Epithelial Ca2+ Model Prediction: Suramin Enhances P2Y2 Receptor Desensitization by Accelerating their Phosphorylation Rate

Abstract

Ca2+ signaling is essential to most biological functions. To understand Ca2+ signaling in retinal pigment epithelium (RPE), we constructed a computational model of Ca2+ wave propagation in ARPE-19 cells based on Ca2+ imaging measurements after mechanical stimulation. We exploited the extensive experimental material from Abu Khamidakh et al. 2013 Exp Eye Res. The model relied on the assumption that cells experience different conditions depending on their location with respect to the stimulation site. In this context, the model was used to simulate the measured Ca2+ waves and predict the drug effects only by changing the appropriate environmental parameters or drug target components.Our model reproduced the measured Ca2+ dynamics in control cells and in cells after α-glycyrrhetinic acid treatment. As an example of model usage, the model was applied to study suramin inhibition mechanisms in P2Y2 receptors. The model suggested that the suramin inhibition of Ca2+ signal propagation may be related to increased P2Y2 receptor phosphorylation rate: the higher phosphorylation rate causes faster desensitization of the receptors after ligand binding shortening the duration of the Ca2+ elevation. The modeling results showed that a relatively larger inhibition occurs with higher Ca2+ waves near the site of mechanical stimulation.In summary, the model predicted suramin drug effects on P2Y2 receptors suggesting that suramin enhances their desensitization by accelerating the phosphorylation rate. This intriguing modeling result requires further investigation and needs to be confirmed experimentally for a deeper understanding of the biological mechanisms related to the phenomenon. In general, to date, this is the first mathematical model of Ca2+ signaling in ARPE-19 cells and one of the first in general to model epithelial Ca2+ dynamics presenting also predictions about the drug modified parameters.