Calcium cooperativity of exocytosis as a measure of Ca ²⁺ channel domain overlap

The number of Ca ²⁺ channels contributing to the exocytosis of a single neurotransmitter vesicle in a presynaptic terminal has been a question of significant interest and debate, and is important for a full understanding of localized Ca ²⁺ signaling in general, and synaptic physiology in particular. This is usually estimated by measuring the sensitivity of the neurotransmitter release rate to changes in the synaptic Ca ²⁺ current, which is varied using appropriate voltage-clamp protocols or via pharmacological Ca ²⁺ channel block under the condition of constant single-channel Ca ²⁺ current. The slope of the resulting log-log plot of transmitter release rate versus presynaptic Ca ²⁺ current is termed Ca ²⁺ current cooperativity of exocytosis, and provides indirect information about the underlying presynaptic morphology. In this review, we discuss the relationship between the Ca ²⁺ current cooperativity and the average number of Ca ²⁺ channels participating in the exocytosis of a single vesicle, termed the Ca ²⁺channel cooperativity. We relate these quantities to the morphology of the presynaptic active zone. We also review experimental studies of Ca ²⁺ current cooperativity and its modulation during development in different classes of synapses.