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A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

Pepke, Shirley and Kinzer-Ursem, Tamara and Mihalas, Stefan and Kennedy, Mary B. (2010) A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II. PLoS Computational Biology, 6 (2). Art. No. e1000675. ISSN 1553-734X. PMCID PMC2820514. https://resolver.caltech.edu/CaltechAUTHORS:20100326-111445101

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Abstract

During the acquisition of memories, influx of Ca^(2+) 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 Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), 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 Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pcbi.1000675DOIArticle
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000675PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820514/PubMed CentralArticle
ORCID:
AuthorORCID
Kennedy, Mary B.0000-0003-1369-0525
Alternate Title:A Dynamic Model of Interactions of Ca2+, Calmodulin, and Catalytic Subunits of Ca2+/Calmodulin-Dependent Protein Kinase II
Additional Information:© 2010 Pepke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received September 15, 2009; Accepted January 11, 2010; Published February 12, 2010. This work was supported by a National Institutes of Health Grant (no. NS44306; www.nih.gov) and the Gordon and Betty Moore Foundation (www. moore.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist.
Funders:
Funding AgencyGrant Number
NIHNS44306
Gordon and Betty Moore FoundationUNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC2820514
Record Number:CaltechAUTHORS:20100326-111445101
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100326-111445101
Official Citation:Pepke S, Kinzer-Ursem T, Mihalas S, Kennedy MB (2010) A Dynamic Model of Interactions of Ca2+, Calmodulin, and Catalytic Subunits of Ca2+/Calmodulin-Dependent Protein Kinase II. PLoS Comput Biol 6(2): e1000675. doi:10.1371/journal.pcbi.1000675
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17804
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:30 Mar 2010 22:41
Last Modified:03 Oct 2019 01:33

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