A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse

Synaptic transmission between neurons is governed by a cascade of stochastic calcium ion reaction–diffusion events within nerve terminals leading to vesicular release of neurotransmitter. Since experimental measurements of such systems are challenging due to their nanometer and sub-millisecond scale, numerical simulations remain the principal tool for studying calcium-dependent neurotransmitter release driven by electrical impulses, despite the limitations of time-consuming calculations. In this paper, we develop an analytical solution to rapidly explore dynamical stochastic reaction–diffusion problems based on first-passage times. This is the first analytical model that accounts simultaneously for relevant statistical features of calcium ion diffusion, buffering, and its binding/unbinding reaction with a calcium sensor for synaptic vesicle fusion. In particular, unbinding kinetics are shown to have a major impact on submillisecond sensor occupancy probability and therefore cannot be neglected. Using Monte Carlo simulations we validated our analytical solution for instantaneous calcium influx and that through voltage-gated calcium channels. We present a fast and rigorous analytical tool that permits a systematic exploration of the influence of various biophysical parameters on molecular interactions within cells, and which can serve as a building block for more general cell signaling simulators.