Validating models of the IP3 receptor: reproduction of experimental data with stochastic simulations

Abstract

Event Abstract Back to Event Validating models of the IP3 receptor: reproduction of experimental data with stochastic simulations Katri Hituri1*, Stefan Wils2, Marja-Leena Linne1 and Erik De Schutter2 1 Tampere University of Technology, Finland 2 Okinawa Inst. of Science and Technology, Japan Transient rises in cytosolic calcium (Ca2+) concentration play a crucial role in initiating long-term depression (LTD) of synaptic activity, an electrophysiological phenomenon related to learning of motor functions in cerebellar Purkinje cells (PC). Ca2+ release from endoplasmic reticulum (ER) is particularly important in LTD. In PCs, the release is mediated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) that are highly expressed in dendritic spines. The small volume of the spine, as well as the small number of molecules involved, increase stochasticity (randomness) in the biochemical processes. Thus deterministic simulations of IP3R activation may not produce realistic results under all conditions [1]. In this work the behavior of two IP3R models [3,4] is compared to experimental data. The ultimate goal of the work is to find a model that is simple but enough yet succeeds in reproducing experimental data satisfactorily. The models were simulated with the stochastic simulation software STEPS. STEPS (STochastic Engine for Pathway Simulation) is a tool for full stochastic simulation of reaction kinetics, as well as diffusion, of molecules in three dimension. STEPS extends the stochastic simulation algorithm (SSA) described by Gillespie [2]. There exist a couple of studies on characterizing the single-channel behavior of the cerebellar IP3Rs in lipid bilayer. However, the data presented in the articles is quite limited. Information on mean open times of the IP3R, as well as some distributions of the open time times, related to a limited number of concentrations of IP3 and Ca2+, can be obtained from literature. The selected models were simulated to reproduce similar data. The IP3R model of Doi et al. (2005) was found to reproduce the available experimental data more accurately than the model of Fraiman and Dawson (2004). This indicates that the model of Doi et al. would be better choice for modeling IP3Rs in cerebellar PC spines. The results of the present work also indicate that the models for IP3R used in this work might need to be refined structurally and functionally more or less to reproduce correct time series behavior of IP3Rs. This would facilitate a better model to simulate the processes related to LTD induction and information storage in cerebellum.