Ca2+-dependent signaling is often localized in spatially restricted microdomains and may involve only 1 to 100 Ca2+ ions. Fluctuations in the microdomain Ca2+ concentration (Ca2+) can arise from a wide range of elementary processes, including diffusion, Ca2+ influx, and association/dissociation with Ca2+ binding proteins or buffers. However, it is unclear to what extent these fluctuations alter Ca2+-dependent signaling. We construct Markov models of a general Ca2+-dependent signaling cascade and Ca2+-triggered synaptic vesicle release. We compare the hitting (release) time distribution and statistics for models that account for [Ca2+] fluctuations with the corresponding models that neglect these fluctuations. In general, when Ca2+ fluctuations are much faster than the characteristic time for the signaling event, the hitting time distributions and statistics for the models with and without Ca2+ fluctuation are similar. However, when the timescale of Ca2+ 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 Ca2+ ions is small, a consequence of a long-tailed hitting time distribution. In a model of Ca2+-triggered synaptic vesicle release, we demonstrate the conditions for which [Ca2+] 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 Ca2+ fluctuations are an important aspect of microdomain Ca2+ signaling and further suggesting that Ca2+ fluctuations in the presynaptic terminal may contribute to variability in synaptic vesicle release and thus variability in neuronal spiking.

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