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

Abstract : 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.
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Submitted on : Thursday, March 11, 2021 - 3:21:19 PM
Last modification on : Wednesday, June 2, 2021 - 1:27:27 PM
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Maria Reva, David Digregorio, Denis Grebenkov. A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse. Scientific Reports, Nature Publishing Group, 2021, 11 (1), pp.5377. ⟨10.1038/s41598-021-84340-4⟩. ⟨pasteur-03166835⟩

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