A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
Open Access
- 8 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 11 (1), 1-17
- https://doi.org/10.1038/s41598-021-84340-4
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.Funding Information
- Agence Nationale de la Recherche (ANR-2010-BLANC-1411, ANR-13-BSV4-0016, ANR-17-CE16-0019, ANR-17-CE16-0026)
- Fondation pour la Recherche Médicale
- Ile de France (MALINF: DIM120121)
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