Computational model of Ca2+ wave propagation in human retinal pigment epithelium

Abstract

Purpose Ca2+ signaling is relevant to most biological functions. In retinal pigment epithelium (RPE) a significant Ca2+ wave is produced by mechanical stimulation. To understand this process in detail, we modeled Ca2+ wave propagation in ARPE‐19 cells. Methods Mechanically induced Ca2+ wave was recorded from ARPE‐19 cells by Ca2+ imaging. Based on the measurements, a mathematical model was constructed. The model assessed Ca2+ wave propagation by assuming that cells were experiencing different conditions depending on their location with respect to the stimulation site. Results The model describes Ca2+ metabolism after stimulation as follows: 1) Cells near the stimulus site are likely to conduct Ca2+ through plasma membrane stretch‐sensitive Ca2+ channels and gap junctions. 2) The extracellular ligand and inositol 1,4,5‐trisphosphate (IP3) diffusion through gap junctions mediate the signal in all locations of the monolayer, ligand concentration decreasing with distance. 3) The kinase activity targeted to IP3 receptor defines the sensitivity of the cell to the ligand. The model predicts suramin drug effects on P2Y2 receptors suggesting that suramin accelerates the phosphorylation rate of the receptors by enhancing their desensitization. Conclusion Our model is the first mathematical model of Ca2+ signaling in ARPE‐19 cells. The model enables the analysis of the Ca2+ signal propagation mechanisms, and predicts new pathways of suramin drug effects.