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

Abstract

Synaptic transmission between neurons is governed by a cascade of stochastic reaction-diffusion events that lead to calcium-induced vesicle release of neurotransmitter. Since experimental measurements of such systems are challenging due their nanometer and sub-millisecond scale, numerical simulations remain the principal tool for studying calcium dependent synaptic vesicle fusion, despite 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 vesicular sensor. In particular, unbinding kinetics are shown to have a major impact on the calcium sensor's occupancy probability on a millisecond scale 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. Overall we present a fast and rigorous analytical tool to study simplified reaction-diffusion systems that allow a systematic exploration of the biophysical parameters at a molecular scale, while correctly accounting for the statistical nature of molecular interactions within cells, that can also serve as a building block for more general cell signaling simulators.

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• Strong defocusing of molecular reaction times results from an interplay of geometry and reaction control
• First passage time statistics for two-channel diffusion
• Partially Reflected Brownian Motion: A Stochastic Approach to Transport Phenomena
• Reversible reactions controlled by surface diffusion on a sphere

Cited by in corpus (13)

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• A molecular relay race: sequential first-passage events to the terminal reaction centre in a cascade of diffusion controlled processes
• Fastest first-passage time statistics for time-dependent particle injection
• Survival in a nanoforest of absorbing pillars
• Escape from textured adsorbing surfaces
• Adsorption and permeation events in molecular diffusion
• Mean first-passage time to a small absorbing target in three-dimensional elongated domains
• An encounter-based approach for restricted diffusion with a gradient drift