Comparison of Models for IP3 Receptor Kinetics Using Stochastic Simulations

Abstract

Inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitous intracellular calcium (Ca2+) channel which has a major role in controlling Ca2+ levels in neurons. A variety of computational models have been developed to describe the kinetic function of IP3R under different conditions. In the field of computational neuroscience, it is of great interest to apply the existing models of IP3R when modeling local Ca2+ transients in dendrites or overall Ca2+ dynamics in large neuronal models. The goal of this study was to evaluate existing IP3R models, based on electrophysiological data. This was done in order to be able to suggest suitable models for neuronal modeling. Altogether four models (Othmer and Tang, 1993; Dawson et al., 2003; Fraiman and Dawson, 2004; Doi et al., 2005) were selected for a more detailed comparison. The selection was based on the computational efficiency of the models and the type of experimental data that was used in developing the model. The kinetics of all four models were simulated by stochastic means, using the simulation software STEPS, which implements the Gillespie stochastic simulation algorithm. The results show major differences in the statistical properties of model functionality. Of the four compared models, the one by Fraiman and Dawson (2004) proved most satisfactory in producing the specific features of experimental findings reported in literature. To our knowledge, the present study is the first detailed evaluation of IP3R models using stochastic simulation methods, thus providing an important setting for constructing a new, realistic model of IP3R channel kinetics for compartmental modeling of neuronal functions. We conclude that the kinetics of IP3R with different concentrations of Ca2+ and IP3 should be more carefully addressed when new models for IP3R are developed.

Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity

“…Likewise, β and μ were adjusted for a basal IP 3 concentration of 120nM [85]. Note that this value is based on recent, precise measurements of IP 3 concentration and differs by an order of magnitude from IP 3 concentration values routinely used in IP 3 R -mediated calcium models [59, 125, 126]. IP 3 R density on the ER surface has been measured from TIRF-microscopy analysis in cell cultures [89], reporting IP 3 R cluster diameters of 0.3 μ m at most, with up to 10 IP 3 R per cluster.…”

Inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum: A single-channel point of view

“…Many computational kinetic models have been developed over the years to account for the observed InsP 3 and Ca 2+ i regulation of single InsP 3 R channel gating ([81] and references therein). These kinetic models were then used to simulate the generation and propagation of more complex intracellular Ca 2+ signals (blips, puffs and waves) by organized clusters of InsP 3 R channels [72].…”

Reproducibility and Comparability of Computational Models for Astrocyte Calcium Excitability

“…In our previous studies, we have assessed reproducibility and comparability issues in computational neuroscience and in computational cell biology (see, e.g., Pettinen et al, 2005 ; Manninen et al, 2010 , 2011 ; Hituri and Linne, 2013 ; Manninen et al, in press ). Especially in Manninen et al ( in press ), we briefly discussed the reproducibility issues related to five astrocyte and astrocyte-neuron models (Nadkarni and Jung, 2003 ; Di Garbo et al, 2007 ; Lavrentovich and Hemkin, 2008 ; Dupont et al, 2011 ; Wade et al, 2012 ).…”