Negative feedback of extracellular ADP on ATP release in goldfish hepatocytes: A theoretical study

A mathematical model was built to account for the kinetic of extracellular ATP (ATPe) and extracellular ADP (ADPe) concentrations from goldfish hepatocytes exposed to hypotonicity The model was based on previous experimental results on the time course of ATPe accumulation, ectoATPase activity, and cell viability [Pafundo et al 2008] The kinetic of ATPe is controlled by a lytic ATP flux, a non-lytic ATP flux, and ecto-ATPase activity, whereas ADPe kinetic is governed by a lyric ADP flux and both ecto-ATPase and ecto-ADPase activities Non-lytic ATPe efflux was included as a diffusion equation modulated by ATPe activation (positive feedback) and ADPe inhibition (negative feedback). The model yielded physically meaningful and stable steady-state solutions, was able to fit the experimental time evolution of ATPe and simulated the concomitant kinetic of ADPe According to the model during the first minute of hypotonicity the concentration of ATPe is mainly governed by both lyric and non-lytic ATP efflux, with almost no contribution from ecto-ATPase activity Later on, ectoATPase activity becomes important in defining the time dependent decay of ATPe levels ADPe inhibition of the non-lyric ATP efflux was strong, whereas ATPe activation was minimal Finally, the model was able to predict the consequences of partial inhibition of ecto-ATPase activity on the ATPe kinetic, thus emulating the exposure of goldfish cells to hypotonic medium in the presence of the ATP analog AMP-PCP The model predicts this analog to both inhibit ectoATPase activity and increase non-lytic ATP release (C) 2010 Elsevier Ltd. All rights reserved