Kiss-and-run fusion is a type of synaptic vesicle release in which the vesicle opens and closes transiently. In this form of exocytosis, the vesicle docks and temporarily fuses at the presynaptic membrane, releasing neurotransmitters across the synapse through a fusion pore. The vesicle can then be quickly reused after fusion due to proper maintenance of its initial structure, allowing for more kinetically efficient energy use. Kiss-and-run differs from full-fusion, in which secretory vesicles quickly release their contents through the complete dilation of a fusion pore. After these chemical messengers are released into the extracellular space, the vesicle collapses fully into the plasma membrane and is then later retrieved by a clathrin-coat-dependent process. The idea that neurotransmitter might be released in "quanta" by the fusion of synaptic vesicles with the presynaptic membrane was first introduced by Bernard Katz and Jose del Castillo in 1955, when the first EM images of nerve terminals first appeared. The possibility of transient fusion and rapid retrieval of vesicle membrane was proposed by Bruno Ceccarelli in 1973, after examining in the electron microscope strongly stimulated frog neuromuscular junctions, and indirectly supported by the work of his group in the following years, using electrophysiology, electron microscopy, and quick freezing techniques. The actual term, kiss-and-run, was introduced by Ceccarelli's collaborators after the first studies of simultaneous membrane capacitance and amperometric transmitter release measurements were performed and indicated that secretory products could actually be released during transient vesicle fusion. Today, there is back and forth debate over full fusion and kiss-and-run fusion and which model portrays a more accurate picture of the mechanisms behind synaptic release. The increased accumulation of partially empty secretory vesicles following secretion, observed in electron micrographs, are the most compelling evidence in favor of the kiss-and-run model. This accumulation suggests that during the secretory process, only a portion of the vesicular contents are able to exit the cell, which could only be possible if secretory vesicles were to temporarily establish continuity with the cell plasma membrane, expel a portion of their contents, then detach and reseal.
Discovery Transient vesicle fusion was hypothesized by Katz and del Castillo in 1955. However, the first systematic studies were conducted by Ceccarelli et al. in 1973, using tetanic stimulation. Ceccarelli et al. studied frog neuromuscular junctions, stimulating them with markers such as horseradish peroxidase (HRP) to identify endocytosed organelles, and using either mild stimulation (2 Hz) or strong stimulation (10 Hz) protocols for periods ranging from 20 minutes to 4 hours. At low stimulation for a period of 4 hours, Ceccarelli et al. found that there was an increase in HRP labeled vesicles over time, and no increases in large organelles, indicative of the vesicles fusing quickly with the presynaptic membrane and then separating after releasing its neurotransmitters. They hypothesized that at low frequencies of stimulation, most of the vesicles are quickly re-formed from the presynaptic membrane during and after stimulation. Further studies in Ceccarelli's lab accumulated evidence on the hypothesis of transient fusion by comparing electrophysiological and morphological data. In particular, images of vesicle fusions were examined on freeze-fractured presynaptic membranes and on electron-microscope images obtained from terminals quick-frozen few ms after the delivery of a single shock to the nerve. In 1993, Alvarez de Toledo and colleagues directly demonstrated the occurrence of secretory product release during the momentary opening of a transiently fusing vesicle, by combining the measurement of membrane capacitance (that monitors changes in surface area) with amperometric detection of the release of mediators. This led Fesce et al. to recapitulate all the indirect evidence in favor of transient fusion and coin the term kiss-and-run. The most compelling evidence for transient or kiss-and-run fusion has come from the discovery of the porosome, a permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.
Evidence for kiss-and-run With the discovery of the kiss-and-run mechanism by Ceccarelli et al., there have been many subsequent studies done that give evidence supporting kiss-and-run fusion. All studies have suggested that there are two main advantages kiss-and-run fusion has over full fusion: 1) kiss-and-run enables more efficient vesicle recycling, as the secretory vesicle's form remains stable and 2) kiss-and-run can limit how much neurotransmitter is released due to a smaller fusion pore and a shorter time during which neurotransmitters can actually be released One of the major problems of kiss-and-run evidence, and subsequently the basis for many counterarguments against kiss-and-run, is that because fusion is so short, it is very hard to capture an actual kiss-and-run event. However, accumulation of partially empty vesicles following secretion strongly favors the kiss-and-run mechanism, suggesting that during the secretory process, only a portion of the vesicular contents are able to exit the cell, which could only be possible if secretory vesicles were to temporarily establish continuity with the cell plasma membrane, expel a portion of their contents, then detach and reseal. Since porosomes are permanent structures at the cell plasma membrane measuring just a fraction of the secretory vesicle size, demonstrates that secretory vesicles "transiently" dock and establish continuity, as opposed to complete collapse.
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