Exact Stochastic Simulation of a Calcium Microdomain Reveals the Impact of Ca2+ Fluctuations on IP3R Gating

Abstract

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.

Stochastic initiation and termination of calcium-mediated triggered activity in cardiac myocytes

“…Finally, our model assumes that the Ca 2+ concentration is spatially uniform inside the submicron dyadic space. Higher-resolution models (56,60,61) but remain computationally prohibitive to characterize statistical properties of TA.…”

Padé Approximation of a Stationary Single-Channel Ca 2+ Nanodomain

“…They allow avoiding computationally expensive integration of reaction-diffusion equations or stochastic simulations, while retaining considerable accuracy (19)(20)(21)(22)(23). These approximate solutions of deterministic reaction-diffusion equations can be combined with stochastic simulations of channel gating for computational efficiency in modeling cell Ca 2þ dynamics (20,24), noting however that buffering may increase Ca 2þ fluctuations (25), which may in turn influence stochastic gating of Ca 2þ -dependent Ca 2þ channels (24,26). Importantly, approximate closedform solutions also provide deep insight into the dependence of Ca 2þ concentration on buffering conditions.…”

Suppression of Protective Responses upon Activation of L-Type Voltage Gated Calcium Channel in Macrophages during Mycobacterium bovis BCG Infection

“…To further explore the role of intermediates which are downstream of TLR signalling, biopharmacological inhibitors to key signalling second messengers were used. Extracellular calcium was inhibited using EGTA [ 31 ], intracellular calcium release was inhibited with IP 3 R antagonist TMB-8 [ 32 ], PKC was inhibited using Calphostin C [ 33 ] and ERK-MAP kinase was inhibited using U0126 [ 34 ]. As shown in Fig 4 , inhibiting calcium from either external influx or intracellular release decreased ROS generation upon BCG infection, while no significant effect was observed upon PKC and MAP Kinase pathway (panel A).…”