A Dynamic Model of Interactions of Ca2+, Calmodulin, and Catalytic Subunits of Ca2+/Calmodulin-Dependent Protein Kinase II
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During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.
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CaM can activate CaMKII when only two of its four Ca2+ binding sites are occupied.
“This is despite the fact that CaM can activate CaMKII when only two of its four Ca2+ binding sites are occupied (112, 113).”
From Synaptic memory and CaMKII (2023) · cites this paper as [113]
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A methodology for performing global uncertainty and sensitivity analysis in systems biology
Marino, S., Hogue, I. B., Ray, C. J., & Kirschner, D. E. (2008) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2008.04.011 · Cited by 2,999 · see citing works
The molecular basis of CaMKII function in synaptic and behavioural memory
Lisman, J., Schulman, H., & Cline, H. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn753 · Cited by 1,860 · see citing works
Deficient Hippocampal Long-Term Potentiation in α-Calcium-Calmodulin Kinase II Mutant Mice
Silva, A. J., Stevens, C. F., Tonegawa, S., & Wang, Y. (1992) · Science · doi:10.1126/science.1378648 · Cited by 1,472 · see citing works
Blower, S. M., & Dowlatabadi, H. (1994) · International Statistical Review · doi:10.2307/1403510 · Cited by 1,360 · see citing works
Impaired Spatial Learning in α-Calcium-Calmodulin Kinase II Mutant Mice
Silva, A. J., Paylor, R. E., Wehner, J. M., & Tonegawa, S. (1992) · Science · doi:10.1126/science.1321493 · Cited by 1,351 · see citing works
Sensitivity of CaM Kinase II to the Frequency of Ca <sup>2+</sup> Oscillations
De Koninck, P., & Schulman, H. (1998) · Science · doi:10.1126/science.279.5348.227 · Cited by 1,269 · see citing works
Target Enzyme Recognition by Calmodulin: 2.4 Å Structure of a Calmodulin-Peptide Complex
Meador, W. E., Means, A. R., & Quiocho, F. A. (1992) · Science · doi:10.1126/science.1519061 · Cited by 1,032 · see citing works
Structure of calmodulin refined at 2.2 Å resolution
Babu, Y. S., Bugg, C. E., & Cook, W. J. (1988) · Journal of Molecular Biology · doi:10.1016/0022-2836(88)90608-0 · Cited by 1,026 · see citing works
Miller, S. (1986) · Cell · doi:10.1016/0092-8674(86)90008-5 · Cited by 864 · see citing works
Phillips, R., Kondev, J., Theriot, J. A., García, H. G., & Orme, N. (2012) · Garland Science eBooks · doi:10.1201/9781134111589 · Cited by 832 · see citing works
Signal-Processing Machines at the Postsynaptic Density
Kennedy, M. B. (2000) · Science · doi:10.1126/science.290.5492.750 · Cited by 788 · see citing works
Self-citationCalmodulin structure refined at 1.7 Å resolution
Chattopadhyaya, R., Meador, W. E., Means, A. R., & Quiocho, F. A. (1992) · Journal of Molecular Biology · doi:10.1016/0022-2836(92)90324-d · Cited by 731 · see citing works
Calmodulin Trapping by Calcium-Calmodulin-Dependent Protein Kinase
Meyer, T., Hanson, P. I., Stryer, L., & Schulman, H. (1992) · Science · doi:10.1126/science.256.5060.1199 · Cited by 637 · see citing works
Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain
Erondu, N., & Kennedy, M. (1985) · The Journal of Neuroscience · doi:10.1523/jneurosci.05-12-03270.1985 · Cited by 630 · see citing works
Self-citationAn Investigation of Uncertainty and Sensitivity Analysis Techniques for Computer Models
Iman, R. L., & Helton, J. C. (1988) · Risk Analysis · doi:10.1111/j.1539-6924.1988.tb01155.x · Cited by 610 · see citing works
Kennedy, M. B., Bennett, M. K., & Erondu, N. E. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.23.7357 · Cited by 610 · see citing works
Self-citationLocal Calcium Signaling in Neurons
Augustine, G. J., Santamarı́a, F., & Tanaka, K. (2003) · Neuron · doi:10.1016/s0896-6273(03)00639-1 · Cited by 603 · see citing works
Watterson, D. M., Harrelson, W. G., Keller, P. M., Sharief, F. S., & VANAMAN, T. C. (1976) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)33231-3 · Cited by 514 · see citing works
Hanson, P. I., Meyer, T., Stryer, L., & Schulman, H. (1994) · Neuron · doi:10.1016/0896-6273(94)90306-9 · Cited by 500 · see citing works
Calcium binding to calmodulin and its globular domains
Linse, S. S., Helmersson, A., & Forsén, S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)92938-8 · Cited by 484 · see citing works
Bennett, M. K., Erondu, N. E., & Kennedy, M. B. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44239-6 · Cited by 481 · see citing works
Self-citationThe role of calmodulin as a signal integrator for synaptic plasticity
Xia, Z., & Storm, D. R. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1647 · Cited by 441 · see citing works
Estimating Intracellular Calcium Concentrations and Buffering without Wavelength Ratioing
Maravall, M., Mainen, Z. F., Sabatini, B. L., & Svoboda, K. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76809-3 · Cited by 416 · see citing works
Kerr, R. A., Bartol, T. M., Kaminsky, B., Dittrich, M., Chang, J.-C. J., Baden, S. B., B, T. J. S. A., & Stiles, J. R. (2008) · SIAM Journal on Scientific Computing · doi:10.1137/070692017 · Cited by 364 · see citing works
Positive cooperative binding of calcium to bovine brain calmodulin
Crouch, T. H., & Klee, C. B. (1980) · Biochemistry · doi:10.1021/bi00557a009 · Cited by 334 · see citing works
Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis of the Holoenzyme
Rosenberg, O. S., Deindl, S., Sung, R.-J., Nairn, A. C., & Kuriyan, J. (2005) · Cell · doi:10.1016/j.cell.2005.10.029 · Cited by 333 · see citing works
Illustration of Sampling‐Based Methods for Uncertainty and Sensitivity Analysis
Helton, J. C., & Davis, F. J. (2002) · Risk Analysis · doi:10.1111/0272-4332.00041 · Cited by 310 · see citing works
Integration of biochemical signalling in spines
Kennedy, M. B., Beale, H. C., Carlisle, H. J., & Washburn, L. R. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1685 · Cited by 286 · see citing works
Self-citationMalenka, R. C., Lancaster, B., & Zucker, R. S. (1992) · Neuron · doi:10.1016/0896-6273(92)90227-5 · Cited by 250 · see citing works
Spike timing, calcium signals and synaptic plasticity
Sjöström, P. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00325-2 · Cited by 231 · see citing works
Ouyang, Y., Kantor, D. B., Harris, K. M., Schuman, E. M., & Kennedy, M. B. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-14-05416.1997 · Cited by 227 · see citing works
Self-citationKakiuchi, S., Yasuda, S., Yamazaki, R., Teshima, Y., Kanda, K., Kakiuchi, R., & Sobue, K. (1982) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a134019 · Cited by 212 · see citing works
Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II
Shen, K., Teruel, M. N., Connor, J. H., Shenolikar, S., & Meyer, T. (2000) · Nature Neuroscience · doi:10.1038/78783 · Cited by 206 · see citing works
Hoelz, A., Nairn, A. C., & Kuriyan, J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00171-0 · Cited by 182 · see citing works
Colbran, R. J., Fong, Y. L., Schworer, C. M., & Soderling, T. R. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)81337-6 · Cited by 158 · see citing works
Calcium binding to complexes of calmodulin and calmodulin binding proteins
Olwin, B. B., & Storm, D. R. (1985) · Biochemistry · doi:10.1021/bi00348a037 · Cited by 151 · see citing works
Shifman, J. M., Choi, M. H., Mihalas, S., Mayo, S. L., & Kennedy, M. B. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606433103 · Cited by 143 · see citing works
Self-citationShapiro, B. E., Levchenko, A., Meyerowitz, E. M., Wold, B. J., & Mjolsness, E. (2003) · Bioinformatics · doi:10.1093/bioinformatics/btg042 · Cited by 122 · see citing works
Olwin, B. B., Edelman, A. M., Krebs, E. G., & Storm, D. R. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)90605-8 · Cited by 119 · see citing works
Endogenous Ca 2+ Buffer Concentration and Ca 2+ Microdomains in Hippocampal Neurons
Müller, A., Kukley, M., Stausberg, P., Beck, H., Müller, W. S., & Dietrich, D. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3799-04.2005 · Cited by 117 · see citing works
Rose, J. K., Jin, S., & Craig, A. M. (2009) · Neuron · doi:10.1016/j.neuron.2008.12.030 · Cited by 100 · see citing works
Gaertner, T. R., Putkey, J. A., & Waxham, M. N. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405352200 · Cited by 96 · see citing works
Complexity of calcium signaling in synaptic spines
Franks, K. M., & B, T. J. S. A. (2002) · BioEssays · doi:10.1002/bies.10193 · Cited by 95 · see citing works
An allosteric model of calmodulin explains differential activation of PP2B and CaMKII
Stefan, M. I., Edelstein, S. J., & Novère, N. G. L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804672105 · Cited by 95 · see citing works
Calmodulin Activation by Calcium Transients in the Postsynaptic Density of Dendritic Spines
Keller, D. X., Franks, K. M., Bartol, T. M., & B, T. J. S. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002045 · Cited by 94 · see citing works
The evolving model of calmodulin structure,function and activation
Finn, B. E., & Forsén, S. (1995) · Structure · doi:10.1016/s0969-2126(01)00130-7 · Cited by 88 · see citing works
Kinzer‐Ursem, T. L., & Linderman, J. J. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030006 · Cited by 81 · see citing works
Self-citationBradshaw, J. M., Hudmon, A., & Schulman, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202154200 · Cited by 76 · see citing works
Santucci, D. M., & Raghavachari, S. (2008) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000208 · Cited by 71 · see citing works
Kinetic Control of the Dissociation Pathway of Calmodulin-Peptide Complexes
Brown, S. E., Martin, S. R., & Bayley, P. M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3389 · Cited by 70 · see citing works
Persechini, A., White, H. D., & Gansz, K. J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.1.62 · Cited by 67 · see citing works
Martin, S. R., Maune, J. F., Beckingham, K., & Bayley, P. M. (1992) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1992.tb16879.x · Cited by 64 · see citing works
Transient Versus Asymptotic Dynamics of CaM Kinase II: Possible Roles of Phosphatase
Kubota, Y., & Bower, J. M. (2001) · Journal of Computational Neuroscience · doi:10.1023/a:1013727331979 · Cited by 55 · see citing works
Mirzoeva, S., Weigand, S. L., Lukas, T. J., Shuvalova, L., Anderson, W. F., & Watterson, D. M. (1999) · Biochemistry · doi:10.1021/bi9821263 · Cited by 34 · see citing works
The structure of apo‐calmodulin
Finn, B. E., Drakenberg, T., & Forsén, S. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80839-m · Cited by 33 · see citing works
Mirzoeva, S., Weigand, S. L., Lukas, T. J., Shuvalova, L., Anderson, W. F., & Waterson, D. M. (1999) · Biochemistry · doi:10.1021/bi9950894 · Cited by 8 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [40]Wolfram Research I 2007 Mathematica Edition 6.0 Champaign, Illinois
- [51]De Koninck P Schulman H 1998 Sensitivity of CaM Kinase II to the frequency of Ca2+ oscillations. Science 279 227 230 9422695
- [54]Bradshaw JM Hudmon A Shulman H 2002 Chemical Quenched Flow Kinetic Studies Indicate an Intraholoenzyme Autophosphorylation Mechanism for Ca2+. J Biol Chem 277 20991 20998 11925447
Cited by
Sorted by citations
Mechanisms of CaMKII action in long-term potentiation
Lisman, J., Yasuda, R., & Raghavachari, S. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3192 · Cited by 1,134 · see citing works
Chao, L. H., Stratton, M. M., Lee, I., Rosenberg, O. S., Levitz, J., Mandell, D. J., Kortemme, T., Groves, J. T., Schulman, H., & Kuriyan, J. (2011) · Cell · doi:10.1016/j.cell.2011.07.038 · Cited by 253 · see citing works
Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
“This is despite the fact that CaM can activate CaMKII when only two of its four Ca 2 1 binding sites are occupied (112, 113).”
BackgroundLi, L., Stefan, M. I., & Novère, N. G. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043810 · Cited by 119 · see citing works
Bhattacharyya, M., Stratton, M. M., Going, C. C., McSpadden, E. D., Huang, Y., Susa, A. C., Elleman, A., Cao, Y. M., Pappireddi, N., Burkhardt, P., et al. (2016) · eLife · doi:10.7554/elife.13405 · Cited by 112 · see citing works
Bhattacharyya, M., Karandur, D., & Kuriyan, J. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035147 · Cited by 95 · see citing works
Yeast eIF4A enhances recruitment of mRNAs regardless of their structural complexity
Yourik, P., Aitken, C. E., Zhou, F., Gupta, N., Hinnebusch, A. G., & Lorsch, J. R. (2017) · eLife · doi:10.7554/elife.31476 · Cited by 85 · see citing works
Mechanisms of Ca2+/calmodulin-dependent kinase II activation in single dendritic spines
Chang, J.-Y., Nakahata, Y., Hayano, Y., & Yasuda, R. (2019) · Nature Communications · doi:10.1038/s41467-019-10694-z · Cited by 77 · see citing works
Walkup, W. G., Mastro, T. L., Schenker, L. T., Vielmetter, J., Hu, R., Iancu, A., Reghunathan, M., Bannon, B. D., & Kennedy, M. B. (2016) · eLife · doi:10.7554/elife.16813 · Cited by 76 · see citing works
Self-citationCooperative binding mitigates the high-dose hook effect
Roy, R. D., Rosenmund, C., & Stefan, M. I. (2017) · BMC Systems Biology · doi:10.1186/s12918-017-0447-8 · Cited by 73 · see citing works
Liu, J., Whalley, H. J., & Knight, M. R. (2015) · New Phytologist · doi:10.1111/nph.13428 · Cited by 67 · see citing works
Reaction-diffusion in the NEURON simulator
McDougal, R. A., Hines, M. L., & Lytton, W. W. (2013) · Frontiers in Neuroinformatics · doi:10.3389/fninf.2013.00028 · Cited by 65 · see citing works
Postsynaptic Signal Transduction Models for Long-Term Potentiation and Depression
Manninen, T., Hituri, K., Kotaleski, J. H., Blackwell, K. T., & Linne, M. (2010) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2010.00152 · Cited by 50 · see citing works
Zhang, W., Zhang, J., Wang, Z., Li, T., Liu, C., Kang, X., Cui, X., Yang, J., Qu, H., Duanmu, J., et al. (2024) · Circulation · doi:10.1161/circulationaha.123.068595 · Cited by 49 · see citing works
Computational Modeling Reveals Frequency Modulation of Calcium-cAMP/PKA Pathway in Dendritic Spines
Ohadi, D., Schmitt, D. L., Calabrese, B., Halpain, S., Zhang, J., & Rangamani, P. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.10.003 · Cited by 44 · see citing works
Masoli, S., Sánchez-Ponce, D., Vrieler, N., Abu-Haya, K., Lerner, V., Shahar, T., Nedelescu, H., Rizza, M. F., Benavides‐Piccione, R., DeFelipe, J., et al. (2024) · Communications Biology · doi:10.1038/s42003-023-05689-y · Cited by 43 · see citing works
Ebner, C., Clopath, C., Jedlička, P., & Cuntz, H. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.068 · Cited by 43 · see citing works
The Potential of Corticospinal-Motoneuronal Plasticity for Recovery after Spinal Cord Injury
Jo, H. J., Richardson, M. S. A., Oudega, M., & Pérez, M. A. (2020) · Current Physical Medicine and Rehabilitation Reports · doi:10.1007/s40141-020-00272-6 · Cited by 38 · see citing works
Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase
Karandur, D., Bhattacharyya, M., Xia, Z., Lee, Y. K., Muratcioglu, S., McAffee, D., McSpadden, E. D., Qiu, B., Groves, J. T., Williams, E. R., et al. (2020) · eLife · doi:10.7554/elife.57784 · Cited by 35 · see citing works
Tutorial: Neuromorphic spiking neural networks for temporal learning
Jeong, D. S. (2018) · Journal of Applied Physics · doi:10.1063/1.5042243 · Cited by 34 · see citing works
Eriksson, O., Jauhiainen, A., Sasane, S. M., Kramer, A., Nair, A. G., Sartorius, C., & Kotaleski, J. H. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty607 · Cited by 32 · see citing works
Mapping protein structural changes by quantitative cross-linking
Kukačka, Z., Rosůlek, M., Strohalm, M., Kavan, D., & Novák, P. (2015) · Methods · doi:10.1016/j.ymeth.2015.05.027 · Cited by 29 · see citing works
Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator
Ordyan, M., Bartol, T., Kennedy, M. B., Rangamani, P., & B, T. J. S. A. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008015 · Cited by 28 · see citing works
Self-citationCerebellar Golgi cell models predict dendritic processing and mechanisms of synaptic plasticity
Masoli, S., Ottaviani, A., Casali, S., & D'Angelo, E. U. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007937 · Cited by 28 · see citing works
Quantitative Operating Principles of Yeast Metabolism during Adaptation to Heat Stress
Pereira, T., Vilaprinyó, E., Bellı́, G., Herrero, E., Salvadó, B., Albert Sorribas, B., Altés, G., & Alves, R. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.020 · Cited by 28 · see citing works
Mathematical Model Predicts Effective Strategies to Inhibit VEGF-eNOS Signaling
Wu, Q., & Finley, S. D. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051255 · Cited by 26 · see citing works
Intracellular calcium stores mediate metaplasticity at hippocampal dendritic spines
Mahajan, G., & Nadkarni, S. (2019) · The Journal of Physiology · doi:10.1113/jp277726 · Cited by 25 · see citing works
Romano, D. R., Pharris, M. C., Patel, N. M., & Kinzer‐Ursem, T. L. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005820 · Cited by 25 · see citing works
Self-citationAlzheimer’s Disease: A short introduction to the calmodulin hypothesis
O’Day, D. H. (2019) · AIMS neuroscience · doi:10.3934/neuroscience.2019.4.231 · Cited by 25 · see citing works
Structural Analysis and Stochastic Modelling Suggest a Mechanism for Calmodulin Trapping by CaMKII
Stefan, M. I., Marshall, D. P., & Novère, N. G. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029406 · Cited by 24 · see citing works
Jędrzejewska‐Szmek, J., & Blackwell, K. T. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.01.006 · Cited by 24 · see citing works
Exact maximal reduction of stochastic reaction networks by species lumping
Cardelli, L., Pérez-Verona, I. C., Tribastone, M., Tschaikowski, M., Vandin, A., & Waizmann, T. (2021) · Bioinformatics · doi:10.1093/bioinformatics/btab081 · Cited by 23 · see citing works
The Delicate Bistability of CaMKII
Michalski, P. J. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2013.06.038 · Cited by 22 · see citing works
Design Principle for Decoding Calcium Signals to Generate Specific Gene Expression Via Transcription
Liu, J., Lenzoni, G., & Knight, M. R. (2019) · PLANT PHYSIOLOGY · doi:10.1104/pp.19.01003 · Cited by 22 · see citing works
Pharris, M. C., Patel, N. M., VanDyk, T. G., Bartol, T. M., B, T. J. S. A., Kennedy, M. B., Stefan, M. I., & Kinzer‐Ursem, T. L. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006941 · Cited by 22 · see citing works
Self-citationHuang, C., Wu, J., Liao, R., & Zhang, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049954 · Cited by 20 · see citing works
A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics
Rodrigues, Y. E., Tigaret, C. M., Marie, H., O’Donnell, C., & Veltz, R. (2023) · eLife · doi:10.7554/elife.80152 · Cited by 19 · see citing works
Gamella, M., Guo, Z., Alexandrov, K. A., & Katz, E. (2019) · ChemElectroChem · doi:10.1002/celc.201801095 · Cited by 19 · see citing works
Michalski, P. J., & Loew, L. M. (2012) · Physical Biology · doi:10.1088/1478-3975/9/3/036010 · Cited by 17 · see citing works
He, Y., Kulasiri, D., & Samarasinghe, S. (2014) · Biosystems · doi:10.1016/j.biosystems.2014.06.005 · Cited by 15 · see citing works
Control of Allosteric Protein Electrochemical Switches with Biomolecular and Electronic Signals
Bollella, P., Edwardraja, S., Guo, Z., Alexandrov, K. A., & Katz, E. (2020) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.0c01223 · Cited by 15 · see citing works
Micheli, P., Ribeiro, R. P., & Giorgetti, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041536 · Cited by 15 · see citing works
Revealing eEF-2 kinase: recent structural insights into function
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He, Y., Kulasiri, D., & Samarasinghe, S. (2014) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2014.11.001 · Cited by 14 · see citing works
Qin, C., Bian, X.-L., Wu, H., Xian, J.-Y., Lin, Y., Cai, C.-Y., Zhou, Y., Kou, X., Li, T., Chang, L., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01118-w · Cited by 14 · see citing works
Simplified calcium signaling cascade for synaptic plasticity
Kornijčuk, V., Kim, D., Kim, G., & Jeong, D. S. (2019) · Neural Networks · doi:10.1016/j.neunet.2019.11.022 · Cited by 14 · see citing works
Johnson, T., Bartol, T., B, T. J. S. A., & Mjolsness, E. (2015) · Physical Biology · doi:10.1088/1478-3975/12/4/045005 · Cited by 13 · see citing works
Zhao, Y., Zhang, W., Hong, J., Yang, L., Wang, Y., Qu, F., & Xu, W. L. (2024) · The Analyst · doi:10.1039/d4an00378k · Cited by 11 · see citing works
Neuronal calmodulin levels are controlled by CAMTA transcription factors
Vuong-Brender, T. T. K., Flynn, S. M., Vallis, Y., Sönmez, S. E., & de Bono, M. (2021) · eLife · doi:10.7554/elife.68238 · Cited by 11 · see citing works
Calcium Messenger Heterogeneity: A Possible Signal for Spike Timing-Dependent Plasticity
Mihalaş, Ş. (2011) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2010.00158 · Cited by 10 · see citing works
Kirkness, K. B., & Scarlata, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms27010160 · Cited by 9 · see citing works
Exact Linear Reduction for Rational Dynamical Systems
Jiménez-Pastor, A., Jacob, J. P., & Pogudin, G. (2022) · Lecture notes in computer science · doi:10.1007/978-3-031-15034-0_10 · Cited by 8 · see citing works
Bartol, T. M., Ordyan, M., B, T. J. S. A., Rangamani, P., & Kennedy, M. B. (2025) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2025.1547948 · Cited by 8 · see citing works
Self-citationMultiscale Modeling and Synaptic Plasticity
Bhalla, U. S. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-397897-4.00012-7 · Cited by 8 · see citing works
Li, X., & Holmes, W. R. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005946 · Cited by 8 · see citing works
Jiang, S., Shen, Z., & Xu, W. (2021) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2021/9639131 · Cited by 8 · see citing works
Short-term Hebbian learning can implement transformer-like attention
Ellwood, I. T. (2024) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1011843 · Cited by 7 · see citing works
A Novel Explanation for Observed CaMKII Dynamics in Dendritic Spines with Added EGTA or BAPTA
Matolcsi, M., & Giordano, N. J. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2014.12.044 · Cited by 7 · see citing works
CLUE: exact maximal reduction of kinetic models by constrained lumping of differential equations
Ovchinnikov, A., Pérez-Verona, I. C., Pogudin, G., & Tribastone, M. (2021) · Bioinformatics · doi:10.1093/bioinformatics/btab258 · Cited by 7 · see citing works
Santos, J. P. G., Pajo, K., Trpevski, D., Stepaniuk, A., Eriksson, O., Nair, A. G., Keller, D. X., Kotaleski, J. H., & Kramer, A. (2021) · Neuroinformatics · doi:10.1007/s12021-021-09546-3 · Cited by 7 · see citing works
Pharris, M. C., Patel, N. M., & Kinzer‐Ursem, T. L. (2018) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-018-0549-4 · Cited by 7 · see citing works
Self-citationThe Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases
O’Day, D. H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413424 · Cited by 6 · see citing works
Analysis of proteins in computational models of synaptic plasticityPreprint
Heil, K. F., Wysocka, E., Sorokina, O., Kotaleski, J. H., Simpson, T. I., Armstrong, J. D., & Sterratt, D. C. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/254094 · Cited by 5 · see citing works
Real-time single-molecule imaging of CaMKII-calmodulin interactions
Khan, S., Molloy, J. E., Puhl, H. L., Schulman, H., & Vogel, S. S. (2024) · Biophysical Journal · doi:10.1016/j.bpj.2024.02.021 · Cited by 4 · see citing works
Voros, C., Mavrogianni, D., Athanasiou, D., Sapantzoglou, I., Bananis, K., Athanasiou, A. I., Athanasiou, A. V., Papadimas, G. K., Τsimpoukelis, C., Papapanagiotou, I., et al. (2025) · Biomedicines · doi:10.3390/biomedicines13082007 · Cited by 4 · see citing works
Scheler, G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055762 · Cited by 4 · see citing works
Still Looking for the Memories: Molecules and Synaptic Plasticity
Bhalla, U. S. (2013) · Springer eBooks · doi:10.1007/978-1-4614-1424-7_9 · Cited by 4 · see citing works
Integration of Rule-Based Models and Compartmental Models of Neurons
Sterratt, D. C., Sorokina, O., & Armstrong, J. D. (2015) · Lecture notes in computer science · doi:10.1007/978-3-319-27656-4_9 · Cited by 3 · see citing works
Severino, A., Gaido, O. E. R., Liu, B., Lopez-Cecetaite, G., Wei, A., Rosales‐Soto, G., Hernández‐Ochoa, E. O., & Luczak, E. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.11.658946 · Cited by 2 · see citing works
CaMKII as a Multimodal Signalling Hub in Neural Connectivity and Vulnerability
Olliff, S., & Sundaramoorthy, V. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05777-0 · Cited by 1 · see citing works
Shah, K., & Zhang, Y. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1831452 · Cited by 1 · see citing works
High-Voltage-Activated Calcium Channels
Solinas, S. M. G., Masoli, S., & Subramaniyam, S. (2014) · Springer eBooks · doi:10.1007/978-1-4614-7320-6_230-1 · Cited by 1 · see citing works
High-Voltage-Activated Calcium Channels
Solinas, S. M. G., Masoli, S., & Subramaniyam, S. (2022) · Springer eBooks · doi:10.1007/978-1-0716-1006-0_230 · Cited by 1 · see citing works
Multi-Stage Modeling of the Kinetics of Activation of CaMKII
Mary, K. (2011) · Frontiers in Neuroinformatics · doi:10.3389/conf.fninf.2011.08.00033
Mahdavi, A., Mirjalili, M., Bahrami, F., & Janahmadi, M. (2015) · National and International Iranian Conference on Biomedical Engineering (ICBME) · doi:10.1109/icbme.2015.7404134
Molecular basis for memory storage and addiction
Bhatt, K. (2013)
High-Voltage-Activated Calcium Channels
Solinas, S. M. G., Masoli, S., & Subramaniyam, S. (2015) · Springer eBooks · doi:10.1007/978-1-4614-6675-8_230
(2020) · Society for Neuroscience eBooks · doi:10.1523/hon.011004
Deep Learning to Detect the Function of Calmodulin in Alzheimer’s Disease
Dong, L. (2023) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v36i.5781
Linkevicius, D., Chadwick, A., Faas, G. C., Stefan, M. I., & Sterratt, D. C. (2025) · PLoS ONE · doi:10.1371/journal.pone.0318646
Tian, J., Zhang, A., Li, L., Liu, H., Jiang, H., & Liang, R. (2025) · Cancer Science · doi:10.1111/cas.70051
Quantitative Models of Calcium-Dependent Protein Signaling in Neuronal Dendritic Spines
Pharris, M. C. (2019) · Purdue e-Pubs (Purdue University System) · doi:10.25394/pgs.8285963
Unifying experimental heterogeneity in a geometrical synaptic plasticity model
Rodrigues, Y. E. (2021) · theses.fr (ABES) · doi:10.70675/62ca5e06zd2c0z4133za51ez04d3f2ee6023
Regulation of different kinases for Alzheimer's disease therapy: progresses and perspectives
Han, M., Liao, Q., He, S., Guo, L., Lu, Z., Wang, X., Sun, W., Duan, Y. B., Lyu, W., & Li, Q. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110300
Calmodulin: The Essential Biological Regulator Self-Regulates Its Activity, Structure and Function
O’Day, D. H. (2026) · Biology · doi:10.3390/biology15191750
- Authors
- Pepke, S., Kinzer-Ursem, T., Mihalas, S., & Kennedy, M. B.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Kennedy, Mary B.
- Venue
- PLoS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-02-12
- Volume
- 6
- Issue
- 2
- Pages
- e1000675
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC2820514
- OpenAlex
- W2017789880
- Cited by
- 92
- References
- 56
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 13 · 2018: 6 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 5
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Gordon and Betty Moore Foundation
- National Institutes of Health (NS44306)
- National Institute on Drug Abuse (R01DA030749)
- National Institute of Neurological Disorders and Stroke (NS 44306, P01NS044306)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- CaMKII, calmodulin, calcium signaling, synaptic plasticity, NMDA receptor, postsynaptic spines, autophosphorylation, kinetic modeling, parameter sensitivity analysis, calcium transients, synaptic potentiation and depression, learning
- MeSH terms
- Calcium, Calmodulin, Kinetics, Models, Chemical, Phosphorylation, Protein Binding, Thermodynamics, Multiprotein Complexes, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Molecular Dynamics Simulation
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