Modelling the effect of specific inositol 1,4,5-trisphosphate receptor isoforms on cellular Ca2+ signals

Background information. Oscillations of cytosolic Ca^2+ are well-known to rely on the regulatory properties of the InsP3R (inositol 1,4,5-trisphosphate receptor). Three isoforms of this channel have been identified. They differ in their regulatory properties by Ca^2+ and InsP3. Experiments in different cell types clearly indicate that the relative amounts of each isoform affect the time course of Ca^2+ changes after agonist stimulation. In the present study, we investigate whether different steady-state curves for the open probability of the InsP3Rs as a function of Ca^2+ imply different dynamical behaviours when these receptors are present in a cellular environment. We therefore describe by a specific phenomenological model the three main types of curves that have been reported: (i) the classical bell-shaped curve, (ii) the bell-shaped curve that is shifted towards higher Ca^2+ concentrations when InsP3 is increased, and (iii) a monotonous increasing function of cytosolic Ca^2+. Results. We show that, although these types of curves can be ascribed to slight differences in the channel regulation by Ca^2+ and InsP3, they can indicate important variations as to the receptor role in cellular Ca^2+ control. Thus the receptor associated with the classical bell-shaped curve appears to be the most robust Ca^2+ oscillator. If the steady-state curve is supposed to be a monotonous increasing function of cytosolic Ca^2+, the modelled receptor cannot sustain Ca^2+ oscillations in the absence of Ca^2+ exchanges with the extracellular medium. When the bell-shaped curve is shifted towards higher Ca^2+ concentrations with increasing InsP3 levels, the model predicts that the receptor is less robust to changes in density; this receptor, however, provides a finer control of the steadystate level of Ca^2+ when varying the InsP3 concentration. Conclusions. Our model allows us to propose an explanation for the experimental observations about the effect of selectively expressing or down-regulating InsP3R isoforms, as well as to make theoretical predictions.