Quantitative Models of Calcium-Dependent Protein Signaling in Neuronal Dendritic Spines
Biochemical signaling at the connections between neurons, called synapses, regulates dynamic shifts in a synapse’s size and connective strength. Called synaptic plasticity, these shifts are initiated by calcium ion (Ca2+) flux into message-receiving structures called dendritic spines. Within dendritic spines, Ca2+ binds sensor proteins such as calmodulin (CaM). Importantly, Ca2+/CaM may bind and activate a wide variety of proteins, which subsequently facilitate signaling pathways regulating the dendritic spine’s size and connective strength.
In this thesis, I use computational models to characterize molecular mechanisms regulating Ca2+-dependent protein signaling within the dendritic spine. Specifically, I explore how Ca2+/CaM differentially activates binding partners and how these binding partners transduce signals downstream. For this, I present deterministic models of Ca2+, CaM, and CaM-dependent proteins, and in analyzing model output I demonstrate in-part that competition for CaM-binding alone may be sufficient to set the Ca2+ frequency-dependence of protein activation. Subsequently, I adapt my deterministic models into particle-based, spatial-stochastic frameworks to quantify how spatial effects influence model output, showing evidence that spatial gradients of Ca2+/CaM may set spatial gradients of activated proteins downstream. Additionally, I incorporate into my models the most detailed model to-date of Ca2+/CaM-dependent protein kinase II (CaMKII), a multi-subunit protein essential to synaptic plasticity. With this detailed model of CaMKII, my analysis suggests that the many subunits of CaMKII provide avidity effects that significantly increase the protein’s effective affinity for binding partners, particularly Ca2+/CaM. Altogether, this thesis provides a detailed analysis of Ca2+-dependent signaling within dendritic spines, characterizing molecular mechanisms that may be useful for the development of novel therapeutics for patients of neurological disorders.
History
Degree Type
- Doctor of Philosophy
Department
- Biomedical Engineering
Campus location
- West Lafayette