Vesicle Shrinking and Enlargement Play Opposing Roles in the Release of Exocytotic Contents

For decades, two fusion modes were thought to control hormone and transmitter release essential to life; one facilitates release via fusion pore dilation and flattening (full collapse), and the other limits release by closing a narrow fusion pore (kiss-and-run). Using super-resolution stimulated emission depletion (STED) microscopy to visualize fusion modes of dense-core vesicles in neuroendocrine cells, we find that facilitation of release is mediated not by full collapse but by shrink fusion, in which the Ω-profile generated by vesicle fusion shrinks but maintains a large non-dilating pore. We discover that the physiological osmotic pressure of a cell squeezes, but does not dilate, the Ω-profile, which explains why shrink fusion prevails over full collapse. Instead of kiss-and-run, enlarge fusion, in which Ω-profiles grow while maintaining a narrow pore, slows down release. Shrink and enlarge fusion may thus account for diverse hormone and transmitter release kinetics observed in secretory cells, previously interpreted within the full-collapse/kiss-and-run framework.