Metabotropic receptor activation, desensitization and sequestration—I: modelling calcium and inositol 1,4,5-trisphosphate dynamics following receptor activation

A mathematical account is given of the processes governing the time courses of calcium ions (Ca2+), inositol 1,4,5-trisphosphate (IP3) and phosphatidylinositol 4,5-bisphosphate (PIP2) in single cells following the application of external agonist to metabotropic receptors. A model is constructed that incorporates the regulation of metabotropic receptor activity, the G-protein cascade and the Ca2+ dynamics in the cytosol. It is subsequently used to reproduce observations on the extent of desensitization and sequestration of the P2Y2 receptor following its activation by uridine triphosphate (UTP). The theory predicts the dependence on agonist concentration of the change in the number of receptors in the membrane as well as the time course of disappearance of receptors from the plasmalemma, upon exposure to agonist. In addition, the extent of activation and desensitization of the receptor, using the calcium transients in cells initiated by exposure to agonist, is also predicted. Model predictions show the significance of membrane PIP2 depletion and resupply on the time course of IP3 and Ca2+ levels. Results of the modelling also reveal the importance of receptor recycling and PIP2 resupply for maintaining Ca2+ and IP3 levels during sustained application of agonist.