Recently there has been significant interest and progress in the study of spatiotemporal dynamics of Ca2+ that triggers exocytosis at a fast chemical synapse, which requires understanding the contribution of individual calcium channels to the release of a single vesicle. Experimental protocols provide insight into this question by probing the sensitivity of exocytosis to Ca2+ influx. While varying extracellular or intracellular Ca 2+ concentration assesses the intrinsic biochemical Ca2+ cooperativity of neurotransmitter release, varying the number of open Ca 2+ channels using pharmacological channel block or the tail current titration probes the cooperativity between individual Ca2+ channels in triggering exocytosis. Despite the wide use of these Ca2+ sensitivity measurements, their interpretation often relies on heuristic arguments. Here we provide a detailed analysis of the Ca2+ sensitivity measures probed by these experimental protocols, present simple expressions for special cases, and demonstrate the distinction between the Ca2+ current cooperativity, defined by the relationship between exocytosis rate and the whole-terminal Ca2+ current magnitude, and the underlying Ca2+ channel cooperativity, defined as the average number of channels involved in the release of a single vesicle. We find simple algebraic expressions that show that the two are different but linearly related. Further, we use three-dimensional computational modeling of buffered Ca 2+ diffusion to analyze these distinct Ca2+ cooperativity measures, and demonstrate the role of endogenous Ca2+ buffers on such measures. We show that buffers can either increase or decrease the Ca 2+ current cooperativity of exocytosis, depending on their concentration and the single-channel Ca2+ current.
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