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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2021-03-01
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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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