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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Autores principales:	Maria Reva, David A. DiGregorio, Denis S. Grebenkov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b040b918167b495f80b62a121bd38354
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spelling	oai:doaj.org-article:b040b918167b495f80b62a121bd383542021-12-02T11:37:26ZA first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse10.1038/s41598-021-84340-42045-2322https://doaj.org/article/b040b918167b495f80b62a121bd383542021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84340-4https://doaj.org/toc/2045-2322Abstract 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.Maria RevaDavid A. DiGregorioDenis S. GrebenkovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Maria Reva David A. DiGregorio Denis S. Grebenkov
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 Portfolio
publishDate	2021
url	https://doaj.org/article/b040b918167b495f80b62a121bd38354
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A first-passage approach to diffusion-influenced reversible binding and its insights into nanoscale signaling at the presynapse

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