Modelling the effect of specific inositol 1,4,5‐trisphosphate receptor isoforms on cellular Ca 2+ signals

Abstract

Background information . Oscillations of cytosolic Ca 2+ are well‐known to rely on the regulatory properties of the InsP 3 R (inositol 1,4,5‐trisphosphate receptor). Three isoforms of this channel have been identified. They differ in their regulatory properties by Ca 2+ and InsP 3 . 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 InsP 3 Rs 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 InsP 3 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 InsP 3 , 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 InsP 3 levels, the model predicts that the receptor is less robust to changes in density; this receptor, however, provides a finer control of the steady‐state level of Ca 2+ when varying the InsP 3 concentration. Conclusions . Our model allows us to propose an explanation for the experimental observations about the effect of selectively expressing or down‐regulating InsP 3 R isoforms, as well as to make theoretical predictions.