Abstract
A model for the regulation of CaM kinase II is presented based on the following reported properties of the molecule: 1) The holoenzyme is composed of 8-12 subunits, each with the same set of autophosphorylation sites; 2) Autophosphorylation at one group of sites (A sites) requires the presence of Ca2+ and causes a subunit to remain active following the removal of Ca2+; 3) Autophosphorylation at another group of sites (B sites) occurs only after the removal of Ca2+ but requires prior phosphorylation of a threshold number of A sites within the holoenzyme. Because B-site phosphorylation inhibits Ca2+/calmodulin binding, we propose that, for a given subunit, phosphorylation of a B site before an A site prevents subsequent phosphorylation at the A site and thereby locks that subunit in an inactive state. The model predicts that a threshold activation by Ca2+ will initiate an "autophosphorylation phase." Once started, intra-holoenzyme autophosphorylation will proceed, on A sites during periods of high [Ca2+] and on B sites during periods of low [Ca2+]. At "saturation," that is when every subunit has been phosphorylated on a B site, the number of phosphorylated A sites and, therefore, the kinase activity will reflect the relative durations of periods of high [Ca2+] to periods of low [Ca2+] that occurred during the autophosphorylation phase. Using a computer program designed to simulate the above mechanism, we show that the ultimate state of phosphorylation of an array of CaM kinase II molecules could be sensitive to the temporal pattern of Ca2+ pulses. We speculate that such a mechanism may allow arrays of CaM kinase II molecules in postsynaptic densities to act as synaptic frequency detectors involved in setting the direction and level of synaptic modification.
Full text
PDF








Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bear M. F., Malenka R. C. Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol. 1994 Jun;4(3):389–399. doi: 10.1016/0959-4388(94)90101-5. [DOI] [PubMed] [Google Scholar]
- Brickey D. A., Bann J. G., Fong Y. L., Perrino L., Brennan R. G., Soderling T. R. Mutational analysis of the autoinhibitory domain of calmodulin kinase II. J Biol Chem. 1994 Nov 18;269(46):29047–29054. [PubMed] [Google Scholar]
- Colbran R. J., Fong Y. L., Schworer C. M., Soderling T. R. Regulatory interactions of the calmodulin-binding, inhibitory, and autophosphorylation domains of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1988 Dec 5;263(34):18145–18151. [PubMed] [Google Scholar]
- Dosemeci A., Gollop N., Jaffe H. Identification of a major autophosphorylation site on postsynaptic density-associated Ca2+/calmodulin-dependent protein kinase. J Biol Chem. 1994 Dec 16;269(50):31330–31333. [PubMed] [Google Scholar]
- Dosemeci A., Reese T. S. Inhibition of endogenous phosphatase in a postsynaptic density fraction allows extensive phosphorylation of the major postsynaptic density protein. J Neurochem. 1993 Aug;61(2):550–555. doi: 10.1111/j.1471-4159.1993.tb02158.x. [DOI] [PubMed] [Google Scholar]
- Dudek S. M., Bear M. F. Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus. J Neurosci. 1993 Jul;13(7):2910–2918. doi: 10.1523/JNEUROSCI.13-07-02910.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dudek S. M., Bear M. F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4363–4367. doi: 10.1073/pnas.89.10.4363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Erondu N. E., Kennedy M. B. Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain. J Neurosci. 1985 Dec;5(12):3270–3277. doi: 10.1523/JNEUROSCI.05-12-03270.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fukunaga K., Goto S., Miyamoto E. Immunohistochemical localization of Ca2+/calmodulin-dependent protein kinase II in rat brain and various tissues. J Neurochem. 1988 Oct;51(4):1070–1078. doi: 10.1111/j.1471-4159.1988.tb03070.x. [DOI] [PubMed] [Google Scholar]
- Fukunaga K., Stoppini L., Miyamoto E., Muller D. Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1993 Apr 15;268(11):7863–7867. [PubMed] [Google Scholar]
- Gamble E., Koch C. The dynamics of free calcium in dendritic spines in response to repetitive synaptic input. Science. 1987 Jun 5;236(4806):1311–1315. doi: 10.1126/science.3495885. [DOI] [PubMed] [Google Scholar]
- Hanson P. I., Kapiloff M. S., Lou L. L., Rosenfeld M. G., Schulman H. Expression of a multifunctional Ca2+/calmodulin-dependent protein kinase and mutational analysis of its autoregulation. Neuron. 1989 Jul;3(1):59–70. doi: 10.1016/0896-6273(89)90115-3. [DOI] [PubMed] [Google Scholar]
- Hanson P. I., Meyer T., Stryer L., Schulman H. Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron. 1994 May;12(5):943–956. doi: 10.1016/0896-6273(94)90306-9. [DOI] [PubMed] [Google Scholar]
- Hanson P. I., Schulman H. Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed mutagenesis. J Biol Chem. 1992 Aug 25;267(24):17216–17224. [PubMed] [Google Scholar]
- Huang Y. Y., Colino A., Selig D. K., Malenka R. C. The influence of prior synaptic activity on the induction of long-term potentiation. Science. 1992 Feb 7;255(5045):730–733. doi: 10.1126/science.1346729. [DOI] [PubMed] [Google Scholar]
- Ikeda A., Okuno S., Fujisawa H. Studies on the generation of Ca2+/calmodulin-independent activity of calmodulin-dependent protein kinase II by autophosphorylation. Autothiophosphorylation of the enzyme. J Biol Chem. 1991 Jun 25;266(18):11582–11588. [PubMed] [Google Scholar]
- Ito I., Hidaka H., Sugiyama H. Effects of KN-62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, on long-term potentiation in the rat hippocampus. Neurosci Lett. 1991 Jan 2;121(1-2):119–121. doi: 10.1016/0304-3940(91)90663-e. [DOI] [PubMed] [Google Scholar]
- Kanaseki T., Ikeuchi Y., Sugiura H., Yamauchi T. Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy. J Cell Biol. 1991 Nov;115(4):1049–1060. doi: 10.1083/jcb.115.4.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kelly P. T., McGuinness T. L., Greengard P. Evidence that the major postsynaptic density protein is a component of a Ca2+/calmodulin-dependent protein kinase. Proc Natl Acad Sci U S A. 1984 Feb;81(3):945–949. doi: 10.1073/pnas.81.3.945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kennedy M. B., Bennett M. K., Erondu N. E. Biochemical and immunochemical evidence that the "major postsynaptic density protein" is a subunit of a calmodulin-dependent protein kinase. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7357–7361. doi: 10.1073/pnas.80.23.7357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lickteig R., Shenolikar S., Denner L., Kelly P. T. Regulation of Ca2+/calmodulin-dependent protein kinase II by Ca2+/calmodulin-independent autophosphorylation. J Biol Chem. 1988 Dec 15;263(35):19232–19239. [PubMed] [Google Scholar]
- Lisman J. E., Goldring M. A. Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5320–5324. doi: 10.1073/pnas.85.14.5320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9574–9578. doi: 10.1073/pnas.86.23.9574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lou L. L., Schulman H. Distinct autophosphorylation sites sequentially produce autonomy and inhibition of the multifunctional Ca2+/calmodulin-dependent protein kinase. J Neurosci. 1989 Jun;9(6):2020–2032. doi: 10.1523/JNEUROSCI.09-06-02020.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malenka R. C., Kauer J. A., Perkel D. J., Mauk M. D., Kelly P. T., Nicoll R. A., Waxham M. N. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature. 1989 Aug 17;340(6234):554–557. doi: 10.1038/340554a0. [DOI] [PubMed] [Google Scholar]
- Malenka R. C., Nicoll R. A. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 1993 Dec;16(12):521–527. doi: 10.1016/0166-2236(93)90197-t. [DOI] [PubMed] [Google Scholar]
- Malinow R., Schulman H., Tsien R. W. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science. 1989 Aug 25;245(4920):862–866. doi: 10.1126/science.2549638. [DOI] [PubMed] [Google Scholar]
- Mayford M., Wang J., Kandel E. R., O'Dell T. J. CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell. 1995 Jun 16;81(6):891–904. doi: 10.1016/0092-8674(95)90009-8. [DOI] [PubMed] [Google Scholar]
- Meyer T., Hanson P. I., Stryer L., Schulman H. Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science. 1992 May 22;256(5060):1199–1202. doi: 10.1126/science.256.5060.1199. [DOI] [PubMed] [Google Scholar]
- Miller S. G., Kennedy M. B. Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch. Cell. 1986 Mar 28;44(6):861–870. doi: 10.1016/0092-8674(86)90008-5. [DOI] [PubMed] [Google Scholar]
- Mukherji S., Soderling T. R. Regulation of Ca2+/calmodulin-dependent protein kinase II by inter- and intrasubunit-catalyzed autophosphorylations. J Biol Chem. 1994 May 13;269(19):13744–13747. [PubMed] [Google Scholar]
- Mulkey R. M., Endo S., Shenolikar S., Malenka R. C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature. 1994 Jun 9;369(6480):486–488. doi: 10.1038/369486a0. [DOI] [PubMed] [Google Scholar]
- Mulkey R. M., Herron C. E., Malenka R. C. An essential role for protein phosphatases in hippocampal long-term depression. Science. 1993 Aug 20;261(5124):1051–1055. doi: 10.1126/science.8394601. [DOI] [PubMed] [Google Scholar]
- Mulkey R. M., Malenka R. C. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron. 1992 Nov;9(5):967–975. doi: 10.1016/0896-6273(92)90248-c. [DOI] [PubMed] [Google Scholar]
- Ouimet C. C., McGuinness T. L., Greengard P. Immunocytochemical localization of calcium/calmodulin-dependent protein kinase II in rat brain. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5604–5608. doi: 10.1073/pnas.81.17.5604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patton B. L., Miller S. G., Kennedy M. B. 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. 1990 Jul 5;265(19):11204–11212. [PubMed] [Google Scholar]
- Pettit D. L., Perlman S., Malinow R. Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons. Science. 1994 Dec 16;266(5192):1881–1885. doi: 10.1126/science.7997883. [DOI] [PubMed] [Google Scholar]
- Silva A. J., Stevens C. F., Tonegawa S., Wang Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):201–206. doi: 10.1126/science.1378648. [DOI] [PubMed] [Google Scholar]
- Stevens C. F., Tonegawa S., Wang Y. The role of calcium-calmodulin kinase II in three forms of synaptic plasticity. Curr Biol. 1994 Aug 1;4(8):687–693. doi: 10.1016/s0960-9822(00)00153-6. [DOI] [PubMed] [Google Scholar]