Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles can also fuse with other target cell compartments, such as a lysosome. Exocytosis occurs when secretory vesicles transiently dock and fuse at the base of cup-shaped structures at the cell plasma membrane called porosome, the universal secretory machinery in cells. Vesicle fusion may depend on SNARE proteins in the presence of increased intracellular calcium (Ca2+) concentration.
Triggers
Stimuli that trigger vesicle fusion act by increasing intracellular Ca2+.
Synaptic vesicles commit vesicle fusion by a nerve impulse reaching the synapse, activating voltage-dependent calcium channels that cause influx of Ca2+ into the cell. In the endocrine system, many hormones are released by their releasing hormones binding to G protein coupled receptors coupled to the Gq alpha subunit, activating the IP3/DAG pathway to increase Ca2+. Examples of this mechanism include: Gonadotropin releasing hormone Thyrotropin releasing hormone Growth hormone releasing hormone (minor pathway - main one is cAMP dependent pathway)
Model systems
Model systems consisting of a single phospholipid or a mixture have been studied by physical chemists. Cardiolipin is found mainly in mitochondrial membranes, and calcium ions play an important role in the respiratory processes mediated by the mitochondrion. The forces involved have been postulated to explain this process in terms of nucleation for agglomeration of smaller supramolecular entities or phase changes in the structure of the biomembranes.
Mechanisms
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. Known as the "clamp" hypothesis, the presence of complexin normally inhibits the fusion of the vesicle to the cell membrane. However, binding of calcium ions to synaptotagmin triggers the complexin to be released or inactivated, so that the vesicle is then free to fuse.
According to the "zipper" hypothesis, the complex assembly starts at the N-terminal parts of SNARE motifs and proceeds towards the C-termini that anchor interacting proteins in membranes. Formation of the "trans"-SNARE complex proceeds through an intermediate complex composed of SNAP-25 and syntaxin-1, which later accommodates synaptobrevin-2 (the quoted syntaxin and synaptobrevin isotypes participate in neuronal neuromediator release).
Based on the stability of the resultant cis-SNARE complex, it has been postulated that energy released during the assembly process serves as a means for overcoming the repulsive forces between the membranes. There are several models that propose explanation of a subsequent step – the formation of stalk and fusion pore, but the exact nature of these processes remains debated. Two of the most prominent models on fusion pore formation are the lipid-lined and protein-lined fusion pore theories.