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Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme’s subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of a twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous experimental measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other’s binding to CaMKII. Our results suggest a functional mechanism for the so-called “CaM trapping” phenomenon, wherein Ca2+/CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity.
Highlights
calmodulin-dependent protein kinase II (CaMKII) is a protein of interest because of its crucial role in synaptic plasticity [1,2,3,4,5]
CaMKII becomes activated in the presence of calcium ions (Ca2+) and calmodulin (CaM), allowing it to interact enzymatically with downstream binding partners
To explore the molecular mechanisms that regulate the activity of CaMKII holoenzymes, we use a rule-based approach that reduces computational complexity normally associated with representing the wide variety of functional states that a CaMKII holoenzyme can adopt
Summary
CaMKII is a protein of interest because of its crucial role in synaptic plasticity [1,2,3,4,5]. Synaptic plasticity in the post-synapse occurs within mushroom-shaped protrusions called dendritic spines [6]. Synaptic plasticity is dependent on calcium ion (Ca2+) flux through N-methyl-D-aspartate receptors (NMDARs) located on the dendritic spines of the post-synaptic neuron [7]. Frequency, and location of Ca2+ flux, synaptic plasticity may produce increases or decreases (or neither) in synaptic strength [8, 9]. Whether Ca2+ spikes induce LTP or LTD depends on relative activation of intracellular protein signaling networks. When Ca2+ first enters the dendritic spine, it interacts with a variety of buffer and sensor proteins, calmodulin (CaM), which has many protein targets in the spine, including CaMKII [5, 11, 12]
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