Computational Model of Ca2+ Wave Propagation in Human Retinal Pigment Epithelial ARPE-19 Cells

Abstract

ObjectiveComputational models of calcium (Ca2+) signaling have been constructed for several cell types. There are, however, no such models for retinal pigment epithelium (RPE). Our aim was to construct a Ca2+ signaling model for RPE based on our experimental data of mechanically induced Ca2+ wave in the in vitro model of RPE, the ARPE-19 monolayer.MethodsWe combined six essential Ca2+ signaling components into a model: stretch-sensitive Ca2+ channels (SSCCs), P2Y2 receptors, IP3 receptors, ryanodine receptors, Ca2+ pumps, and gap junctions. The cells in our epithelial model are connected to each other to enable transport of signaling molecules. Parameterization was done by tuning the above model components so that the simulated Ca2+ waves reproduced our control experimental data and data where gap junctions were blocked.ResultsOur model was able to explain Ca2+ signaling in ARPE-19 cells, and the basic mechanism was found to be as follows: 1) Cells near the stimulus site are likely to conduct Ca2+ through plasma membrane SSCCs and gap junctions conduct the Ca2+ and IP3 between cells further away. 2) Most likely the stimulated cell secretes ligand to the extracellular space where the ligand diffusion mediates the Ca2+ signal so that the ligand concentration decreases with distance. 3) The phosphorylation of the IP3 receptor defines the cell’s sensitivity to the extracellular ligand attenuating the Ca2+ signal in the distance.ConclusionsThe developed model was able to simulate an array of experimental data including drug effects. Furthermore, our simulations predict that suramin may interfere ligand binding on P2Y2 receptors or accelerate P2Y2 receptor phosphorylation, which may partially be the reason for Ca2+ wave attenuation by suramin. Being the first RPE Ca2+ signaling model created based on experimental data on ARPE-19 cell line, the model offers a platform for further modeling of native RPE functions.

A simple mechanochemical model for calcium signalling in embryonic epithelial cells

“…A model for the opening and closing of SSCCs was developed in Vainio et al. ( 2015 ) for retinal pigment epithelial cells; we adapt it here for embryonic epithelial cells for which no such modelling has been performed. We denote by the proportion of channels in the closed state, and by the proportion of SSCCs in the open state.…”

“… 2016 ), and for retinal pigment epithelial cells (Vainio et al. 2015 ). However, these models do not include a two-way coupling between calcium signalling and mechanics.…”

Inhibition of Starvation-Triggered Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in ARPE-19 Cells by Taurine through Modulating the Expression of Calpain-1 and Calpain-2

“…Disruption of retinal pigment epithelium (RPE) is one of the major pathological changes in AMD. There are some factors believed to be involved in the development of RPE damage, such as apoptosis, mitochondrial dysfunction, lack of nutrients and oxygen, and calcium overload [ 3 , 4 , 5 ]. However, the exact mechanism is still unknown.…”

Curcumin regulates intracellular calcium release and inhibits oxidative stress parameters, VEGF, and caspase-3/-9 levels in human retinal pigment epithelium cells

“…All internal and external body surfaces are covered by epithelial tissues. These cell layers have various functions depending on their location, and many of these functions are controlled by calcium (Ca 2+ ) activity (30,36). The retinal pigment epithelium (RPE) cells belong to this type, and play a key role in the pathophysiology of age-related macular degeneration (AMD).…”

“…The pigmented monolayer of retina and/or the RPE cell layer is the pigmented and polarized cell layer just outside the neurosensory system and forms part of the blood-retinal barrier (17). The RPE plays a crucial role in the maintenance (36) and protection of photoreceptors. The RPE is also responsible for absorbing light, regulating the nutrient uptake mechanism, ion transfer with water, and eliminating waste from the subretinal tissue, as well as secretion (39).…”