Distinct Calcium Sources Define Compartmentalized Synaptic Signaling Domains

Nervous system communication relies on neurotransmitter release for synaptic transmission between neurons. Neurotransmitter is contained within vesicles in presynaptic terminals and intraterminal calcium governs the fundamental step of their release into the synaptic cleft. Despite a common dependence on calcium, synaptic transmission and its modulation varies highly across the nervous system. The precise mechanisms that underlie this heterogeneity, however, remain unclear. The present review highlights recent data that reveal vesicles sourced from separate pools define discrete modes of release. A rich diversity of regulatory machinery may further distinguish the different forms of vesicle release, including presynaptic proteins involved in trafficking, alignment, and exocytosis. These multiple vesicle release mechanisms and vesicle pools likely depend on the arrangement of vesicles in relation to specific calcium entry pathways that create compartmentalized spheres of calcium influence (i.e., domains). This diversity permits release specialization. This review details examples of how individual neurons rely on multiple calcium sources and unique regulatory schemes to provide differential release and discrete modulation of neurotransmitter release from specific vesicle pools-as part of network signal integration.