Weinberg Seth H
Virginia Modeling, Analysis and Simulation Center, Old Dominion University, Suffolk, Virginia 23435, U.S.A.
Neural Comput. 2016 Mar;28(3):493-524. doi: 10.1162/NECO_a_00811. Epub 2016 Jan 6.
Ca(2+)-dependent signaling is often localized in spatially restricted microdomains and may involve only 1 to 100 Ca(2+) ions. Fluctuations in the microdomain Ca(2+) concentration (Ca(2+)) can arise from a wide range of elementary processes, including diffusion, Ca(2+) influx, and association/dissociation with Ca(2+) binding proteins or buffers. However, it is unclear to what extent these fluctuations alter Ca(2+)-dependent signaling. We construct Markov models of a general Ca(2+)-dependent signaling cascade and Ca(2+)-triggered synaptic vesicle release. We compare the hitting (release) time distribution and statistics for models that account for [Ca(2+)] fluctuations with the corresponding models that neglect these fluctuations. In general, when Ca(2+) fluctuations are much faster than the characteristic time for the signaling event, the hitting time distributions and statistics for the models with and without Ca(2+) fluctuation are similar. However, when the timescale of Ca(2+) fluctuations is on the same order as the signaling cascade or slower, the hitting time mean and variability are typically increased, in particular when the average number of microdomain Ca(2+) ions is small, a consequence of a long-tailed hitting time distribution. In a model of Ca(2+)-triggered synaptic vesicle release, we demonstrate the conditions for which [Ca(2+)] fluctuations do and do not alter the distribution, mean, and variability of release timing. We find that both the release time mean and variability can be increased, demonstrating that Ca(2+) fluctuations are an important aspect of microdomain Ca(2+) signaling and further suggesting that Ca(2+) fluctuations in the presynaptic terminal may contribute to variability in synaptic vesicle release and thus variability in neuronal spiking.
钙离子（Ca(2+)）依赖的信号传导通常定位于空间受限的微区，且可能仅涉及1至100个钙离子。微区钙离子浓度（Ca(2+)）的波动可源于多种基本过程，包括扩散、钙离子内流以及与钙离子结合蛋白或缓冲剂的结合/解离。然而，这些波动在多大程度上改变钙离子依赖的信号传导尚不清楚。我们构建了一般钙离子依赖信号级联和钙离子触发的突触小泡释放的马尔可夫模型。我们比较了考虑[Ca(2+)]波动的模型与忽略这些波动的相应模型的击中（释放）时间分布和统计数据。一般来说，当钙离子波动比信号事件的特征时间快得多时，有和没有钙离子波动的模型的击中时间分布和统计数据相似。然而，当钙离子波动的时间尺度与信号级联相同或更慢时，击中时间的平均值和变异性通常会增加，特别是当微区钙离子的平均数量较少时，这是长尾巴击中时间分布的结果。在一个钙离子触发的突触小泡释放模型中，我们展示了[Ca(2+)]波动改变和不改变释放时间的分布、平均值和变异性的条件。我们发现释放时间的平均值和变异性都可能增加，这表明钙离子波动是微区钙离子信号传导的一个重要方面，进一步表明突触前末端的钙离子波动可能导致突触小泡释放的变异性，从而导致神经元放电的变异性。
