Calcium cooperativity of exocytosis as a measure of Ca2+ channel domain overlap

The number of Ca2+ 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 Ca2+ 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 Ca2+ current, which is varied using appropriate voltage-clamp protocols or via pharmacological Ca2+ channel block under the condition of constant single-channel Ca2+ current. The slope of the resulting log–log plot of transmitter release rate versus presynaptic Ca2+ current is termed Ca2+current cooperativity of exocytosis, and provides indirect information about the underlying presynaptic morphology. In this review, we discuss the relationship between the Ca2+ current cooperativity and the average number of Ca2+ channels participating in the exocytosis of a single vesicle, termed the Ca2+channel cooperativity. We relate these quantities to the morphology of the presynaptic active zone. We also review experimental studies of Ca2+ current cooperativity and its modulation during development in different classes of synapses.