Skip to main content
SpringerLink
Log in

Multifunctional Ca2+/calmodulin-dependent protein kinase

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) is a prominent mediator of neurotransmitters which elevate Ca2+. It coordinates cellular responses to external stimuli by phosphorylating proteins involved in neurotransmitter synthesis, neurotransmitter release, carbohydrate metabolism, ion flux and neuronal plasticity. Structure/function studies of CaM kinase have provided insights into how it decodes Ca2+ signals. The kinase is kept relatively inactive in its basal state by the presence of an autoinhibitory domain. Binding of Ca2+/calmodulin eliminates this inhibitory constraint and allows the kinase to phosphorylate its substrates, as well as itself. This autophosphorylation significantly slows dissociation of calmodulin, thereby trapping calmodulin even when Ca2+ levels are subthreshold. The kinase may respond particularly wel to multiple Ca2+ spikes since trapping may enable a spike frequency-dependent recruitment of calmodulin with each successive Ca2+ spike leading to increased activation of the kinase. Once calmodulin dissociates, CaM kinase remains partially active until it is dephosphorylated, providing for an additional period in which its response to brief Ca2+ transients is potentiated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Krebs, E. G. 1989. Role of the cyclic AMP-dependent protein kinase in signal tranduction. JAMA 262:1815–1818.

    Google Scholar 

  2. Greengard, P. 1978. Phosphorylated proteins as physiological effectors. Science 199:146–152.

    Google Scholar 

  3. Blackshear, P. J., Nairn, A. C., and Kuo, J. F. 1988. Protein kinases 1988: a current perspective. FASEB J. 2:2957–2969.

    Google Scholar 

  4. Hanson, P. I. and Schulman, H. 1992. Neuronal Ca2+/calmodulin-dependent protein kinases. Ann. Rev. Biochem. 61:559–601.

    Google Scholar 

  5. Colbran, R. J., and Soderling, T. R. 1990. Calcium/calmodulin-dependent protein kinase II. Curr. Topics in Cell. Reg. 31:181–221.

    Google Scholar 

  6. Cohen, P. 1988. The calmodulin-dependent multiprotein kinase. 145–194 145–194,in P. Cohen and C. Klee, Calmodulin, Elsevier Science Publishers, Amsterdam.

    Google Scholar 

  7. Schulman, H. 1988. The multifunctional Ca2+/calmodulin-dependent protein kinase. Adv. Second Mess. Phosphoprotein Res. 22:39–112.

    Google Scholar 

  8. Schulman, H., and Lou, L. L. 1989. Multifunctional Ca2+/calmodulin-dependent protein kinase: domain structure and regulation. TIBS 14:62–66.

    Google Scholar 

  9. Schulman, H. 1991. Serine/threonine kinases in the nervous system. Curr. Opin. Neurobiol. 1:43–52.

    Google Scholar 

  10. Rostas, J. A. P. 1991. Molecular mechanisms of neuronal maturation: a model for synaptic plasticity. 177–211 177–211,in R. J. Andrew, Neural and behavioral plasticity. The use of the domestic chicken as a model., Oxford Science Publications.

  11. Rostas, J. A. P., and Dunkley, P. R. 1992. Distribution of multiple forms of calcium/calmodulin stimulated protein kinase II in brain. J. Neurochem. in press.

  12. Dunkley, P. R. 1992. Autophosphorylation of neuronal calcium/calmodulin-stimulated protein kinase II. Mol. Neurobiol., in press.

  13. Krueger, B. K., Forn, J., and Greengard, P. 1977. Depolarization-induced phosphorylation of specific proteins, mediated by calcium ion influx, in rat brain synaptosomes. J. Biol. Chem. 252:2764–2773.

    Google Scholar 

  14. Schulman, H., and Greengard, P. 1978. Stimulation of brain membrane protein phosphorylation by calcium and an endogenous heat-stable protein. Nature 271:478–479.

    Google Scholar 

  15. Schulman, H., and Greengard, P. 1978. Ca2+-dependent protein phosphorylation system in membranes from various tissues and its activation by “calcium-dependent regulator.”. Proc. Natl. Acad. Sci., USA 75:5432–5436.

    Google Scholar 

  16. Fukunaga, K., Yamamoto, H., Matsui, K., Higashi, K., and Miyamoto, E. 1982. Purification and characterization of a Ca2+ and calmodulin-dependent protein kinase from rat brain. J. Neurosci. 39:1607–1617.

    Google Scholar 

  17. Bennett, M. K., Erondu, N. E., and Kennedy, M. B. 1983. Purification and characterization of a calmodulin-dependent protein kinase that is highly concentrated in brain. J. Biol. Chem. 258:12735–12744.

    Google Scholar 

  18. Kennedy, M. B., McGuinness, T., and Greengard, P. 1983. A calcium/calmodulin-dependent protein kinase from mammalian brain that phosphorylates synapsin I: partial purification and characterization. J. Neurosci. 3:818–831.

    Google Scholar 

  19. Yamauchi, T., and Fujisawa, H. 1983. Purification and characterization of the brain calmodulin-dependent protein kinase (kinase II), which is involved in the activation of tryptophan 5-mono-oxygenase. Eur. J. Biochem. 132:15–21.

    Google Scholar 

  20. Goldenring, J. R., Gonzalez, B., Mcguire J. S., and DeLorenzo, R. J. 1983. Purification and characterization of a calmodulin-dependent kinase from rat brain cytosol able to phosphorylate tubulin and microtubule associated proteins. J. Biol. Chem. 258:12632–12640.

    Google Scholar 

  21. Schulman, H. 1984. Phosphorylation of microtubule-associated proteins by a Ca2+/calmodulin-dependent protein kinase. J. Cell Biol. 99:11–19.

    Google Scholar 

  22. Kuret, J., and Schulman, H. 1984. Purification and characterization of a Ca2+/calmodulin-dependent protein kinase from rat brain. Biochemistry 23:5495–5504.

    Google Scholar 

  23. Woodgett, J. R., Davison, M. T., and Cohen, P. 1983. The calmodulin-dependent glycogen synthase kinase from rabbit skeletal muscle. Purification, subunit structure and substrate specificity. Eur. J. Biochem. 136:481–487.

    Google Scholar 

  24. Ahmad, Z., DePaoli-Roach, A. A., and Roach, P. J. 1982. Purification and characterization of a rabbit liver calmodulindependent protein kinase able to phosphorylate glycogen synthase. J. Biol. Chem. 257:8348–8355.

    Google Scholar 

  25. Payne, M. E., Schworer, C. M., and Soderling, T. R. 1983. Purification and characterization of rabbit liver calmodulin-dependent glycogen, synthase kinase. J. Biol. Chem. 258:2376–2382.

    Google Scholar 

  26. McGuinness, T. L., Lai, Y., Greengard, P., Woodgett, J. R., and Cohen, P. 1983. A multifunctional calmodulin-dependent protein kinase. Similarities between skeletal muscle glycogen synthase kinase and a brain synapsin I kinase. FEBS Lett. 163:329–334.

    Google Scholar 

  27. Pearson, R. B., Woodgett, J. R., Cohen, P., and Kemp, B. E. 1985. Substrate specificity of a multifunctional calmodilin-dependent protein kinase. J. Biol. Chem. 260:14471–14476.

    Google Scholar 

  28. Kennelly, P. J., and Krebs, E. G. 1991. Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J. Biol. Chem. 266:15555–15558.

    Google Scholar 

  29. Ando, S., Tokui, T., Yamauchi, T., Sugiura, H., Tangbe, K. and Inagaki, M. 1991. Evidence that Ser-82 is a unique phosphorylation site on vimentin for Ca2+/calmodulin-dependent protein kinase II. Biochem. Biophys. Res. Commun. 175:955–962.

    Google Scholar 

  30. Nestler, E. J., and Greengard, P. 1982. Distribution of protein I and regulation of its state of phosphorylation in the rabbit superior cervical ganglion. J. Neurosci. 2:1011–1023.

    Google Scholar 

  31. Nestler, E. J., and Greengard, P. 1982. Nerve impulses increase the phosphorylation state of protein I in rabbit superior cervical ganglion. 296:452–454.

  32. Connelly, P. A., Sisk, R. B., Schulman, H., and Garrison, J. C. 1987. Evidence for the activation of the multifunctional Ca2+/ calmodulin-dependent protein kinase in response to hormones that increase intracellular Ca2+. J. Biol. Chem. 262:10154–10163.

    Google Scholar 

  33. Garrison, J. C., Johnsen, D. E., and Campanile, C. P. 1984. Evidence for the role of phosphorylase kinase, protein kinase C, and other Ca2+-sensitive protein kinases in the response, of hepatocytes to angiotensin II and vasopressin. J. Biol. Chem. 259:3283–3292.

    Google Scholar 

  34. Griffith, L. C., and Schulman, H. 1988. The multifunctional Ca2+/calmodulin-dependent protein kinase mediates Ca2+-dependent phosphorylation of tyrosine hydroxylase. J. Biol. Chem. 263:9542–9549.

    Google Scholar 

  35. Waymire, J. C., Johnston, J. P., Hummer-Lickteig, K., Lloyd, A., Vigny, A., and Craviso, G. L. 1988. Phosphorylation of bovine adrenal chromaffin cell tyrosine hydroxylase. Temporal correlation of acetylcholine's effect on site phosphorylation, enzyme activation, and catecholamine synthesis. J. Biol. Chem. 263:12439–12447.

    Google Scholar 

  36. Wegener, A. D., Simmerman, H. K. B., Lindemann, J. P., and Jones, L. R. 1989. Phospholamban phosphorylation intact ventricles. J. Biol. Chem. 264:11468–11474.

    Google Scholar 

  37. Stull, J. T., Hsu, L., Tansey, M. G., and Kamm, K. E. 1990. Myosin light chain kinase phosphorylation in tracheal smooth muscle. J. Biol. Chem. 265:16683–16690.

    Google Scholar 

  38. Jefferson, A. B., and Schulman, H. 1991. Phosphorylation of microtubule-associated protein-2 in GH3 cells. Regulation by cAMP and by calcium. J. Biol. Chem. 266:346–354.

    Google Scholar 

  39. Malinow, R., Schulman, H., and Tsien, R. W. 1989. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP Science 245:862–866.

    Google Scholar 

  40. Baitinger, C., Alderton, J., Poenie, M., Schulman, H., and Steinhardt, R. A. 1990. Multifunctional Ca2+/calmodulin-dependent protein kinase is necessary, for nuclear envelope breakdown. J. Cell Biol. 111:1763–1773.

    Google Scholar 

  41. Nichols., R. A., Sihra, T. S., Czernik A. J., Nair., A. C., and Greengard P. 1990. Calcium/calmodulin-dependent protein kinase II increases glutamate and noradrenaline release from synaptosomes. Nature 343:647–651.

    Google Scholar 

  42. Wagner, J. A., Cozens, A. L., Schulman, H., Gruenert, D. C., Stryer, L., and Gardner, P. 1991. Activation of chloride channels in normal and cystic fibrosis airway epithelial cells by multifunctional calcium/calmodulin-dependent protein kinase. Nature 349:793–796.

    Google Scholar 

  43. Worrell, R. T., and Frizzell, R. A. 1991. CaMKII mediates stimulation of chloride conductance by calcium in, T84 cells. Am. J. Physiol. 260:C877–882.

    Google Scholar 

  44. Cohen, M. E., Reinlib, L., Watson, A. J. M., Gorelick, F., Rys-Sikora, K., Tse, M., Rood, R. P., Czernik A. J., Sharp, G. W. G., and Donowitz, M. 1990. Rabbit ileal villus cell brush border Na+/H+ exchange is regulated by Ca2+/calmodulin-dependent protein kinase II, a brush border membrane protein. Proc. Natl. Acad. Sci., USA 87:8990–8994.

    Google Scholar 

  45. McGuinness, T. L., Lai, Y., and Greengard, P. 1985. Ca2+/calmodulin-dependent protein kinase II. Isozymic forms from rat forebrain and cerebellum. J. Biol. Chem. 260:1696–1704.

    Google Scholar 

  46. Miller, S. G., and Kennedy, M. B. 1985. Distinct forebrain and cerebellar isozymes of type II Ca2+/calmodulin-dependent protein kinase associate differently with the postsynaptic density fraction. J. Biol. Chem. 260:9039–9046.

    Google Scholar 

  47. Kanaseki, T., Ikeuchi., Y., Sugiura H. and Yamauchi, T. 1991. Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy. J. Cell biol. 115:1049–1060.

    Google Scholar 

  48. Ouimet, C. C., McGuinness, T. L., and Greengard, P. 1984. Immunocytochemical localization of calcium/calmodulin-dependent protein kinase II in rat brain. Proc. Natl. Acad. Sci. USA 81:5604–5608.

    Google Scholar 

  49. Erondu, N. E., and Kennedy, M. B. 1985. Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain. J. Neurosci. 5:3270–3277.

    Google Scholar 

  50. Fukunaga, K., Goto, S., and Miyamoto, E. 1988. Immunohistochemical localization of Ca2+/calmodulin-dependent protein kinase II in rat brain and various tissues. J. Neurochem. 51:1070–1078.

    Google Scholar 

  51. Lin, C. R., Kapiloff, M. S., Durgerian, S., Tatemoto, K., Russo, A. F., Hanson, P., Schulman, H., and Rosenfeld, M. G. 1987. Molecular cloning of a brain-specific calcium/calmodulin-dependent protein kinase. Proc. Natl. Acad. Sci. USA 84:5962–5966.

    Google Scholar 

  52. Burgin, K. E., Waxham, M. N., Rickling, S., Westgate, S. A., Mobley, W. C. and Kelly, P. T. 1990.In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J. Neurosci. 10:1788–1798.

    Google Scholar 

  53. Kelly, P. T., and Vernon, P. 1985. Changes in the subcellular distribution of calmodulin-kinase II during brain development. Brain Res. 350:211–224.

    Google Scholar 

  54. Dunkley, P. R., Cote, A., and Harrison, S. M. 1991. Autophosphorylation of calmodulin-stimulated protein kinase II intact synaptosomes. J. Mol. Neurosci. 2:193–201.

    Google Scholar 

  55. Kennedy, M. B., Bennett, M. K., and Erondu, N. E. 1983. Biochemical and immunochemical evidence that the “major postsynaptic density protein” is a subunit of a calmodulin-dependent protein kinase Proc. Natl. Acad. Sci., USA 80:7357–7361.

    Google Scholar 

  56. Goldenring, J. R., McGuire, J. S., and DeLorenzo, R. J. 1984. Identification of the major postsynaptic density protein as homologous with the major calmodulin-binding subunit of a calmodulin-dependent protein kinase. J. Neurochem. 42:1077–1084.

    Google Scholar 

  57. Kelly, P. T., McGuinness, T. L., and Greengard, P. 1984. Evidence that the major postsynaptic density protein is a component of a Ca2+/calmodulin-dependent protein kinase. Proc. Natl. Acad. Sci., USA 81:945–949.

    Google Scholar 

  58. Rostas, J. A. P., Weinberger, R. P., and Dunkley, P. R. 1986. Multiple pools and multiple forms of calmodulin-stimulated protein kinase during development: relationship to postsynaptic, densities. Prog. Brain Res. 69:355–370.

    Google Scholar 

  59. Rich, D. P., Colbran, R. J., Schworer, C. M., and Soderling, T. R. 1989. Regulatory, properties of calcium/calmodulin-dependent protein kinase II in rat brain postsynaptic densities. J. Neurochem. 53:807–816.

    Google Scholar 

  60. Garner C. C., Tucker, R. P., and Matus, A. 1988. Selective localization of messenger RNA for cytoskeletal protein MAP2 in dendrites. Nature 336:674–677.

    Google Scholar 

  61. Saitoh, T., and Schwartz, J. H. 1985. Phosphorylation-dependent subcellular translocation of a Ca2+/calmodulin-dependent protein kinase produces an autonomous enzyme inAplysia neurons. J. Cell Biol. 100:835–842.

    Google Scholar 

  62. Bronstein, J., Wasterlain, C. G., Lasher, R., and Farber, D. B., 1989. Dark-induced changes in activity and compartmentalization of retinal calmodulin, kinase in the rat. Brain Res. 495:83–88.

    Google Scholar 

  63. Willmund, R., Mitschulat H., and Schneider, K. 1986. Longterm modulation of Ca2+-stimulated autophosphorylation and subcellular distribution of the Ca2+/calmodulin-dependent protein kinase in the brain ofDrosophila. Proc. Natl. Acad. Sci., USA 83:9789–9793.

    Google Scholar 

  64. Sahyoun, N. H., LeVine, I., Burgess, S. K., Blanchard, S., Chang, K. J., and Cuatrecasas, P. 1985. Early postnatal, development of calmodulin-dependent protein kinase II in rat brain. Biochem. Biophys. Res. Commun. 132:878–884.

    Google Scholar 

  65. Weinberger, R. P., and Rostas, J. A. P. 1986. Subcelluar distribution of a calmodulin-dependent protein kinase activity in rat cerebral cortex during development. Dev. Brain Res. 29:37–50.

    Google Scholar 

  66. Kelly, P. T., Shields, S., Conway, K., Yip, R., and Burgin, K. 1987. Developmental changes in calmodulin-kinase II activity at brain synaptic junctions: alterations in holoenzyme composition. J. Neurochem. 49:1927–1940.

    Google Scholar 

  67. Vallano, M. L. 1990. Developmental regulation of type II calcium/calmodulin-dependent kinase isoforms in rat cerebellum. J. Neurobiol. 21:1262–1273.

    Google Scholar 

  68. Hanley, R. M., Means, A. R., Ono, T., Kemp, B. E., Burgin, K. E., Waxham, N., and Kelly, P. T. 1987. Functional analysis of a complementary, DNA for the 50-kilodalton subunit of calmodulin kinase II. Science 237:293–297.

    Google Scholar 

  69. Bennett, M. K., and Kennedy, M. B. 1987. Deduced primary structure of the b subunit of brain type II Ca2+/calmodulin-dependent protein kinase determined by molecular cloning. Proc. Natl. Acad. Sci., USA 84:1794–1798.

    Google Scholar 

  70. Bulleit, R. F., Bennett, M. K., Molloy, S. S., Hurley, J. B., and Kennedy, M. B. 1988. Conserved and variable regions in the subunits of brain type II Ca2+/calmodulin-dependent protein kinase. Neuron. 1:63–72.

    Google Scholar 

  71. Tobimatsu, T., Kameshita, I., and Fujisawa, H. 1988. Molecular cloning of the cDNA encoding the third polypeptide (gamma) of brain calmodulin-dependent protein kinase II. J. Biol. Chem. 263:16082–16086.

    Google Scholar 

  72. Tobimatsu, T., and Fujisawa, H. 1989. Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs. J. Biol. Chem. 264:17907–17912.

    Google Scholar 

  73. Pausch, M. H., Kaim, D., Kunisawa, R., Admon, A., and Thorner, J. 1991. Multiple Ca2+/calmodulin-dependent protein kinase genes in a unicellular eukaryote. EMBO J. 10:1511–1522.

    Google Scholar 

  74. Ohya, Y., Kawasaki, H., Suzuki, K., Londesborough, J., and Anraku, Y. 1991. Two yeast genes encoding calmodulin,-dependent protein kinases. J. Biol. Chem. 266:12784–12794.

    Google Scholar 

  75. Hanks, S. K., Quinn, A. M., and Hunter, T. 1988. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:41–52.

    Google Scholar 

  76. LeVine, H., and Sahyoun, N. E. 1987. Characterization of a soluble Mr-30 000 catalytic fragment of the neuronal calmodulin-dependent protein kinase II. Eur. J. Biochem. 168:481–486.

    Google Scholar 

  77. Yamauchi, T., Ohsako, S., and Deguchi, T. 1989. Expression and characterization of calmodulin-dependent protein kinase II from cloned cDNAs in chinese hamster ovary cells. J. Biol. Chem. 264:19108–19116.

    Google Scholar 

  78. Kwiatkowski, A. P., and King, M. M. 1989. Autophosphorylation of the type II calmodulin-dependent protein kinase is essential for formation of a proteolytic fragment with catalytic activity. Implications for long-term snyaptic potentiation. Biochemistry 28:5380–5385.

    Google Scholar 

  79. Yamagata, Y., Czernik, A. J., and Greengard, P. 1991. Active catalytic fragment of Ca2+/calmodulin-dependent protein kinase II. Purification, characterization, and structural analysis. J. Biol. Chem. 266:15391–15397.

    Google Scholar 

  80. Stull, J. T. 1988. Myosin light chain kinases and caldesmon: biochemical properties and roles in skeletal and smooth muscle contractions. 91–122 91–122.,in P. Cohen and C. B. Klee, Calmodulin, Elsevier Science Publishers, Amsterdam.

    Google Scholar 

  81. Klee, C. B., and Cohen, P. 1988. The calmodulin-regulated protein phosphatase. 225–248 225–248,in C. B. Klee and P. Cohen, Calmodulin, Elsevier Science Publishers, Amsterdam.

    Google Scholar 

  82. LeVine, H., Sahyoun, N. E., and Cuatrecasas, P. 1986. Binding of calmodulin to the neuronal cytoskeletal protein kinase type II cooperatively stimulates autophosphorylation. Proc. Natl. Acad. Sci., USA 83:2253–2257.

    Google Scholar 

  83. Katoh, T., and Fujisawa, H. 1991. Calmodulin-dependent protein kinase II. Kinetic studies on the interaction with, substrates and calmodulin. Biochim. Biophys. Acta 1091:205–212.

    Google Scholar 

  84. Payne, M. E., Fong, Y.-L., Ono, T., Colbran., R. J., Kemp, B. E., Soderling, T. R., and Means., A. R. 1988. Calcium/ calmodulin-dependent protein kinase II: characterization of distinct calmodulin binding and inhibitory domains. J. Biol. Chem. 263:7190–7195.

    Google Scholar 

  85. Hanley, R. M., Means, A. R., Kemp, B. E., and Shenolikar, S. 1988. Mapping of calmodulin-binding domain of Ca2+/calmodulin-dependent protein kinase II from rat brain. Biochem. Biophy. Res. Commun. 152:122–128.

    Google Scholar 

  86. Kelly, P. T., Weinberger, R. P., and Waxham, M. N. 1988. Active site-directed, inhibition of Ca2+/calmodulin-dependent protein kinase II by a bifunctional calmodulin-binding peptide. Proc. Natl. Acad. Sci., USA 85:4991–4995.

    Google Scholar 

  87. Waldmann, R., Hanson, P. I., and Schulman, H. 1990. Multifunctional Ca2+/calmodulin-dependent protein kinase made Ca2+ independent for functional studies. Biochemistry 29:1679–1684.

    Google Scholar 

  88. Fong, Y.-L., and Soderling, T. R. 1990. Studies on the regulatory domain of Ca2+/calmodulin-dependent protein kinase II. Functional analyses of arginine 283 using synthetic inhibitory peptides and site-directd mutagenesis of the α subunit. J. Biol. Chem. 265:11091–11097.

    Google Scholar 

  89. Hagiwara, T., Ohsako, S., and Yamauchi, T. 1991. Studies on the regulatory domain of Ca2+/calmodulin-dependent protein kinase II by expression of mutated cDNAs inEscherichia coli. J. Biol. Chem. 266:16401–16408.

    Google Scholar 

  90. Colbran, R. J., Fong, Y.-L., Schworer, C. M., and Soderling, T. R. 1988. Regulatory interactions of the calmodulin-binding, inhibitory, and autophosphorylation domains of the Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 263:18145–18151.

    Google Scholar 

  91. Colbran, R. J., Smith, M. K., Schworer, C. M., Fong, Y.-L., and Soderling, T. R. 1989. Regulatory domain of calcium/calmodulinp-dependent protein kinase II. Mechanism of inhibition and regulation of phosphorylation. J. Biol. Chem. 264:4800–4804.

    Google Scholar 

  92. Hardie, G. 1988. Pseudosubstrates turn off protein kinases. Nature 335:592–593.

    Google Scholar 

  93. Soderling, T. R. 1990. Protein kinases. Regulation by autoinhibitory domains. J. Biol. Chem. 265:1823–1826.

    Google Scholar 

  94. Miller, S. G., and Kennedy, M. B. 1986. Regulation of brain type II Ca2+/camodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered swith. Cell 44:861–870.

    Google Scholar 

  95. Lai, Y., Naim, A. C., and Greengard, P. 1986. Autophosphorylation reversibly regulates the Ca2+/calmodulin-dependence of Ca2+/calmodulin-dependent protein kinase II. Proc. Natl. Acad. Sci., USA 83:4253–4257.

    Google Scholar 

  96. Lou, L. L., Lloyd, S. J., and Schulman., H. 1986. Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase by autophosphorylation: ATP modulates production of an autonomous enzyme. Proc. Natl. Acad. Sci., USA 83:9497–9501.

    Google Scholar 

  97. Schworer C. M., Colbran R. J., and Soderling, T. R. 1986. Reversible generation of a Ca2+-independent form of Ca2+ (calmodulin)-dependent protein kinase II by an autophosphorylation mechanism. J. Biol. Chem. 261:8581–8584.

    Google Scholar 

  98. Hashimoto, Y., Schworer, C. M., Colbran, R. J., and Soderling, T. R. 1987. Autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. Effects on total and Ca2+-independent activities and kinetic parameters. J. Biol. Chem. 262:8051–8055.

    Google Scholar 

  99. Ikeda, A., Okuno, S., and Fujisawa, H. 1991. Studies on the generation of Ca2+/calmodulin-independent activity of calmodulin-dependent protein kinase II by autophosphorylation. Autothiophosphorylation of the enzyme. J. Biol. Chem. 266:11582–11588.

    Google Scholar 

  100. Hashimoto, Y., King, M. M., and Soderling, T. R. 1988. Regulatory interactions of calmodulin-binding proteins: phosphorylation of calcineurin by autophosphorylated Ca2+/calmodulindependent protein kinase II. Proc. Natl. Acad. Sci., USA 85:7001–7005.

    Google Scholar 

  101. Hashimoto, Y., and Soderling, T. R. 1989. Regulation of calcineurin by phosphorylation. J. Biol. Chem. 264:16524–16529.

    Google Scholar 

  102. Martensen, T. M., Martin, B. M., and Kincaid., R. L. 1989. Identification of the site on calcineurin phosphorylated by Ca2+/ CaM-dependent kinase II: modification of the CaM-binding domain. Biochemistry 28:9243–9247.

    Google Scholar 

  103. Hashimoto, Y., Sharma, R. K., and Soderling, T. R. 1989. Regulation of Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase by the autophosphorylated form of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 264:10884–10887.

    Google Scholar 

  104. Ikebe, M., and Reardon, S. 1990. Phosphorylation of smooth muscle myosin light chain kinase by smooth muscle Ca2+/calmodulin-dependent multifunctional protein kinase. J. Biol. Chem. 265:8975–8978.

    Google Scholar 

  105. Hashimoto, Y., and Soderling, T. R. 1990. Phosphorylation of smooth muscle myosin light chain kinase by Ca2+/calmodulin-dependent protein kinase I: comparative study of the phosphorylation sites. Arch. Biochem. Biophys. 278:41–45.

    Google Scholar 

  106. Lai, Y., Nairm, A. C., Gorelick, F., and Greengard, P. 1987. Ca2+/calmodulin-dependent protein kinase II: identification of autophosphorylation sites responsible for generation of Ca2+/calmodulin-independence. Proc. Natl. Acad. Sci., USA 84:5710–5714.

    Google Scholar 

  107. Schworer, C. M., Colbran, R. J., Keefer, J. R., and Soderling, T. R. 1988. Ca2+/calmodulin-dependent protein kinase II Identification of a regulatory autophosphorylation site adjacent to the inhibitory and calmodulin-binding domains. J. Biol. Chem. 263:13486–13489.

    Google Scholar 

  108. Lou, L. L., and Schulman, H. 1989. distinct autophosphorylation sites sequentially produce autonomy and inhibition of the multifunctional Ca2+/calmodulin-dependent protein kinase. J. Neurosci. 9:2020–2032.

    Google Scholar 

  109. Thiel, G., Czernik, A. J., Gorelik, F., Nairn, A. C., and Greengard, P. 1988. Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+/independent activity. Proc. Natl. Acad. Sci., USA 85:6337–6341.

    Google Scholar 

  110. Miller, S. G., Patton, B. L., and Kennedy, M. B. 1988. Sequences of autophosphorylation sites in neuronal type II CaM kinase that contral Ca2+-independent activity Neuron. 1:593–604.

    Google Scholar 

  111. Hanson, P. I., Kapiloff, M. S., Lou, L. L., Rosenfeld, M. G., and Schulman, H. 1989. Expression of a multifunctional Ca2+/ calmodulin-dependent protein kinase and mutational analysis of its autoregulation. Neuron 3:59–70.

    Google Scholar 

  112. Fong, Y.-L. Taylor, W. L., Means, A. R., and Soderling, T. R. 1989. Studies of the regulatory mechanism of Ca2+/calmodulin-dependent protein kinase II. Mutation of threonine 286 to alanine and aspartate. J. Biol. Chem. 264:16759–16763.

    Google Scholar 

  113. Waxham, M. N., Aronowski, J., Westgate, S. A., and Kelly, P. T. 1990. Mutagenesis of Thr-286 in monomeric Ca2+/calmodulin-dependent protein kinase II eliminates Ca2+/calmodulin-independent activity. Proc. Natl. Acad. Sci., USA 87:1273–1277.

    Google Scholar 

  114. Ohsako, S., Nakazawa, H., Sekihara, S., Ikai, A., and Yamauchi, T. 1991. Role of threonine-286 as autophosphorylation site for appearance of Ca2+-independent activity of calmodulin-dependent protein kinase II a subunit. J. Biochem. (Tokyo) 109:137–143.

    Google Scholar 

  115. Kuret, J., and Schulman, H. 1985. Mechanism of autophosphorylation of the multifunctional Ca2+/calmodulin-dependent protein kinase. J. Biol. Chem. 260:6427–6433.

    Google Scholar 

  116. Gorelick, F. S., Wang, J. K. T., Lai, Y., Nairn A. C., and Greengard, P. 1988. Autophosphorylation and activation of Ca2+/ calmodulin-dependent protein kinase II in intact nerve terminals. J. Biol. Chem. 263:17209–17212.

    Google Scholar 

  117. Fukunaga, K., Rich, D. P., and Soderling, T. R. 1989. Gen eration of the Ca2+-independent form of Ca2+/calmodulin-dependent protein kinase II in cerebellar granule cells. J. Biol. Chem. 264:21830–21836.

    Google Scholar 

  118. MacNicol, M., Jefferson, A. B., and Schulman, H. 1990. Ca2+/ calmodulin kinase is activated by the phosphatidylinositol signaling pathway and becomes Ca2+-independent in PC12 cells. J. Biol. Chem. 265:18055–18058.

    Google Scholar 

  119. Jefferson, A. B., Travis, S. M., and Schulman, H. 1991. Activation of multifunctional Ca2+/calmodulin-dependent protein kinase in GH3 cells. J. Biol. Chem. 266:1484–1490.

    Google Scholar 

  120. Ocorr, K. A., and Schulman, H. 1991. Activation of multifunctional Ca2+/calmodulin-dependent kinase in intact hippocampal slices. Neuron 6:907–914.

    Google Scholar 

  121. Molloy, S. S., and Kennedy, M. B. 1991. Autophosphorylation of type II Ca2+/calmodulin-dependent protein kinase in cultures of postnatal rat hippocampal slices. Proc. Natl. Acad. Sci., USA 88:4756–4760.

    Google Scholar 

  122. Lickteig, R., Shenolikar, S., Denner, L., and Kelly, P. T. 1988. Regulation of Ca2+/calmodulin-dependent protein kinase II by Ca2+/calmodulin-independent autophosphorylation.. J. Biol. Chem. 263:19232–19239.

    Google Scholar 

  123. Patton, B. L., Miller, S. G., and Kennedy, M. B. 1990. Activation of type II calcium/calmodulin-dependent protein kinase by Ca2+/calmodulin is inhibited by autophosphorylation of threonine within the calmodulin-binding domain. J. Biol. Chem. 265:11204–11212.

    Google Scholar 

  124. Hanson, P. I., and Schulman, H. 1992. Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed muragenesis. J. Biol. Chem., 267:in press.

  125. Crick, F. 1984. Memory and molecular turnover 312:101.

    Google Scholar 

  126. Lisman J. E. 1985. A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. Proc. Natl. Acad. Sci. USA 82:3055–3057.

    Google Scholar 

  127. Lisman, J. E., and Goldring, M. A. 1988. Feasibility of longterm storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density. Proc. Natl. Acad. Sci., USA 85:5320–5324.

    Google Scholar 

  128. Lisman, J., and Goldring, M. 1988. Evaluation of a model of long-term memory based on the properties of the Ca2+/calmodulin-dependent protein kinase. J. Physiol. (Paris) 83:187–197.

    Google Scholar 

  129. Meyer, T., Hanson, P. I., Stryer, L., and Schulman, H. 1992. Calmodulin trapping by CaM kinase enables frequency detection. Science, 256:1199–1202.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Stanford University School of Medicine, Stanford, California, 94305-5332

    Howard Schulman & Phyllis I. Hanson

Authors
  1. Howard Schulman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Phyllis I. Hanson
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Special issue dedicated to Dr. Paul Greengard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schulman, H., Hanson, P.I. Multifunctional Ca2+/calmodulin-dependent protein kinase. Neurochem Res 18, 65–77 (1993). https://doi.org/10.1007/BF00966924

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00966924

Key Words

Search

Navigation