Competitive Tuning of Ca2+/Calmodulin-Activated Proteins Provides a Compensatory Mechanism for AMPA Receptor Phosphorylation in Synaptic Plasticity

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By Matthew C Pharris1, Tamara L. Kinzer-Ursem1

Purdue University

Code for the basic 4-state competitive binding model that builds on previous work by incorporating an additional competitor for calmodulin along with a number of downstream proteins. Also include is sample code for global sensitivity analysis...

Version 2.0 - published on 30 Jul 2018 doi:10.4231/R7VX0DS0 - cite this Archived on 30 Aug 2018

Licensed under CC0 1.0 Universal


Introduction: Dynamic changes in the strength of synaptic connections, known as synaptic plasticity, are thought to be fundamental to learning and memory. In excitatory neurons, synaptic plasticity occurs when calcium ions (Ca2+) flux through NMDA receptors and bind the Ca2+-sensor calmodulin (CaM). The activation of downstream Ca2+/CaM binding proteins (CBPs) is a function of the frequency of Ca2+ flux, such that each CBP is preferentially “tuned” to different Ca2+ input signals. We have recently reported that competition among CBPs for CaM binding is alone sufficient to recreate in silico the observed in vivo frequency-dependence of several CBPs. However, CBP activation may strongly depend on the identity and concentration of proteins that constitute the competitive pool; with important implications in the regulation of CBPs that are implicated in learning and memory disorders.

Methods: We hypothesize that although perturbations may decrease activation of one CBP, increased activation of another CBP could compensate this loss, providing a homeostatic effect. Using computational models, we explore this compensatory mechanism by quantifying the effect of parameter perturbations on competitive tuning. We also extend our model to include AMPA receptor phosphorylation, a hallmark of synaptic plasticity.

Results and Conclusions: Although knockout of the CaM buffer neurogranin causes a decrease in CaMKII activation, overall AMPAR phosphorylation levels are maintained by a concomitant increase in AC8 activation. In some instances, increases AMPAR phosphorylation is seen. Our results explain recent counter-intuitive results in neurogranin knockout mice, provide further evidence that competitive tuning is an important mechanism in synaptic plasticity, and suggest new experiments to test this hypothesis.

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This version contains our model's primary Mathematica notebook file, a script for performing Latin Hypercube Sampling over the complete set of kinetic parameters, and scripts with the explicit reactions (not the ODE's) for the 2- and 4-state calmodulin binding network.

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