University College London Institute of Neurology, University College London, London, WC1N 3BG, UK.
Department of Computer Science, University of Warwick, Coventry, CV4 7AL, UK.
Commun Biol. 2023 Oct 27;6(1):1091. doi: 10.1038/s42003-023-05445-2.
Calcium-evoked release of neurotransmitters from synaptic vesicles (SVs) is catalysed by SNARE proteins. The predominant view is that, at rest, complete assembly of SNARE complexes is inhibited ('clamped') by synaptotagmin and complexin molecules. Calcium binding by synaptotagmins releases this fusion clamp and triggers fast SV exocytosis. However, this model has not been quantitatively tested over physiological timescales. Here we describe an experimentally constrained computational modelling framework to quantitatively assess how the molecular architecture of the fusion clamp affects SV exocytosis. Our results argue that the 'release-of-inhibition' model can indeed account for fast calcium-activated SV fusion, and that dual binding of synaptotagmin-1 and synaptotagmin-7 to the same SNARE complex enables synergistic regulation of the kinetics and plasticity of neurotransmitter release. The developed framework provides a powerful and adaptable tool to link the molecular biochemistry of presynaptic proteins to physiological data and efficiently test the plausibility of calcium-activated neurotransmitter release models.
钙引发的神经递质从突触小泡（SVs）释放是由 SNARE 蛋白催化的。主要观点是，在静止状态下，完整的 SNARE 复合物的组装被突触融合蛋白和复合蛋白分子抑制（“钳制”）。钙结合后，突触融合蛋白释放这种融合钳，并触发快速 SV 胞吐。然而，这个模型还没有在生理时间尺度上进行定量测试。在这里，我们描述了一个实验约束的计算建模框架，以定量评估融合钳的分子结构如何影响 SV 胞吐。我们的结果表明，“释放抑制”模型确实可以解释快速钙激活的 SV 融合，并且突触融合蛋白-1 和突触融合蛋白-7 对同一 SNARE 复合物的双重结合可以协同调节神经递质释放的动力学和可塑性。所开发的框架提供了一个强大而适应性强的工具，可以将突触前蛋白的分子生物化学与生理数据联系起来，并有效地测试钙激活神经递质释放模型的合理性。
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