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¹ Department of Biological Sciences, University of Illinois at Chicago, 840 West Taylor Street, Chicago, IL 60607, USA

Synaptic transmission requires spatial and temporal coordination of a specific sequence of events. The trigger for synaptic vesicle exocytosis is Ca²⁺ entry into presynaptic terminals, leading to neurotransmitter release at highly specialized sites known as active zones. Ca²⁺ channel proximity to exocytotic proteins and vesicle clusters at active zones have been inferred from biochemical, histological and ultrastructural data, but direct evidence about functional relationships between these elements in central synapses is absent. We have utilized the lamprey giant reticulospinal synapse to characterize functional colocalization of known synaptic markers in the presynaptic terminal, as well as their reliability during repeated activation. Recycling vesicle clusters, surrounding actin filaments, and physiologically relevant Ca²⁺ influx all show identical morphological distribution. Ca²⁺ influx is mediated by clusters of Ca²⁺ channels that colocalize with the vesicle clusters, defined by imaged sites of vesicle recycling and actin localization. Synaptic transmission is inhibited by block of actin depolymerization, but Ca²⁺ signalling is unaffected. Functional Ca²⁺ channels are localized to presynaptic clusters, and Ca²⁺ transients at these sites account for neurotransmitter release based on their spatial and temporal profiles. Ca²⁺ transients evoked by single axonal action potentials are mediated solely by voltage-operated Ca²⁺ channel activation, and slower Ca²⁺ rises observed throughout the axon result from Ca²⁺ diffusion from the synaptic regions. We conclude that at lamprey giant reticulospinal synapses, Ca²⁺ channels and release sites colocalize, creating a close spatial relationship between active zones and Ca²⁺ entry sites, which is necessary for site-specific, Ca²⁺-dependent secretion.

(Received 24 May 2005; accepted after revision 30 August 2005; first published online 1 September 2005)
Corresponding author S. Alford: Department of Biological Sciences, University of Illinois at Chicago, 840 W. Taylor Street, Chicago, IL 60607, USA. Email: sta{at}uic.edu

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