Modeling Ca2+-mediated spontaneous ATP release by neurons

Stochastic fluctuations in cytosolic Ca2+ play a crucial role in the spontaneous release of ATP and other neurotransmitters by neurons. Here we ask how Ca2+ fluctuations quantitatively relate to various statistics involving the release of ATP. We hypothesized that an increase in Ca2+ concentration in a neuron increases the rate at which ATP is released and decreases the time it takes for ATP to reach its peak release rate. To test this hypothesis, we use a kinetic scheme where the transition rates between different states of the vesicle encapsulating ATP depend on Ca2+ concentration. The model also includes a simple formalism for Ca2+ fluctuations in a neuron. The model agrees well with experimental results and shows that when Ca2+ concentration is increased, peak ATP release rate increases and the time to peak ATP release rate decreases. Since the model is specifically fit to experimental data for the release of ATP, these results may not be generalizable to the release of other neurotransmitters. Additionally, since a simple formalism for Ca2+ dynamics was used, we expect that using a more nuanced model for Ca2+ dynamics will improve the model fit to the experimental data. Finally, we believe that our work sets the stage for investigating the effects of impairments in neuronal Ca2+ homeostasis on ATP release during different neurological diseases.