title: Computational Modeling of Spatiotemporal Ca(2+) Signal Propagation Along Hepatocyte Cords.
abstract: The purpose of this study is to model the dynamics of lobular Ca(2+) wave propagation induced by an extracellular stimulus, and to analyze the effect of spatially systematic variations in cell-intrinsic signaling parameters on sinusoidal Ca(2+) response.
  
  
  
  We developed a computational model of lobular scale Ca(2+) signaling that accounts for receptor- mediated initiation of cell-intrinsic Ca(2+) signal in hepatocytes and its propagation to neighboring hepatocytes through gap junction-mediated molecular exchange.
  
  
  
  Analysis of the simulations showed that a pericentral-to-periportal spatial gradient in hormone sensitivity and/or rates of IP3 synthesis underlies the Ca(2+) wave propagation. We simulated specific cases corresponding to localized disruptions in the graded pattern of these parameters along a hepatic sinusoid. Simulations incorporating locally altered parameters exhibited Ca(2+) waves that do not propagate throughout the hepatic plate. Increased gap junction coupling restored normal Ca(2+) wave propagation when hepatocytes with low Ca(2+) signaling ability were localized in the midlobular or the pericentral region.
  
  
  
  Multiple spatial patterns in intracellular signaling parameters can lead to Ca(2+) wave propagation that is consistent with the experimentally observed spatial patterns of Ca(2+) dynamics. Based on simulations and analysis, we predict that increased gap junction-mediated intercellular coupling can induce robust Ca(2+) signals in otherwise poorly responsive hepatocytes, at least partly restoring the sinusoidally oriented Ca (2+) waves.
  
  
  
  Our bottom-up model of agonist-evoked spatial Ca(2+) patterns can be integrated with detailed descriptions of liver histology to study Ca(2+) regulation at the tissue level.
authors.forename: Aalap
authors.initials: A
authors.lastname: Verma
authors.forename: Hirenkumar
authors.initials: H
authors.lastname: Makadia
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.forename: Babatunde A
authors.initials: BA
authors.lastname: Ogunnaike
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Vadigepalli
mesh_terms: D000818:Animals; D001698:Biomedical Engineering; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D017483:Receptors, Vasopressin / Q000378:metabolism
chemical_list: D017483:Receptors, Vasopressin