Synaptic cleft fusion In
synaptic vesicle fusion, the vesicle must be within a few nanometers of the target membrane for the fusion process to begin. This closeness allows the cell membrane and the vesicle to exchange lipids which is mediated by certain proteins which remove water that comes between the forming junction. Once the vesicle is in position it must wait until Ca2+ enters the cell by the propagation of an
action potential to the presynaptic membrane. Ca2+ binds to specific proteins, one of which is
Synaptotagmin, in neurons which triggers the complete fusion of the vesicle with the target membrane. SNARE proteins are also thought to help mediate which membrane is the target of which vesicle.
SNARE protein and pore formation Assembly of the SNAREs into the "trans" complexes likely bridges the opposing
lipid bilayers of membranes belonging to cell and secretory granule, bringing them in proximity and inducing their fusion. The influx of calcium into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the putative calcium sensor,
synaptotagmin, with membrane lipids and/or the partially assembled SNARE complex. One hypothesis implicates the molecule
Complexin within the SNARE complex and its interaction with the molecule synaptotagmin.
Lipid-lined fusion pore theory One possible model for fusion pore formation is the lipid-line pore theory. In this model, once the membranes have been brought into sufficiently close proximity via the "zipper" mechanism of the
SNARE complex, membrane fusion occurs spontaneously. It has been shown that when the two membranes are brought within a critical distance, it is possible for hydrophilic lipid headgroups of one membrane to merge with the opposing membrane. In the lipid-lined fusion pore model, the SNARE complex acts as a scaffold, pulling on the membrane, causing both membranes to pucker so they may reach the critical fusion distance. As the two membranes begin to fuse, a lipid-lined stalk is produced, expanding radially outward as fusion proceeds. While a lipid-lined pore is possible and can achieve all the same properties observed in early pore formation, sufficient data does not exist to prove it is the sole method of formation. There is not currently a proposed mechanism on inter-cellular regulation for fluctuation of lipid-lined pores, and they would have a substantially more difficult time producing effects such as the "kiss-and-run" when compared with their protein-lined counterparts. Lipid-lined pores effectiveness would also be highly dependent on the composition of both membranes, and its success or failure could vary wildly with changes in elasticity and rigidity. As the initial pore expands it incorporates lipids from both bilayers, eventually resulting in complete fusion of the two membranes. The SNARE complex has a much more active role in the protein-lined pore theory; because the pore consists initially entirely of SNARE proteins, the pore is easily able to undergo intercellular regulation, making fluctuation and "kiss-and-run" mechanisms easily attainable. This suggests that in Ca2+-dependent neuronal exocytosis
synaptotagmin is a dual regulator, in absence of Ca2+ ions to inhibit SNARE dynamics, while in presence of Ca2+ ions to act as
agonist in the membrane fusion process.
Kiss-and-run hypothesis In
synaptic vesicles, some neurochemists have suggested that vesicles occasionally may not completely fuse with presynaptic membranes in neurotransmitter release into the
synaptic cleft. The controversy lies in whether or not
endocytosis always occurs in vesicle reforming after release of the neurotransmitter. Another proposed mechanism for release of vesicle contents into extracellular fluid is called
kiss-and-run fusion. There is some indication that vesicles may only form a small pore in the presynaptic membrane allowing contents to be released by standard diffusion for a short while before retreating back into the presynaptic cell. This mechanism may be a way around
clathrin-mediated endocytosis. It is also proposed that the vesicle does not need to return to an
endosome to refill, though it is not thoroughly understood by which mechanism it would refill. This does not exclude full vesicle fusion, but only states that both mechanisms may operate in synaptic clefts. "Kiss and run" has been shown to occur in endocrine cells, though it has not been directly witnessed in synaptic gaps. ==See also==