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The fate of secretory membrane after fusion with the cell surface has been a subject of interest and considerable debate for almost 30 years. At nerve terminals, the limited number of synaptic vesicles and often high rates of action potential firing require that efficient machinery be in place to recover and replenish the vesicle pool to sustain the flow of information across the synapse over time. Since the first description of vesicle recycling at synapses (1, 2), a debate about the nature of the machinery responsible for this task has persisted. One of the hallmarks of this debate has been the discussion of whether secretory vesicles (donor), after fusion with the plasma membrane (acceptor), are retrieved via endocytosis after a complete intermixing with the acceptor membrane or in a more intact form via a mechanism that directly pinches off the vesicle. This latter pathway, often referred to as kiss-and-run, circumvents the need for endocytic resorting of donor from acceptor membrane components during the process of resculpting a secretory vesicle. Two new studies by Holroyd et al. (3) and Taraska et al. (4) provide some of the most convincing evidence to date that in PC-12 cells, a model neurosecretory cell line, a direct retrieval route is manifest for a sizeable fraction of secretory events. This was achieved by clever imaging methods that can visualize individual secretory vesicles and some of their proteins before, during, and after exocytosis in intact cells (4), as well as semiintact membrane sheets (3) that offers complete access to the cytoplasmic space. The debate about the mechanism of vesicle retrieval began over differing interpretations of images of ultrastructure of synaptic terminals after intense action potential firing (1, 2). Although clathrin-coated pits and membrane-associated clathrin lattices were clearly observed peripheral to sites of exocytosis during stimulation, …

Kiss-and-run, fuse-pinch-and-linger, fuse-and-collapse: The life and times of a neurosecretory granule