Exact stochastic simulation of a calcium microdomain reveals the impact of Ca²⁺ fluctuations on IP₃R gating.

In this study, we numerically analyzed the nonlinear Ca(2+)-dependent gating dynamics of a single, nonconducting inositol 1,4,5-trisphosphate receptor (IP₃R) channel, using an exact and fully stochastic simulation algorithm that includes channel gating, Ca(2+) buffering, and Ca(2+) diffusion. The IP₃R is a ubiquitous intracellular Ca(2+) release channel that plays an important role in the formation of complex spatiotemporal Ca(2+) signals such as waves and oscillations. Dynamic subfemtoliter Ca(2+) microdomains reveal low copy numbers of Ca(2+) ions, buffer molecules, and IP₃Rs, and stochastic fluctuations arising from molecular interactions and diffusion do not average out. In contrast to models treating calcium dynamics deterministically, the stochastic approach accounts for this molecular noise. We varied Ca(2+) diffusion coefficients and buffer reaction rates to tune the autocorrelation properties of Ca(2+) noise and found a distinct relation between the autocorrelation time τac, the mean channel open and close times, and the resulting IP₃R open probability PO. We observed an increased PO for shorter noise autocorrelation times, caused by increasing channel open times and decreasing close times. In a pure diffusion model the effects become apparent at elevated calcium concentrations, e.g., at [Ca(2+)] = 25 μM, τac = 0.082 ms, the IP₃R open probability increased by ≈20% and mean open times increased by ≈4 ms, compared to a zero noise model. We identified the inactivating Ca(2+) binding site of IP₃R subunits as the primarily noise-susceptible element of the De Young and Keizer model. Short Ca(2+) noise autocorrelation times decrease the probability of Ca(2+) association and consequently increase IPvR activity. These results suggest a functional role of local calcium noise properties on calcium-regulated target molecules such as the ubiquitous IP₃R. This finding may stimulate novel experimental approaches analyzing the role of calcium noise properties on microdomain behavior.