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- Title
A Dynamic Model of Interactions of Ca<sup>2+</sup>, Calmodulin, and Catalytic Subunits of Ca<sup>2+</sup>/Calmodulin-Dependent Protein Kinase II.
- Authors
Pepke, Shirley; Kinzer-Ursem, Tamara; Mihalas, Stefan; Kennedy, Mary B.
- Abstract
During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-Daspartate- 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 bind up 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.
- Subjects
CALCIUM ions; CALMODULIN; PROTEIN kinases; PHOSPHORYLATION; SYNAPSES; NEURAL circuitry
- Publication
PLoS Computational Biology, 2010, Vol 6, Issue 2, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1000675