The Signaling Function of Calcium and Its Regulation

  • Ernesto Carafoli


In the course of evolution Ca has become a signaling agent of universal significance, which controls a large number of cellular functions: prominent among them are the synthesis and release of hormones, muscle and non-muscle motility, and a multiplicity of membrane-linked processes (see Carafoli, 1987, for a recent comprehensive review). It is self evident that the signaling function of Ca demands its maintenance within cells at a very low free concentration, and mechanisms to efficiently modulate it in the cell compartments where the targets of the signaling function are located. Other signaling agents are regulated within cells by biosynthesis and breakdown. Since this is impossible in the case of Ca, evolution has selected an entirely different control mechanism, i.e., the reversible complexation by specific proteins, which are either soluble, organized in non membranous structures, or intrinsic to membranes. These proteins “buffer” intracellular Ca at a concentration which is at least 10,000 fold lower than in the external spaces. The functional cycle of cells requires both short and long term regulation of Ca. The rapid and precise modulation is performed by intracel1ular Ca binding proteins but also (in fact mostly, see below) by high Ca affinity membrane intrinsic proteins. The Ca-filtering function of the plasma membrane, which depends on the operation of membrane-intrinsic Ca binding proteins, is responsible for the long term maintenance of the Ca gradient between cells and medium.


Sarcoplasmic Reticulum Plasmic Reticulum Inositol Tris Phosphate Fast Skeletal Muscle Isocitric Acid 
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  1. Babu, Y.S., Sack, J.S., Greenhough, T.J., Bugg, C.E., Means, A.R., and Cook, W.J., 1985, Three-dimensional structure of calmodulin, Nature, 315: 37.PubMedCrossRefGoogle Scholar
  2. Borsotto, M., Norman, R.I., Fosset, M., and Lazdunski, M., 1984, Eur. J. Biochem., 14: 449.CrossRefGoogle Scholar
  3. Carafoli, E, 1979, The calcium cycle of mitochondria, FEBS Letters, 104: 1.PubMedCrossRefGoogle Scholar
  4. Carafoli, E., 1982, The transport of calcium across the inner membrane of mitochondria, in: “Membrane Transport of Calcium”, E. Carafoli, ed., Academic Press, London, pp 109.Google Scholar
  5. Carafoli, E., 1982, Membrane transport and the regulation of the cell calcium levels, in: “Pathophysiology of Shock, Anoxia, and Ischemia”, R.A. Cowley, and B.F. Trump, eds., Williams and Wilkins, pp 95.Google Scholar
  6. Carafoli, E., 1987, Intracellular calcium homeostasis, Ann. Rev. Biochem., 56: 395.PubMedCrossRefGoogle Scholar
  7. Carafoli, E., Tiozzo, G., Lugli, F., Crovetti, F., and Kratzing, C., 1974, The release of calcium from heart mitochondria by sodium, J. Molec. Cell. Cardiol., 6: 361.CrossRefGoogle Scholar
  8. Caroni, P., and Carafoli, E., 1981, Regulation of Ca2+ -pumping ATPase of heart sarcolemma by a phosphorylation-dephosphorylation process, J. Biol. Chem., 256: 9371.PubMedGoogle Scholar
  9. Caroni, P., and Carafoli, E., 1983, The regulation of the Na+/Ca2+ exchanger of heart sarcolemma, Eur. J. Biochem., 132: 451.PubMedCrossRefGoogle Scholar
  10. Crompton, M., Moser, R., Lüdi, H., and Carafoli, E., 1978, The interrelations between the transport of sodium and calcium in mitochondria of various mammalian tissues, Eur. J. Biochem., 82: 25.PubMedCrossRefGoogle Scholar
  11. Crompton, M., Sigel, E., Salzmann, M., and Carafoli, E., 1976, A kinetic study of the energy-linked influx of Ca into heart mitochondria, Eur. J. Biochem., 69: 429.CrossRefGoogle Scholar
  12. Curtis, B.M., and Catterall, W.A., 1985, Phosphorylation of the calcium antagonist receptor of the voltage-sensitive calcium channel by cAMP-dependent protein kinase, Proc. Nat. Acad. Sci., USA, 82: 2528.CrossRefGoogle Scholar
  13. Denton, R.M., Randle, P.J., and Martin, B.R., 1972, Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase, Biochem. J., 128: 161.PubMedGoogle Scholar
  14. Denton, R.M., Richards, D.A., and Chin, J.G., 1978, Calcium ions and the regulation of NAD+ -linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues, Biochem. J., 176: 899.PubMedGoogle Scholar
  15. Fabiato, A., and Fabiato, F., 1975, Contractions induced by a calcium triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells, J. Physiol., 249: 457.Google Scholar
  16. Fleckenstein, A., 1973, Calcium antagonism in heart and smooth muscle, John Wiley, New York.Google Scholar
  17. Grand, R.J.A., Perry, S.V., and Weeks, R.A., 1979, Troponin-C like proteins (calmodulin) from mammalian smooth muscle and other tissues, Biochem. J., 177: 521.PubMedGoogle Scholar
  18. Herzberg, 0., and James, M.N.G., 1985, Structure of the calcium regulatory muscle protein troponin-C at 2.8. A resolution, Nature, 313: 665.CrossRefGoogle Scholar
  19. Krause, K.H., Volpe, P., Zorzato, F., Hashimoto, S., Pozzan, T., Meldolesi, J., and Lew, P.D., 1987, Calciosomesi evidence for a new type of organelle regulating intracellular Ca, Seventh Intern. Washington Spring Symposium, Abstract 64.Google Scholar
  20. Kretsinger, R.H., and Nelson, D.J., 1977, Calcium in biological systems, Coord. Chem. Rev., 18: 29.CrossRefGoogle Scholar
  21. Kretsinger, R.H., and Nockolds, C.E., 1973, Carp muscle calcium-binding protein, J. Biol. Chem., 248: 3313.PubMedGoogle Scholar
  22. Longoni, S. and Carafoli, E., 1987, Identification of the Na+/Ca2+ exchanger of calf heart sarcolemma with the help of specific antibodies, Biochem. Biophys. Res. Commun., 145: 1059.PubMedCrossRefGoogle Scholar
  23. MacLennan, D.H., 1970, Purification an3 properties of an adenosine triphosphatase from sarcoplasmic reticulum, J. Biol. Chem., 245: 4508.PubMedGoogle Scholar
  24. MacLennan, D.H., Brandl, C.J., Korczak, B., and Green, N.M., 1985, Amino-acid sequence of a Ca2+ + Mg2+ -dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence, Nature, 316: 696.PubMedCrossRefGoogle Scholar
  25. McCormack, J.G., and Denton, R.M., 1979, The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex, Biochem. J., 180: 533.PubMedGoogle Scholar
  26. Meissner, G., and Henderson, J.S., 1987, Rapid calcium release from sarcoplasmic reticulum vesicles is dependent on calcium and is modulated by Mg2+, adenine nucleotide, and calmodulin, J. Biol. Chem. 262: 3065.PubMedGoogle Scholar
  27. Niggli, V., Adunyah- Penniston, J.T., and Carafoli, E., 1981, Purified (Ca2+-Mg2+)-ATPase of the erythrocyte membrane; reconstitution and effect of calmodulin and phospholipids, J. Biol. Chem., 256: 395.PubMedGoogle Scholar
  28. Nilius, B., Hess, P., Lansmann, J.B., and Tsien, R.W., 1985, A novel type of cardiac calcium channel in ventricular cells, Nature, 316: 443.PubMedCrossRefGoogle Scholar
  29. Philipson, K.D., 1985, Sodium-calcium exchange in plasma membrane vesicles, Ann. Rev. Physiol., 47: 561.CrossRefGoogle Scholar
  30. Reeves, J.P., and Sutko, J.L., 1979, Sodium-calcium exchange in cardiac membrane vesicles, Proc. Nat. Acad. Sci. USA, 76: 590.PubMedCrossRefGoogle Scholar
  31. Reuter, H., 1984, Ion channels in cardiac cell membranes, Ann. Rev. Physiol., 46: 473.CrossRefGoogle Scholar
  32. Reuter, H., Stevens, C.F., Tsien, R.W., and Yellen, G., 1982, Properties of single calcium channels in cardiac cell culture, Nature, 297: 501.PubMedCrossRefGoogle Scholar
  33. Schatzmann, H., 1982, The calcium pump of erythorcytes and other animal cells, in “Membrane Transport of Calcium”, E. Carafoli, ed., Academic Press, London, pp 41.Google Scholar
  34. Somlyo, A.V., Bond, M., Somlyo, A.P., and Scarpa, A., 1985, Inositol tris phosphate-induced calcium release and contraction in vascular smooth muscle, Proc. Nat. Acad. Sci., 82: 5231.PubMedCrossRefGoogle Scholar
  35. Somlyo, A.P., Somlyo, A.V., and Shuman, H., 1979, Electron probe analysis of vascular smooth muscle, composition of mitochondria, nuclei, and cytoplasm, J. Cell Biol., 81: 316.PubMedCrossRefGoogle Scholar
  36. Streb, H., Irvine, R.F., Berridge, M.J., and Schulz, I., 1983, Release of Ca2+ from a non-mitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate, Nature, 306: 66.CrossRefGoogle Scholar
  37. Szebenyi, D.M.E., Obendorf, S.K., and Moffat, K., 1981, Structure of vitamin D-dependent calcium binding protein from bovine intestine, Nature, 294: 327.PubMedCrossRefGoogle Scholar
  38. Tada, M., Kirchberger, M.A., and Katz, A.M., 1975, Phosphorylation of 22.000-Dalton component of the cardiac sarcoplasmic reticulum by adenosine 3″:5″-monophosphate-dependent protein kinase, J. Biol. Chem., 250: 2640.PubMedGoogle Scholar
  39. Tanabel, T., Takeshima, H., Mikami, A., Flockerzi, V., Takahashi, H., Kangaura, K., Kojima, M., Matsuo, H., Hirose, T., and Numa, S., 1987, Primary structure of the receptor for calcium channel blockers from skeletal muscle, Nature, 328: 313.CrossRefGoogle Scholar
  40. Vaghy, P.L., Johnson, J.D., Matlib, M.A., Wang, T., and Schwarz, A., 1982, Selective inhibition of Na+-induced Ca2+ release from heart mitochondria by diltiazem and certain other Ca2+ antagonist drugs, J. Biol. Chem., 257: 6000.PubMedGoogle Scholar
  41. Volpe, P., Krause, K.H., Hashimoto, G., Zorzato, F., Pozzan, T., Meldolesi, J., and Lew, D.P., 1988, “Calcisome”, a cytoplasmic organelle: the inositol 1,4,5-trisphosphate-sensitive Ca2+ store of non-muscle cells? Proc. Nat. Acad. Sci., U.S.A., 85: 1091.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Ernesto Carafoli
    • 1
  1. 1.Laboratory of BiochemistrySwiss Federal Institute of Technology (ETH)ZürichSwitzerland

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