Modelling the effect of specific inositol 1,4,5-trisphosphate receptor isoforms on cellular Ca2+ signals.
BACKGROUND
Oscillations of cytosolic Ca2+ 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 Ca2+ and InsP3. Experiments in different cell types clearly indicate that the relative amounts of each isoform affect the time course of Ca2+ 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 Ca2+ 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 Ca2+ concentrations when InsP3 is increased, and (iii) a monotonous increasing function of cytosolic Ca2+.


RESULTS
We show that, although these types of curves can be ascribed to slight differences in the channel regulation by Ca2+ and InsP3, they can indicate important variations as to the receptor role in cellular Ca2+ control. Thus the receptor associated with the classical bell-shaped curve appears to be the most robust Ca2+ oscillator. If the steady-state curve is supposed to be a monotonous increasing function of cytosolic Ca2+, the modelled receptor cannot sustain Ca2+ oscillations in the absence of Ca2+ exchanges with the extracellular medium. When the bell-shaped curve is shifted towards higher Ca2+ 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 steady-state level of Ca2+ 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.
Dupont
Geneviève
G
Université Libre de Bruxelles, Faculté des Sciences CP231, Boulevard du Triomphe, B-1050 Brussels, Belgium. gdupont@ulb.ac.be
Combettes
Laurent
L
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007425:Intracellular Membranes / Q000378:metabolism; D008954:Models, Biological; D008962:Models, Theoretical; D020033:Protein Isoforms / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium