Synapses: Coupling of Presynaptic Voltage-gated Ca2+ Channels to Vesicular Release of Neurotransmitter

Abstract

Ca2+ inflow through voltage-gated calcium channels (VGCCs) at the nerve terminal is an indispensable trigger for fusion of synaptic vesicles (SVs) with active zones (AZs) and neurotransmitter release, but many issues regarding how the magnitude and temporal profile of Ca2+ transients influence release efficacy and short-term plasticity remain controversial. One of such issues under intensive debate for the last two and half decades is the coupling modality between VGCCs and SVs. In one view, VGCCs and SVs are physically tethered at release sites and Ca2+ influx can readily reach Ca2+ sensors on SVs situated in the immediate vicinity of the inner mouth of the channel, leading to a fusion event (“nanodomain” model). In the other view, VGCCs are sufficiently far apart from SVs and release of a single SV requires cooperative actions of several neighbouring channels in order for Ca2+ to reach the fusion threshold at the release sensor (“microdomain” model). These two conceptual models are mutually exclusive, supported by compelling but irreconcilable experimental evidence. Because coupling modality plays a critical role in controlling the efficiency of quantal release and dynamic gain range at any given synapse, which modality that central synapses use remains to be one of the core questions for understanding the mechanisms of transmitter release. This chapter will attempt to provide some new insights and prospective outlook for understanding how the nerve terminal develops different release modality so as to fine-tune quantal output and temporal fidelity of synaptic transmission.