Fast, synchronous neurotransmitter release: Past, present and future

This mini-review starts with a summary of the crucial contributions Ricardo Miledi made to our understanding of how the action potential triggers fast, synchronous transmitter release. It then transitions to the discovery of synaptotagmin and its role as the exocytotic Ca²⁺ sensor at nerve terminals. The final section confronts the array of unique models that have been proposed to explain the membrane fusion step of exocytosis. More than a dozen different hypotheses seek to explain the terminal steps of the exocytotic cascade. It will be an interesting challenge for the field to distinguish among these possibilities. Nevertheless, with ongoing technological advances, perhaps we will have a better picture of this process by the end of the coming decade. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.