Extending the IP3 receptor model to include competition with partial agonists

The inositol 1,4,5-trisphosphate (IP3) receptor is a Ca2+ channel located in the endoplasmic reticulum and is regulated by IP3 and Ca2+. This channel is critical to calcium signaling in cell types as varied as neurons and pancreatic beta cells to mast cells. De Young and Keizer (1992) created an eight-state, nine-variable model of the IP3 receptor. In their model, they accounted for three binding sites, a site for IP3, activating Ca2+, and deactivating Ca2+. The receptor is only open if IP3 and activating Ca2+ is bound. Li and Rinzel followed up this paper in 1994 by introducing a reduction that made it into a two variable system. A recent publication by Rossi et al. (2009) studied the effect of introducing IP3-like molecules, referred to as partial agonists (PA), into the cell to determine the structure-function relationship between IP3 and its receptor. Initial results suggest a competitive model, where IP3 and PA fight for the same binding site. We extend the original eight-state model to a 12-state model in order to illustrate this competition, and perform a similar reduction to that of Li and Rinzel in the first modeling study we are aware of considering PA effect on an IP3 receptor. Using this reduction we solve for the equilibrium open probability for calcium release in the model. We replicate graphs provided by the Rossi paper, and find that optimizing the subunit affinities for IP3 and PA yields a good fit to the data. We plug our extended reduced model into a full cell model, in order to analyze the effects PA have on whole cell properties specifically the propagation of calcium waves in two dimensions. We conclude that PA creates qualitatively different calcium dynamics than would simply reducing IP3, but that effectively PA can act as an IP3 knockdown. (c) 2012 Elsevier Ltd. All rights reserved.