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Published July 17, 2020 | Published + Supplemental Material + Submitted
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Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator


Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca²⁺ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. Using agent-based models, we computationally investigate the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule, Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that Ng plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase, CaMKII monomers integrate over Ca²⁺ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1, providing a mechanism to precisely control the sensitivity of synapses to calcium signals.

Additional Information

© 2020 Ordyan 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: December 10, 2019; Accepted: June 4, 2020; Published: July 17, 2020. We thank Miriam Bell for useful discussions and assistance with making Fig 11. We thank Miriam Bell, Allen Leung and Kiersten Scott for proofreading the manuscript. Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pcbi.1008015. Data Availability: All bngl files are available on GitHub at the following repository: https://github.com/marordyan/CaMKII_well_mixed/. Funding: PR,MO,TB,TS: FA9550-18-1-0051 US Air Force https://www.airforce.com/, TB,TS: P41GM103712 National Institute of Health https://www.nih.gov/ MK,TB,TS: NS44306MK National Institute of Health https://www.nih.gov/ MK,TB,TS: DA030749 National Institute of Health https://www.nih.gov/ 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. Author Contributions: Conceptualization: Mariam Ordyan, Tom Bartol, Mary Kennedy, Padmini Rangamani, Terrence Sejnowski. Data curation: Mariam Ordyan. Formal analysis: Mariam Ordyan. Funding acquisition: Tom Bartol, Mary Kennedy, Padmini Rangamani, Terrence Sejnowski. Investigation: Mariam Ordyan, Tom Bartol, Mary Kennedy, Padmini Rangamani, Terrence Sejnowski. Methodology: Mariam Ordyan, Tom Bartol, Padmini Rangamani, Terrence Sejnowski. Project administration: Padmini Rangamani, Terrence Sejnowski. Software: Mariam Ordyan, Tom Bartol. Supervision: Padmini Rangamani, Terrence Sejnowski. Visualization: Mariam Ordyan. Writing – original draft: Mariam Ordyan, Padmini Rangamani. Writing – review & editing: Mariam Ordyan, Tom Bartol, Mary Kennedy, Padmini Rangamani, Terrence Sejnowski.

Attached Files

Submitted - 809905.full.pdf

Published - journal.pcbi.1008015.pdf

Supplemental Material - journal.pcbi.1008015.s001.tif

Supplemental Material - journal.pcbi.1008015.s002.tif

Supplemental Material - journal.pcbi.1008015.s003.tif

Supplemental Material - journal.pcbi.1008015.s004.tif

Supplemental Material - journal.pcbi.1008015.s005.tif


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August 19, 2023
September 8, 2023