Understanding anomalous delays in a model of intracellular calcium dynamics

In many cell types, oscillations in the concentration of free intracellular calcium ions are used to control a variety of cellular functions. It has been suggested [J. Sneyd et al., A method for determining the dependence of calcium oscillations on inositol trisphosphate oscillations, Proc. Natl. Acad. Sci. U.S.A. 103, 1675-1680 (2006)] that the mechanisms underlying the generation and control of such oscillations can be determined by means of a simple experiment, whereby a single exogenous pulse of inositol trisphosphate (IP3) is applied to the cell. However, more detailed mathematical investigations [M. Domijan et al., Dynamical probing of the mechanisms underlying calcium oscillations, J. Nonlinear Sci. 16, 483-506 (2006)] have shown that this is not necessarily always true, and that the experimental data are more difficult to interpret than first thought. Here, we use geometric singular perturbation techniques to study the dynamics of models that make different assumptions about the mechanisms underlying the calcium oscillations. In particular, we show how recently developed canard theory for singularly perturbed systems with three or more slow variables [M. Wechselberger, A propos de canards (Apropos canards), Preprint, 2010] applies to these calcium models and how the presence of a curve of folded singularities and corresponding canards can result in anomalous delays in the response of these models to a pulse of IP3. (C) 2010 American Institute of Physics. [doi:10.1063/1.3523264]