title: Microdomain [Ca(2+)] Fluctuations Alter Temporal Dynamics in Models of Ca(2+)-Dependent Signaling Cascades and Synaptic Vesicle Release.
abstract: 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.
authors.affiliation: Virginia Modeling, Analysis and Simulation Center, Old Dominion University, Suffolk, Virginia 23435, U.S.A.
authors.forename: Seth H
authors.initials: SH
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008390:Markov Chains; D021962:Membrane Microdomains / Q000378:metabolism*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D017729:Presynaptic Terminals / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002118:Calcium