A comparison of three models of the inositol trisphosphate receptor

Abstract

The inositol (1,4,5)-trisphosphate receptor (IPR) plays a crucial role in calcium dynamics in a wide range of cell types, and is often a central feature in quantitative models of calcium oscillations and waves. We compare three mathematical models of the IPR, fitting each of them to the same data set to determine ranges for the parameter values. Each of the fits indicates that fast activation of the receptor, followed by slow inactivation, is an important feature of the model, and also that the speed of inositol trisphosphate IP3 binding cannot necessarily be assumed to be faster than Ca2+ activation. In addition, the model which assumed saturating binding rates of Ca2+ to the IPR demonstrated the best fit. However, lack of convergence in the fitting procedure indicates that responses to step increases of Ca2+ and IP3 provide insufficient data to determine the parameters unambiguously in any of the models.

Actin-based confinement of calcium responses during Shigella invasion

“…Equation (2) describes changes in cytosolic Ca 2 þ concentration due to Ca 2 þ release from the endoplasmic reticulum assumed to remain constant, uptake through the SERCA pumps and diffusion. Equations (1) and (2) are based on Dupont and Swillens 32 and represent a classical description of Ca 2 þ dynamics 47 . Equation (3) is a simplified description of intracellular InsP 3 dynamics, taking into account synthesis through PLC at a basal rate (V b ), localized stimulated synthesis due to bacterial invasion (J IP ), linear degradation (k d I) and diffusion.…”

Fundamental properties of Ca2+ signals

“…The refractoriness has often been related to the negative feedback of high Ca 2+ concentrations on the open probability of IP 3 R as observed in patch clamp experiments [27][28][29] (see [5,30,31] for reviews). Together with the positive feedback of CICR at small Ca 2+ concentrations, this negative feedback leads to a bell shaped dependence of the stationary open probability of IP 3 R on cytosolic Ca 2+ [6,32].…”

“…This hypothesized feedback could not be verified experimentally in general and led to further model development. A prominent class of models for the IP 3 receptor (see [5,30,31,41] for reviews) considers one site for IP 3 binding that sensitizes a subunit for Ca 2+ binding, one for Ca 2+ that activates a subunit, and another one for Ca 2+ that dominantly inhibits a subunit. In the DeYoung-Keizer-model [27], it is assumed that a channel opens if at least 3 subunits of the tetrameric IP 3 R are in the active state.…”

Calcium spikes: Chance or necessity?

“…It describes the transient release of calcium from intracellular, calcium rich stores, most notably the endoplasmic reticulum (ER), into the cytosol. The most elemental signals are generated by the release of calcium through small clusters of release channels, called IP 3 Rs or inositol trisphosphate receptor channels (for a review, see [1]), in the ER membrane. These channels are ligand gated and require the second messenger inositol trisphosphate (IP 3 ) and cytosolic calcium bound in order to open.…”