How does synaptotagmin trigger neurotransmitter release?

Neurotransmitter release at synapses involves a highly specialized form of membrane fusion that is triggered by Ca2+ ions and is optimized for speed. These observations were established decades ago, but only recently have the molecular mechanisms that underlie this process begun to come into view. Here, we summarize findings obtained from generically modified neurons and neuroendocrine cells, as well as from reconstituted systems, which are beginning to reveal the molecular mechanism by which Ca2+-acting on the synaptic vesicle (SV) protein synaptotagmin I (syt)-triggers rapid exocytosis. This work sheds light not only on presynaptic aspects of synaptic transmission, but also on the fundamental problem of membrane fusion, which has remained a puzzle that has yet to be solved in any biological system.