Calcium Ion Fluctuations Alter Channel Gating in a Stochastic Luminal Calcium Release Site Model

Stochasticity and small system size effects in complex biochemical reaction networks can greatly alter transient and steady-state system properties. A common approach to modeling reaction networks, which accounts for system size, is the chemical master equation that governs the dynamics of the joint probability distribution for molecular copy number. However, calculation of the stationary distribution is often prohibitive, due to the large state-space associated with most biochemical reaction networks. Here, we analyze a network representing a luminal calcium release site model and investigate to what extent small system size effects and calcium fluctuations, driven by ion channel gating, influx and diffusion, alter steady-state ion channel properties including open probability. For a physiological ion channel gating model and number of channels, the state-space may be between approximately 10(6) - 10(8) elements, and a novel modified block power method is used to solve the associated dominant eigenvector problem required to calculate the stationary distribution. We demonstrate that both small local cytosolic domain volume and a small number of ion channels drive calcium fluctuations that result in deviation from the corresponding model that neglects small system size effects.