Mathematics Honors Thesis Seminar by Greg Handy
Extending the IP3 Receptor Model to Include Competition
Monday, May 2, 2011 · 12:01 - 12:30 PM
Mathematics Honor's Thesis Seminar
Greg Handy
Mentor: Dr. Brad Peercy
Title: Extending the IP3 Receptor Model to Include Competition with Partial Agonists Abstract: The inositol 1,4,5-trisphosphate (IP3) receptor is a Ca2+ channel located in the endoplasmic reticulum and is regulated by IP3 and Ca2+. In 1992, De Young and Keizer created an eight-state, nine-variable model of the IP3 receptor (Young, Keizer, 1992). 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. in 2009 studied the effect of introducing IP3-like molecules, referred to as partial agonists, into the cell (Rossi, 2009). Initial results suggest a competitive model, where IP3 and partial agonists fight for the same binding site. We extend the original eight-state model to a twelve-state model in order to illustrate this competition, and perform a similar reduction to that of Li and Rinzel. Using this reduction we solve for the equilibrium open probability of the model. We then replicated graphs provided by the Rossi paper, and find that while the model misses some of the quantitative measures it captures key qualitative characteristics. Using the model we can suggest biophysical reasons for the mismatch. We then plug the reduced model into a full cell model, in order to analyze the effects partial agonists have on the propagation of calcium waves in two dimensions.