Sensitisation waves in a bidomain fire-diffuse-fire model of intracellular Ca²⁺ dynamics

We present a bidomain threshold model of intracellular calcium (Ca²⁺) dynamics in which, as suggested by recent experiments, the cytosolic threshold for Ca²⁺ liberation is modulated by the Ca²⁺ concentration in the releasing compartment. We explicitly construct stationary fronts and determine their stability using an Evans function approach. Our results show that a biologically motivated choice of a dynamic threshold, as opposed to a constant threshold, can pin stationary fronts that would otherwise be unstable. This illustrates a novel mechanism to stabilise pinned interfaces in continuous excitable systems. Our framework also allows us to compute travelling pulse solutions in closed form and systematically probe the wave speed as a function of physiologically important parameters. We find that the existence of travelling wave solutions depends on the time scale of the threshold dynamics, and that facilitating release by lowering the cytosolic threshold increases the wave speed. The construction of the Evans function for a travelling pulse shows that of the co-existing fast and slow solutions the slow one is always unstable.

Towards a predictive model of Ca²⁺ puffs

We investigate key characteristics of Ca²⁺ puffs in deterministic and stochastic frameworks that all incorporate the cellular morphology of IP[subscript]3 receptor channel clusters. In a first step, we numerically study Ca²⁺ liberation in a three dimensional representation of a cluster environment with reaction-diffusion dynamics in both the cytosol and the lumen. These simulations reveal that Ca²⁺ concentrations at a releasing cluster range from 80 µM to 170 µM and equilibrate almost instantaneously on the time scale of the release duration. These highly elevated Ca²⁺ concentrations eliminate Ca²⁺ oscillations in a deterministic model of an IP[subscript]3R channel cluster at physiological parameter values as revealed by a linear stability analysis. The reason lies in the saturation of all feedback processes in the IP[subscript]3R gating dynamics, so that only fluctuations can restore experimentally observed Ca²⁺ oscillations. In this spirit, we derive master equations that allow us to analytically quantify the onset of Ca²⁺ puffs and hence the stochastic time scale of intracellular Ca²⁺ dynamics. Moving up the spatial scale, we suggest to formulate cellular dynamics in terms of waiting time distribution functions. This approach prevents the state space explosion that is typical for the description of cellular dynamics based on channel states and still contains information on molecular fluctuations. We illustrate this method by studying global Ca²⁺ oscillations.