title: Computational Model of Ca2+ Wave Propagation in Human Retinal Pigment Epithelial ARPE-19 Cells.
abstract: OBJECTIVE
  Computational 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Electronics and Communications Engineering, Tampere University of Technology, Tampere, Finland; Institute of Biosciences and Medical Technology, Tampere University of Technology, Tampere, Finland.
authors.forename: Iina
authors.initials: I
authors.lastname: Vainio
authors.affiliation: Department of Electronics and Communications Engineering, Tampere University of Technology, Tampere, Finland; Institute of Biosciences and Medical Technology, Tampere University of Technology, Tampere, Finland.
authors.forename: Amna
authors.initials: A
authors.lastname: Abu Khamidakh
authors.affiliation: Department of Electronics and Communications Engineering, Tampere University of Technology, Tampere, Finland; Institute of Biosciences and Medical Technology, Tampere University of Technology, Tampere, Finland.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Paci
authors.affiliation: Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Skottman
authors.affiliation: Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Juuti-Uusitalo
authors.affiliation: Department of Electronics and Communications Engineering, Tampere University of Technology, Tampere, Finland; Institute of Biosciences and Medical Technology, Tampere University of Technology, Tampere, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Hyttinen
authors.affiliation: Department of Electronics and Communications Engineering, Tampere University of Technology, Tampere, Finland; Institute of Biosciences and Medical Technology, Tampere University of Technology, Tampere, Finland.
authors.forename: Soile
authors.initials: S
authors.lastname: Nymark
mesh_terms: D000465:Algorithms; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D003198:Computer Simulation; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000378:metabolism*
chemical_list: D002118:Calcium