SNAP25 (red) moves into the bulge (outlined) where sequential exocytosis is taking place (left to right).

Secretory vesicles wishing to play follow-the-leader use a particular SNARE to show them where the leader went, as shown by Takahashi et al. on page 255.

Vesicles heading to the plasma membrane sometimes selectively bind to another that has already fused there. This process, called sequential exocytosis, is efficient at large-scale secretion because vesicles in the cytosol can be mobilized without being transported all the way to the plasma membrane. Using 2-photon imaging, the authors show that sequential exocytosis is directed by a plasma membrane SNARE called SNAP25.

Sequential exocytosis was examined in insulin-secreting pancreatic β cells, in which SNAP25 diffused into the bulge where the leading exiting vesicle had fused with the plasma membrane. SNAP25 rarely diffused into spots where only one vesicle exited, but was seen at the majority of sequential exocytosis sites.

Although sequential exocytosis is common in many exocrine or endocrine cell types (which contain SNAP25), it accounted for only a small fraction of β cell exocytosis. Cholesterol depletion freed SNAP25 for easier diffusion and increased sequential exocytosis several fold. Restricting SNAP25 to lipid rafts might thus be one way to prevent exhausting insulin reserves, which are doled out steadily in small quantities. ▪