Inside insight to membrane fusion

Exocytosis of synaptic vesicles is a central step in neuronal signal transmission (reviewed in 1). On arrival of an action potential, voltage gated Ca2+ channels in the synaptic plasma membrane open. The influx of Ca2+ ions triggers fusion of synaptic vesicles with a delay of less than 1 ms and increases the fusion rate by more than four orders of magnitude (2). During the past 2 decades, major progress has been made in deciphering the molecular events underlying exocytosis of synaptic vesicles. Although details are still controversial, it is widely accepted that membrane fusion itself is catalyzed by the synaptic SNARE proteins, including the R-SNARE synaptobrevin/vesicle-associated membrane protein that resides on synaptic vesicles and the Q-SNAREs syntaxin-1 and synaptosomal-associated protein-25 (SNAP-25) that reside in the presynaptic plasma membrane. On contact, these SNAREs form a helical complex that is initiated at the membrane-distal N-terminal ends and progresses toward the C-terminal transmembrane anchors, thus pulling the membranes together. The tight coupling of fusion to Ca2+ influx is mediated by the protein synaptotagmin, a resident of synaptic vesicles. Synaptotagmin-1 bears two Ca2+-binding C2 domains that interact with both SNAREs and acidic membrane lipids in a Ca2+-dependent manner. However, despite intense research by many groups, it is still unclear exactly how the enormous acceleration by Ca2+ is achieved at the molecular level. Kyoung et al. (3) now provide us with a unique assay in which some of the key steps have been reconstructed in vitro, thus opening the door toward unraveling synaptic membrane fusion.