Development of a Comprehensive Model for Calcium Signaling (2009 - Present)

Investigator:  Sandor Kadar, Salve Regina University

Abstract:  Environmental factors and neurotoxins have been shown to have a profound effect on the complex Ca2+ signaling mechanism of the cell. The first aim of the project is to develop a Comprehensive Model with Biphasic Regulation (CoMBRe) for the calcium dynamics of the cell. The CoMBRe model will be based on a “combined” model that was assembled from a G protein-coupled receptor (GPCR) model and a Ca2+-induced Ca2 release (CICR) based model. The existing hypotheses accounting for the biphasic nature of the regulation of the IP3 receptor (IP3R) on the endoplasmatic reticulum (ER) by cytosolic Ca2+ will be incorporated into the numerical model. The dynamical details such as the activation and inhibition of the IP3R by the cytosolic [Ca2+] and the importance of the binding sequence between the Ca2+ and IP3 will be incorporated into the model. There is evidence in the literature that both environmental and internal noise have impact on the Ca2+ dynamics through a mechanism known as stochastic resonance (SR). If the Ca2+ dynamics exhibits SR, an optimally chosen Gaussian distributed white noise with zero average can facilitate Ca2+ signal propagation in a sub-threshold parameter region relative to the deterministic oscillatory dynamics, however, increasing deviation from the optimal value in either direction increases the signal degradation which is a fingerprint of SR. Random fluctuations of the stochastic events on key dynamical variables (concentrations) and bifurcation parameters will be investigated. We will also investigate what circumstances cause noise to corrupt the frequency-encoded Ca2+ signal. The third aim of the project is the development of a two-cell model for Ca2+ -dependent neurotransmitter release and subsequent signal transmission. The GPCR initiated signal transmission is triggered by an artificial agonist signal in the first cell; however, the oscillating concentration of the released neurotransmitter from the first cell serves as an actual trigger (agonist) for the second cell mimicking a true model of the communication between cells. The CoMBRe model will be modified to account for the Ca2+-dependent activation of synaptotagmin and SNARE proteins, which are intimately involved in the release of neurotransmitters.