Skip to main content
SpringerLink
Log in

Models of Calmodulin Trapping and CaM Kinase II Activation in a Dendritic Spine

  • Published:
Journal of Computational Neuroscience Aims and scope Submit manuscript

Abstract

Activation of calcium/calmodulin-dependent protein kinase II (CaMKII) by calmodulin following calcium entry into the cell is important for long-term potentiation (LTP). Here a model of calmodulin binding and trapping by CaMKII in a dendritic spine was used to estimate levels and durations of CaMKII activation following LTP-inducing tetani. The calcium signal was calcium influx through NMDA receptor channels computed in a highly detailed dentate granule cell model. Calcium could bind to calmodulin and calmodulin to CaMKII. CaMKII subunits were either free, bound with calmodulin, trapped, autonomous, or capped. Strong low-frequency tetanic input produced little calmodulin trapping or CaMKII activation. Strong high-frequency tetanic input caused large numbers of CaMKII subunits to become trapped, and CaMKII was strongly activated. Calmodulin trapping and CaMKII activation were highly dependent on tetanus frequency (particularly between 10 and 100 Hz) and were highly sensitive to relatively small changes in the calcium signal. Repetition of a short high-frequency tetanus was necessary to achieve high levels of CaMKII activation. Three stages of CaMKII activation were found in the model: a short, highly activated stage; an intermediate, moderately active stage; and a long-lasting third stage, whose duration depended on dephosphorylation rates but whose decay rate was faster at low CaMKII activation levels than at high levels. It is not clear which of these three stages is most important for LTP.

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

  • Barnes GN, Slevin JT, Vanaman TC (1995) Rat brain protein phosphatase 2A: An enzyme that may regulate autophosphorylated protein kinases. J. Neurochem. 64:340-353.

    Google Scholar 

  • Barria A, Muller D, Derkach V, Griffith LC, Soderling TR (1997) Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276:2042-2045.

    Google Scholar 

  • Bekkers JM, Stevens CF (1989) NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341:230-233.

    Google Scholar 

  • Bliss TVP, Collingridge GL (1993) A synaptic model of memory: Long-term potentiation in the hippocampus. Nature 361:31-39.

    Google Scholar 

  • Blitzer RD, Connor JH, Brown GP, Wong T, Shenolikar S, Iyengar R, Landau EM (1998) Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280:1940-1942.

    Google Scholar 

  • Brickey DA, Bann JG, Fong Y-L, Perrino L, Brennan RG, Soderling TR (1994) Mutational analysis of the autoinhibitory domain of calmodulin kinase II. J. Biol. Chem. 269:29047-29054.

    Google Scholar 

  • Burger D, Cox JA, Comte M, Stein EA (1984) Sequential conformational changes in calmodulin upon binding of calcium. Biochemistry 23:1966-1971.

    Google Scholar 

  • Burger D, Stein EA, Cox JA (1983) Free energy coupling in the interactions between Ca2+, calmodulin and phosphorylase kinase. J. Biol. Chem. 258:14733-14739.

    Google Scholar 

  • Colbran RJ (1993) Inactivation of Ca2+/calmodulin-dependent protein kinase II by basal autophosphorylation. J. Biol. Chem. 268:7163-7170.

    Google Scholar 

  • Coomber C (1998) Current theories of neuronal information processing performed by Ca2+/calmodulin-dependent protein kinase II with support and insights from computer modelling and simulation. Computers and Chemistry 22:251-263.

    Google Scholar 

  • Coussens CM, Teyler TJ (1996) Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed. Synapse 24:97-103.

    Google Scholar 

  • Cox JH, Comte M, Mamar-Bachi A, Milos M, Schaer J-J (1988) Cation binding to calmodulin and relation to function. In: Gerday C, Gilles R, Bolis L, eds. Calcium and Calcium Binding Proteins. Springer-Verlag, Berlin. pp. 141-162.

    Google Scholar 

  • Crouch TH, Klee CB (1980) Positive cooperative binding of calcium to bovine brain calmodulin. Biochemistry 19:3692-3698.

    Google Scholar 

  • Cummings JA, Mulkey RM, Nicoll RA, Malenka RC (1996) Ca2+ signaling requirements for long-term depression in the hippocampus. Neuron 16:825-833.

    Google Scholar 

  • DeKoninck P, Schulman H (1998) Sensitivity of CaM Kinase II to the frequency of Ca2+ oscillations. Science 279:227-230.

    Google Scholar 

  • Desmond NL, Levy WB (1985) Granule cell dendritic spine density in the rat hippocampus varies with spine shape and location. Neuroscience Letters 54:219-224.

    Google Scholar 

  • Dosemeci A, Albers RW (1996) A mechanism for synaptic frequency detection through autophosphorylation of CaM kinase II. Biophys. J. 70:2493-2501.

    Google Scholar 

  • Dosemeci A, Gollop N, Jaffe H (1994) Identification of a major autophosphorylation site on postsynaptic density-associated Ca2+/calmodulin-dependent protein kinase. J. Biol. Chem. 269:31330-31333.

    Google Scholar 

  • Frey U, Morris RGM (1997) Synaptic tagging and long-term potentiation. Nature 385:533-536.

    Google Scholar 

  • Fukunaga K, Muller D, Miyamoto E (1996) CaM kinase II in long-term potentiation. Neurochem. Int. 28:343-358.

    Google Scholar 

  • Fukunaga K, Stoppini L, Miyamoto E, Muller D (1993) Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 268:7863-7867.

    Google Scholar 

  • Gregori L, Gillevet PM, Doan P, Chau V (1985) Mechanisms of enzyme regulation by calmodulin and Ca2C. Curr. Top. Cell. Regul. 27:447-454.

    Google Scholar 

  • Hanse E, Gustafsson B (1992) Long-term potentiation and field EPSPs in the lateral and medial perforant paths in the dentate gyrus in vitro: A comparison. Eur. J. Neurosci. 4:1191-1201.

    Google Scholar 

  • Hansel C, Artola A, Singer W (1996) Different threshold levels of postsynaptic [Ca2+]i have to be reached to induce LTP and LTD in neocortical pyramidal cells. J. Physiol. (Paris) 90:317-319.

    Google Scholar 

  • Hanson PI, Meyer T, Stryer L, Schulman H (1994) Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron 12:943-956.

    Google Scholar 

  • Hanson PI, Schulman H (1992) Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed mutagenesis. J. Biol. Chem. 267:17216-17224.

    Google Scholar 

  • Hessler NA, Shirke AM, Malinow R (1993) The probability of transmitter release at a mammalian central synapse. Nature 366:569-572.

    Google Scholar 

  • Holmes WR (1990) Is the function of dendritic spines to concentrate calcium? Brain Res. 519:338-342.

    Google Scholar 

  • Holmes WR (1995) Modeling the effect of glutamate diffusion and uptake on NMDA and non-NMDA receptor saturation. Biophys. J. 69:1734-1747.

    Google Scholar 

  • Holmes WR, Levy WB (1990) Insights into associative long-term potentiation from computational models of NMDA receptormediated calcium influx and intracellular calcium concentration changes. J. Neurophysiol. 63:1148-1168.

    Google Scholar 

  • Holmes WR, Levy WB (1997) Quantifying the role of inhibition in associative long-term potentiation in dentate granule cells with computational models. J. Neurophysiol. 78:103-116.

    Google Scholar 

  • Kakiuchi S, Yasuda S, Yamazaki R, Teshima Y, Kanda K, Kakiuchi R, Sobue K (1982) Quantitative determinations of calmodulin in the supernatant and particulate fractions of mammalian tissues. J. Biochem. 92:1041-1048.

    Google Scholar 

  • Kelly PT, McGuinness TL, 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 

  • Kennedy MB, Bennett MK, Erondu NE (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 

  • Klee CB (1988) Interaction of calmodulin with Ca2+ and target proteins. In: Cohen P, Klee CB, eds. Calmodulin. Elsevier, Amsterdam. pp. 35-56.

    Google Scholar 

  • Kretsinger RH (1981) Mechanisms of selective signalling by calcium. Neurosci. Res. Prog. Bull. 19(3):213-328.

    Google Scholar 

  • Linse S, Forsen S (1995) Determinants that govern high-affinity calcium binding. Adv. Second Mess. Phos. Res. 30:89-151.

    Google Scholar 

  • Linse S, Helmersson A, Forsen S (1991) Calcium binding to calmodulin and its globular domains. J. Biol. Chem. 266:8050-8054.

    Google Scholar 

  • Lisman J (1989) A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl. Acad. Sci. USA 86:9574-9578.

    Google Scholar 

  • Lisman J (1994) The CaM kinase II hypothesis for the storage of synaptic memory. Trends Neurosci. 17:406-412.

    Google Scholar 

  • Lisman J, Malenka RC, Nicoll RA, Malinow R (1997) Learning mechanisms: The case for CaM-KII. Science 276:2001-2002.

    Google Scholar 

  • Luby-Phelps K, Hori M, Phelps JM, Won D (1995) Ca2C-regulated dynamic compartmentalization of calmodulin in living smooth muscle cells. J. Biol. Chem. 270:21532-21538.

    Google Scholar 

  • Malenka RC (1991) The role of postsynaptic calcium in the induction of long-term potentiation. Mol. Neurobiol. 5:289-295.

    Google Scholar 

  • Malenka RC, Nicoll RA (1993) NMDA-receptor-dependent synaptic plasticity: Multiple forms and mechanisms. Trends Neurosci. 16:521-527.

    Google Scholar 

  • Matsushita T, Moriyama S, Fukai T (1995) Switching dynamics and the transient memory storage in a model enzyme network involving Ca2+/calmodulin-dependent protein kinase II in synapses. Biol. Cybern. 72:497-509.

    Google Scholar 

  • Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261-263.

    Google Scholar 

  • Mayford M, Wang J, Kandel ER, O'Dell TJ (1995) CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell 81:891-904.

    Google Scholar 

  • Meyer T, Hanson PI, Stryer L, Schulman H (1992) Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science 256:1199-1202.

    Google Scholar 

  • Michelson S, Schulman H (1994) CaM kinase: A model for its activation and dynamics. J. Theor. Biol. 171:281-290.

    Google Scholar 

  • Miller SG, Kennedy MB (1986) Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: A Ca2+-triggered molecular switch. Cell 44:861-870.

    Google Scholar 

  • Miller SG, Patton BL, Kennedy MB (1988) Sequences of autophosphorylation sites in neuronal type II CaM kinase that control Ca2+-independent activity. Neuron 1:593-604.

    Google Scholar 

  • Mukherji S, Soderling TR (1994) Regulation of Ca2+/Calmodulindependent protein kinase II by inter-and intrasubunit-catalyzed autophosphorylations. J. Biol. Chem. 269:13744-13747.

    Google Scholar 

  • Ouyang Y, Kantor D, Harris KM, Schuman EM, Kennedy MB (1997)Visualization of the distribution of autophosphorylated calcium/ calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus. J. Neurosci. 17:5416-5427.

    Google Scholar 

  • Patton BL, Miller SG, Kennedy MD (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 

  • Rosenmund C, Clements JD, Westbrook GL (1993) Nonuniform probability of glutamate release at a hippocampal synapse. Science 262:754-757.

    Google Scholar 

  • Sather W, Dieudonne S, MacDonald JF, Ascher P (1992) Activation and desensitization of N-methyl-D-aspartate receptors in nucleated outside-out patches from mouse neurones. J. Physiol. 450:643-672.

    Google Scholar 

  • Schulman H (1993) The multifunctional Ca2+/calmodulindependent protein kinases. Curr. Opin. Cell. Biol. 5:247-253.

    Google Scholar 

  • Sharma RK, Mooibroek M, Wang JH (1988) Calmodulin-stimulated cyclic nucleotide phosphodiesterase isozymes. In: Cohen P, Klee CB, eds. Calmodulin. Elsevier, Amsterdam. pp. 265-295.

    Google Scholar 

  • Silver RA, Traynelis SF, Cull-Candy SG (1992) Rapid-time-course miniature and evoked excitatory currents at cerebellar synapses in situ. Nature 355:163-166.

    Google Scholar 

  • Soderling TR (1993) Calcium/calmodulin-dependent protein kinase II: Role in learning and memory. Mol. Cell. Biochem. 127-128:93-101.

    Google Scholar 

  • Staley KJ, Mody I (1991) Integrity of perforant path fibers and the frequency of action potential independent excitatory and inhibitory synaptic events in dentate gyrus granule cells. Synapse 9:219-224.

    Google Scholar 

  • Stemmer PM, Klee CB (1994) Dual calcium ion regulation of calcineurin by calmodulin and calcineurin B. Biochemistry 33:6859-6866.

    Google Scholar 

  • Strack S, Barban MA, Wadzinski BE, Colbran RJ (1997a) Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J. Neurochem. 68:2119-2128.

    Google Scholar 

  • Strack S, Choi S, Lovinger DM, Colbran RJ (1997b) Translocation of autophosphorylated calcium/calmodulin-dependent protein kinase II to the postsynaptic density. J. Biol. Chem. 272:13467-13470.

    Google Scholar 

  • Stull JT (1988) Myosin light chain kinases and caldesmon: biochemical properties and roles in skeletal and smooth muscle contractions. In: Cohen P, Klee CB, eds. Calmodulin. Elsevier, Amsterdam. pp. 91-122.

    Google Scholar 

  • Suzuki T, Okumura-Noji K, Tanaka R, Tada T (1994) Rapid translocation of cytosolic Ca2+/calmodulin-dependent protein kinase II into postsynaptic density after decapitation. J. Neurochem. 63:1529-1537.

    Google Scholar 

  • Walmsley B, Edwards FR, Tracey DJ (1988) Nonuniform release probabilities underlie quantal synaptic transmission at a mammalian excitatory central synapse. J. Neurophysiol. 60:889-908.

    Google Scholar 

  • White G, Levy WB, Steward O. (1988) Evidence that associative interactions between synapses during the induction of long-term potentiation occur within local dendritic domains. Proc. Natl. Acad. Sci. USA 85:2368-2372.

    Google Scholar 

  • White G, Levy WB, Steward O (1990) Spatial overlap between populations of synapses determines the extent of their interaction during the induction of long-term potentiation and depression. J. Neurophysiol. 64:1186-1198.

    Google Scholar 

  • Zador A, Koch C, Brown TH (1990) Biophysical model of a Hebbian synapse. Proc. Natl. Acad. Sci. USA 87:6718-6722.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurobiology Program, Department of Biological Sciences, Ohio University, Athens, OH, 45701

    William R. Holmes

Authors
  1. William R. Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holmes, W.R. Models of Calmodulin Trapping and CaM Kinase II Activation in a Dendritic Spine. J Comput Neurosci 8, 65–86 (2000). https://doi.org/10.1023/A:1008969032563

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1008969032563

Search

Navigation