMed  Google Scholar 

  36. Taylor, C. W. & Laude, A. J. IP3 receptors and their regulation by calmodulin and cytosolic Ca2+. Cell Calcium 32, 321–334 (2002).

    CAS  PubMed  Google Scholar 

  37. Yang, J. et al. Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels. Proc. Natl Acad. Sci. USA 99, 7711–7716 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Roderick, H. L. et al. Inhibition of inositol 1,4,5-trisphosphate (InsP3)-induced calcium release by neuronal calcium binding proteins (CaBP). J. Physiol. (Lond.) 547P, PC36 (2003).

    Google Scholar 

  39. Koller, A. et al. Association of phospholamban with a cGMP kinase signaling complex. Biochem. Biophys. Res. Commun. 300, 155–160 (2003).

    CAS  PubMed  Google Scholar 

  40. Yokoyama, K. et al. BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP3 receptor. EMBO J. 21, 83–92 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. DeSouza, N. et al. Protein kinase A and two phosphatases are components of the inositol 1,4,5-trisphosphate receptor macromolecular signaling complex. J. Biol. Chem. 277, 39397–39400 (2002).

    CAS  PubMed  Google Scholar 

  42. Bezprozvanny, I., Watras, J. & Ehrlich, B. E. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351, 751–754 (1991). A classic paper that described the co-activation of Ins(1,4,5)P 3 Rs by Ca2+ and Ins(1,4,5)P 3.

  43. Balshaw, D. M., Xu, L., Yamaguchi, N., Pasek, D. A. & Meissner, G. Calmodulin binding and inhibition of cardiac muscle calcium release channel (ryanodine receptor). J. Biol. Chem. 276, 20144–20153 (2001).

    CAS  PubMed  Google Scholar 

  44. Marks, A. R., Marx, S. O. & Reiken, S. Regulation of ryanodine receptors via macromolecular complexes: a novel role for leucine/isoleucine zippers. Trends Cardiovasc. Med. 12, 166–170 (2002).

    CAS  PubMed  Google Scholar 

  45. Marx, S. O. et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365–376 (2000).

    CAS  PubMed  Google Scholar 

  46. Lokuta, A. J., Meyers, M. B., Sander, P. R., Fishman, G. I. & Valdivia, H. H. Modulation of cardiac ryanodine receptors by sorcin. J. Biol. Chem. 272, 25333–25338 (1997).

    CAS  PubMed  Google Scholar 

  47. Muller, F. U. et al. Junctional sarcoplasmic reticulum transmembrane proteins in the heart. Basic Res. Cardiol. 97, I52–I55 (2002).

    PubMed  Google Scholar 

  48. Zhang, L., Kelley, J., Schmeisser, G., Kobayashi, Y. M. & Jones, L. R. Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. J. Biol. Chem. 272, 23389–23397 (1997). Much attention has focused on accessory cytosolic proteins as modulators of the RYRs, but there also is evidence that the transmembrane proteins junctin and triadin cooperate with the luminal protein calsequestrin to regulate the activity of these release channels.

    CAS  PubMed  Google Scholar 

  49. Nauli, S. M. et al. J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet. 33, 129–137 (2003).

    CAS  PubMed  Google Scholar 

  50. Koulen, P. et al. Polycystin-2 is an intracellular calcium release channel. Nature Cell Biol. 4, 191–197 (2002). The cellular locations and functions of polycystins are not well understood, but they somehow seem to regulate epithelial-cell proliferation. This paper presents evidence that one member of the family forms functional channels that can function in a Ca2+-induced Ca2+ release mode.

    CAS  PubMed  Google Scholar 

  51. Gonzalez-Perrett, S. et al. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc. Natl Acad. Sci. USA 98, 1182–1187 (2001).

    CAS  PubMed  Google Scholar 

  52. Cai, Y. et al. Identification and characterisation of polycystin-2, the PKD2 gene product. J. Biol. Chem. 274, 28557–28565 (1999).

    CAS  PubMed  Google Scholar 

  53. John, L. M., Mosquera-Caro, M., Camacho, P. & Lechleiter, J. D. Control of IP3-mediated Ca2+ puffs in Xenopus laevis oocytes by the Ca2+-binding protein parvalbumin. J. Physiol. (Lond.) 535, 3–16 (2001).

    CAS  Google Scholar 

  54. Palecek, J., Lips, M. B. & Keller, B. U. Calcium dynamics and buffering in motoneurones of the mouse spinal cord. J. Physiol. (Lond.) 520, 485–502 (1999).

    CAS  Google Scholar 

  55. Schwaller, B. et al. Prolonged contraction–relaxation cycle of fast-twitch muscles in parvalbumin knockout mice. Am. J. Physiol. 276, C395–C403 (1999).

    CAS  PubMed  Google Scholar 

  56. Caillard, O. et al. Role of calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc. Natl Acad. Sci. USA 97, 13372–13377 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Collins, T. J., Lipp, P., Berridge, M. J. & Bootman, M. D. Mitochondrial Ca2+ uptake depends on the spatial and temporal profile of cytosolic Ca2+ signals. J. Biol. Chem. 276, 26411–26420 (2001).

    CAS  PubMed  Google Scholar 

  58. Colegrove, S. L., Albrecht, M. A. & Friel, D. D. Quantitative analysis of mitochondrial Ca2+ uptake and release in sympathetic neurons. J. Gen. Physiol. 115, 371–388 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Caride, A. J. et al. Delayed activation of the plasma membrane calcium pump by a sudden increase in Ca2+: fast pumps reside in fast cells. Cell Calcium 30, 49–57 (2001).

    CAS  PubMed  Google Scholar 

  60. Wuytack, F., Raeymaekers, L. & Missiaen, L. The molecular physiology of the SERCA and SPCA pumps. Cell Calcium 32, 279–305 (2002).

    CAS  PubMed  Google Scholar 

  61. Ozil, J. P. & Swann, K. Stimulation of repetitive calcium transients in mouse eggs. J. Physiol. (Lond.) 483, 331–346 (1995)

    CAS  Google Scholar 

  62. Gomez, T. M., Snow, D. M. & Letourneau, P. C. Characterization of spontaneous calcium transients in nerve growth cones and their effect on growth cone migration. Neuron 14, 1233–1246 (1995).

    CAS  PubMed  Google Scholar 

  63. Gomez, T. M. Robles, E., Poo, M -m. & Spitzer, N. C. (2001) Filopodial calcium transients promote substrate-dependent growth cone turning. Science 291, 1983–1987 (2001). This paper shows that filopodia scout ahead of neuronal growth cones to detect preferred growth substrates. When engaged, these substrates induce local Ca2+ signals in the filopodia that are transmitted back to the growth cone to deflect its path. An increased frequency of Ca2+ transients correlates with greater turning.

    CAS  PubMed  Google Scholar 

  64. Tang, F., Dent, E. W. & Kalil, K. Spontaneous calcium transients in developing cortical neurons regulate axonal outgrowth. J. Neurosci. 23, 927–936 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Komuro, H. & Rakic, P. Intracellular Ca2+ fluctuations modulate the rate of neuronal migration. Neuron 17, 275–285 (1996).

    CAS  PubMed  Google Scholar 

  66. Ciccolini, F. et al. Local and global spontaneous calcium events regulate neurite outgrowth and onset of GABAergic phenotype during neural precursor differentiation. J. Neurosci. 23, 103–111 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ehrhardt, D. W., Wais, R. & Long, S. R. Calcium spiking in plant root hairs responding to Rhizobium nodulation signals. Cell 85, 673–681 (1996).

    CAS  PubMed  Google Scholar 

  68. Tashiro, A., Goldberg, J. & Yuste, R. Calcium oscillations in neocortical astrocytes under epileptiform conditions. J. Neurobiol. 50, 45–55 (2001).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Uhlén, P. et al. α-Haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells. Nature 277, 694–697 (2000).

    Google Scholar 

  71. Giannone, G., Rondé, P., Gaire, M., Haiech, J. & Takeda, K. Calcium oscillations trigger focal adhesion disassembly in human U87 astrocytoma cells. J. Biol. Chem. 277, 26364–26371 (2002).

    CAS  PubMed  Google Scholar 

  72. Tse, A., Tse, F. W., Almers, W. & Hille, B. Rhythmic exocytosis stimulated by GnRH-induced calcium oscillations in rat gonadotropes. Science 260, 82–84 (1993).

    CAS  PubMed  Google Scholar 

  73. Hajnóczky, G., Robb-Gaspers, L. D., Seitz, M. B. & Thomas, A. P. Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82, 415–424 (1995).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  75. Li, W -h., Liopis, J., Whitney, M., Xlokarnik, G. & Tsien, R. Y. Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression. Nature 392, 936–941 (1998). References 74 and 75 have helped to establish the importance of frequency-modulated Ca2+ signalling as a mechanism to control differential gene activation.

    CAS  PubMed  Google Scholar 

  76. Haisenleder, D. J. et al. Gonadotrophin subunit transcriptional responses to calcium signals in the rat: evidence for regulation by pulse frequency. Biol. Reprod. 65, 1789–1793 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. Olsen, E. A. & Williams, R. S. Remodelling muscles with calcineurin. Bioessays 22, 510–519 (2000).

    Google Scholar 

  79. De Koninck, P. & Shulman, H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279, 227–230 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  81. Niggli, E. Localized intracellular calcium signaling in muscle: calcium sparks and calcium quarks. Annu. Rev. Physiol. 61, 311–335 (1999).

    CAS  PubMed  Google Scholar 

  82. Thomas, D. et al. Microscopic properties of elementary Ca2+ release sites in non-excitable cells. Curr. Biol. 10, 8–15 (2000).

    CAS  PubMed  Google Scholar 

  83. Euler, T., Detwiler, P. B. & Denk, W. Directionally selective calcium signals in dendrites of starburst amacrine cells. Nature 418, 845–852 (2002).

    CAS  PubMed  Google Scholar 

  84. Fauquier, T., Guérineau, N. C., McKinney, R. A., Bauer, K. & Mollard, P. Folliculostellate cell network: A route for long-distance communication in the anterior pituitary. Proc. Natl Acad. Sci. USA 98, 8891–8896 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wallingford, J. B., Ewald, A. J., Harland, R. M. & Fraser, S. E. Calcium signaling during convergent extension in Xenopus. Curr. Biol. 11, 652–661 (2001).

    CAS  PubMed  Google Scholar 

  86. Robb-Gaspers, L. D. & Thomas, A. P. Coordination of Ca2+ signaling by intercellular propagation of Ca2+ waves in the intact liver. J. Biol. Chem. 270, 8102–8107 (1995).

    CAS  PubMed  Google Scholar 

  87. Yashiro, Y. & Duling, B. R. Integrated Ca2+ signaling between smooth muscle and endothelium of resistance vessels. Circ. Res. 87, 1048–1054 (2000).

    CAS  PubMed  Google Scholar 

  88. Wang, S. -Q., Song, L. -S., Lakatta, E. G. & Cheng, H. Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature 410, 592–596 (2001).

    CAS  PubMed  Google Scholar 

  89. Robert, V. et al. Beat-to-beat oscillations of mitochondrial [Ca2+] in cardiac cells. EMBO J. 20, 4998–5007 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Crabtree, G. R. Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NFAT. Cell 96, 611–614 (1999).

    CAS  PubMed  Google Scholar 

  91. Mellström, B. & Naranjo, J. R. Mechanisms of Ca2+-dependent transcription. Curr. Opin. Neurobiol. 11, 312–319 (2001).

    PubMed  Google Scholar 

  92. West, A. E. et al. Calcium regulation of neuronal gene expression. Proc. Natl Acad. Sci. USA 98, 11024–11031 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. McKinsey, T. A., Zhang, C. L. & Olsen, E. N. MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem. Sci. 27, 40–47 (2002).

    CAS  PubMed  Google Scholar 

  94. Carafoli, E., Genazzani, A. & Guerini, D. Calcium controls the transcription of its own transporters and channels in developing neurons. Biochem. Biophys. Res. Commun. 266, 624–632 (1999).

    CAS  PubMed  Google Scholar 

  95. Guerini, D., Wang, X., Li, L., Genazzani, A. & Carafoli, E. Calcineurin controls the expression of isoforms 4CII of the plasma membrane Ca2+ pump in neurons. J. Biol. Chem. 275, 3706–3712 (2000).

    CAS  PubMed  Google Scholar 

  96. Li, L., Guerini, D. & Carafoli, E. Calcineurin controls the transcription of Na+/Ca2+ exchanger isoforms in developing cerebellar neurons. J. Biol. Chem. 275, 20903–20910 (2000).

    CAS  PubMed  Google Scholar 

  97. Genazzani, A. A., Carafoli, E. & Guerini, D. Calcineurin controls inositol 1,4,5-trisphosphate type 1 receptor expression in neurons. Proc. Natl Acad. Sci. USA 96, 5797–5801 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Graef, I. A. et al. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401, 703–708 (1999). This paper and reference 97 have shown that Ca2+ can regulate the transcription of some of its signalling components, such as Ins(1,4,5)P 3 Rs.

    CAS  PubMed  Google Scholar 

  99. Brini, M., Bano, D., Manni, S., Rizzuto, R. & Carafoli, E. Effects of PMCA and SERCA pump overexpression on the kinetics of cell Ca2+ signalling. EMBO J. 19, 4926–4935 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ji, Y. et al. Disruption of a single copy of the SERCA2 gene results in altered Ca2+ homeostasis and cardiomyocyte function. J. Biol. Chem. 275, 38073–38080 (2000).

    CAS  PubMed  Google Scholar 

  101. Zhao, X. -S., Shin, D. M., Liu, L. H., Shull, G. E. & Muallem, S. Plasticity and adaptation of Ca2+ signalling and Ca2+-dependent exocytosis in SERCA2+/− mice. EMBO J. 20, 2680–2689 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Song, L. -S. et al. Ca2+ signaling in cardiac myocytes overexpressing the α1 subunit of L-type Ca2+ channel. Circ. Res. 90, 174–181 (2002).

    CAS  PubMed  Google Scholar 

  103. Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kirchhefer, U. et al. Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1. J. Biol. Chem. 276, 4142–4149 (2001).

    CAS  PubMed  Google Scholar 

  105. Zhang, L., Franzini-Armstrong, C., Ramesh, V. & Jones, L. R. Structural alterations in cardiac calcium release units resulting from overexpression of junctin. J. Mol. Cell. Cardiol. 33, 233–247 (2001).

    CAS  PubMed  Google Scholar 

  106. Jones, L. R. et al. Regulation of calcium signalling in transgenic mouse cardiac myocytes overexpressing calsequestrin. J. Clin. Invest. 101, 1385–1393 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Mende, U. et al. Transient cardiac expression of constitutively active Gαq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc. Natl Acad. Sci. USA 95, 13893–13898 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Knollmann, B. C., Knollmann-Ritschel, B. E., Weissman, N. J., Jones, L. R. & Morad, M. Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. J. Physiol. (Lond.) 525, 483–498 (2000).

    CAS  Google Scholar 

  109. Wettschureck, N. et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gαq/ Gα11 in cardiomyocytes. Nature Med. 7, 1236–1240 (2001). This paper provides direct evidence that receptors that are coupled to G /G 11α function in cardiac hypertrophy.

    CAS  PubMed  Google Scholar 

  110. Antos, C. L. et al. Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 99, 907–912 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Sato, Y. et al. Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation. J. Biol. Chem. 276, 9392–9399 (2001).

    CAS  PubMed  Google Scholar 

  112. Song, Q. et al. Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. J. Clin. Invest. 111, 859–867 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Haghighi, K. et al. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J. Clin. Invest. 111, 869–876 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Wilkins, B. J. & Molkentin, J. D. Calcineurin and cardiac hypertrophy: where have we been? where are we going? J. Physiol. 541, 1–8 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Xin, H. -B. et al. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 416, 334–337 (2002).

    CAS  PubMed  Google Scholar 

  116. Schwinger et al. Reduced Ca2+-sensitivity of SERCA2a in failing human myocardium due to reduced serine-16 phospholamban phosphorylation. J. Mol. Cell. Cardiol. 31, 479–491 (1999).

    PubMed  Google Scholar 

  117. Piacentino III, V. et al. Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ. Res. 92, 651–658 (2003).

    Google Scholar 

  118. Naga Prasad, S. V., Nienaber, J. & Rockman, H. A. β-adrenergic axis and heart disease. Trends Genet. 17, S44–S49 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Biotechnology and Biological Sciences Research Council. M. D. B. gratefully acknowledges the support of a Royal Society University Fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael J. Berridge.

Related links

Related links

DATABASES

LocusLink

AKAP

CaBP

calsequestrin

CaMKII

Ins(1,4,5)P3Rs

mGluRs

NMDARs

NCX

phospholamban

PLCβ

PMCA

RYRs

SERCA

syntaxin

SwissProt

FKBP12.6

GKAP

PR130

PSD95

SNAP-25

spinophilin

yotiao

Glossary

PHOSPHOLIPASE C

(PLC). A phosphodiesterase that splits the bond between the phosphorus atom and the oxygen atom at C-1 of the glycerol moiety.

RYANODINE RECEPTOR

(RYR). A Ca2+-release channel that is located in the membrane of the endoplasmic/sarcoplasmic reticulum and is regulated by several factors including Ca2+ itself, as well as the intracellular messenger cyclic ADP ribose.

Ca2+-INDUCED Ca2+ RELEASE

(CICR). 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 CHANNEL

(VOC). A plasma-membrane ion channel that is activated by membrane depolarization.

SARCO(ENDO)PLASMIC RETICULUM Ca2+-ATPASE

(SERCA). A pump located in sarcoplasmic or endoplasmic reticulum membranes that couples ATP hydrolysis to the transport of Ca2+ from cytosolic to lumenal spaces.

RECEPTOR-OPERATED CHANNEL

(ROC). A plasma-membrane ion channel that opens in response to the binding of an extracellular ligand.

SECOND-MESSENGER-OPERATED CHANNEL

(SMOC). A plasma-membrane ion channel that opens in response to the binding of intracellular second messengers such as diacylglycerol, cyclic nucleotides or arachidonic acid.

STORE-OPERATED CHANNEL

(SOC). A plasma-membrane ion channel, of uncertain identity, that opens in response to the depletion of internal Ca2+ stores.

FIGHT-OR-FLIGHT RESPONSE

This response occurs in the hypothalamus, which, when stimulated by stress, initiates a sequence of nerve-cell firing and chemical release (including adrenaline and noradrenaline) that prepares our body for running or fighting.

AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY DISEASE

(ADPKD). A fatal disease that is characterized by the progressive development of fluid-filled cysts in the kidney, liver and pancreas.

Ca2+-BINDING RATIO

(KS). The ratio between the amount of Ca2+ that is bound compared to the Ca2+ that is free in the cytosol.

PLASMA-MEMBRANE Ca2+-ATPASE

(PMCA). A pump on the plasma membrane that couples ATP hydrolysis to the transport of Ca2+ from cytosolic to extracellular spaces.

Na+/Ca2+ EXCHANGER

(NCX). A plasma-membrane enzyme that exchanges three moles of Na+ for one mole of Ca2+, either inward or outward, depending on the ionic gradients across the membrane.

MITOCHONDRIAL UNIPORTER

A 'channel' that is located in the inner mitochondrial membrane that transports Ca2+ from the cytosol into the mitochondrial matrix.

HAILEY–HAILEY DISEASE

A rare autosomal-dominant skin disease that is characterized by disturbed keratinocyte adhesion.

SALTATORIC PROPAGATION

A mechanism by which Ca2+ signals leap from one group of Ca2+ channels to the next.

T-TUBULE

(transverse tubule). A tubular invagination of the plasma membrane in a muscle fibre, the function of which is to pass the excitation signal from the muscle-cell surface to the sarcomeres, to ensure rapid and synchronous activation.

JUNCTIONAL ZONE

The narrow space that is located between the T-tubule and sarcoplasmic reticulum in cardiac cells in which the process of excitation–contraction coupling occurs.

INOTROPIC

Affecting the force of cardiac contractions.

SIGNALSOME

The collection of components that constitute the different signalling pathways found in specific cell types.

DARIER'S DISEASE

An autosomal-dominant skin disorder.

CONGESTIVE HEART FAILURE

A syndrome that is characterized by the failure of the heart to maintain the circulation of the blood adequately.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berridge, M., Bootman, M. & Roderick, H. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4, 517–529 (2003). https://doi.org/10.1038/nrm1155

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1155

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing