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-millisec...

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Main Authors: Maria Reva, David A. DiGregorio, Denis S. Grebenkov
Format: Article
Language:English
Published: Nature Publishing Group 2021-03-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-84340-4
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spelling doaj-b040b918167b495f80b62a121bd383542021-03-11T12:15:05ZengNature Publishing GroupScientific Reports2045-23222021-03-0111111710.1038/s41598-021-84340-4A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapseMaria Reva0David A. DiGregorio1Denis S. Grebenkov2Unit of Synapse and Circuit Dynamics, CNRS UMR 3571, Institut PasteurUnit of Synapse and Circuit Dynamics, CNRS UMR 3571, Institut PasteurLaboratoire de Physique de la Matière Condensée (UMR 7643), CNRS – Ecole Polytechnique, IP ParisAbstract 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.https://doi.org/10.1038/s41598-021-84340-4
collection DOAJ
language English
format Article
sources DOAJ
author Maria Reva
David A. DiGregorio
Denis S. Grebenkov
spellingShingle Maria Reva
David A. DiGregorio
Denis S. Grebenkov
A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
Scientific Reports
author_facet Maria Reva
David A. DiGregorio
Denis S. Grebenkov
author_sort Maria Reva
title A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
title_short A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
title_full A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
title_fullStr A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
title_full_unstemmed A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
title_sort first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse
publisher Nature Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2021-03-01
description 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.
url https://doi.org/10.1038/s41598-021-84340-4
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