The Study of Calcium Dynamics with a Comprehensive Model (2010 - Present)

Investigator:  Sandor Kadar, Salve Regina University

Abstract:  Heavy metals, pesticides, and other environmental factors have been shown to have a profound effect on the complex Ca2+ signaling mechanism of the cell. We found evidence, that synchronized random variation (correlated environmental noise) on the operation of the calcium channels and on the on the binding process of an agonist to the G-protein coupled receptor (GPCR) have an impact on the Ca2+ dynamics through a mechanism known as stochastic resonance (SR). We will extend the investigation to study the effect of uncorrelated noise, which is the case when the calcium channels and the GPCR are impacted by noise either from different source or with different spatial and temporal properties. We will also consider internal noise, which arises from the highly inhomogeneous nature of the cell, on dynamical variables such as cytosolyc Ca2+, and IP3 concentrations and on the operation of the IP3 receptor (IP3R). We continue to develop a Comprehensive Model with Biphasic Regulation (CoMBRe) for the calcium dynamics of the cell.  The CoMBRe model is based on a “combined” model that was assembled from a GPCR-based model and a Ca2+-induced Ca2+-release (CICR) based model. Based on recent results, the current representation for biphasic regulation of IP3R will be replaced by an approach that accounts for the interaction among the activating and inhibiting calcium binding sites as well as the IP3 binding site. Basic experimental setup will be established with the necessary student training to collect experimental data (cytosolic calcium vs. time traces) in response to various environmental factors, such as K+ ions and dopamine. The experimental data will be used to modify and ultimately validate the model. The principle goal of the project is to establish a numerical model which is sensitive to environmental noise and validated by experimental results obtained in PC12 cells. Ultimately we expect this to provide a viable tool to gain better understanding of calcium dynamics as well as being able to predict physiological effects of various environmental factors.