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Synaptic Cleft Fusion edit
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 wall 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.[1] Ca2+ binds to specific proteins, one of which is synaptotagmin, in neurons which triggers the complete fusion of the vesicle with the target membrane.[2]
SNARE proteins are also thought to help mediate which membrane is the target of which vesicle.[3]
SNARE Protein and Pore Formation edit
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.[5] 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.[6]
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[7].
Lipid-Lined Fusion Pore Theory edit
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[8]. 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[9]. 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[9].
Protein-Lined Fusion Pore Theory edit
Another possible model for fusion pore formation is the protein-lined pore theory. In this model, after activation of synaptotagmin by calcium, several SNARE complexes come together to form a ring structure, with synaptobrevin forming the pore in the vesicle membrane and syntaxin forming the pore in the cell membrane[10]. 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[5].
A protein-lined pore perfectly meets all the observed requirements of the early fusion pore, and while some data does support this theory[10], sufficient data does not exist to pronounce it the primary method of fusion. It also must be noted that a protein-lined pore requires at least five copies of the SNARE complex would be necessary, while currently fusion has been observed with as few as two[10].
In both theories the function of the SNARE complex remains largely unchanged, and the entire SNARE complex is necessary to initiate fusion. It has, however, been proven that in vitro syntaxin per se is sufficient to drive spontaneous calcium independent fusion of synaptic vesicles containing v-SNAREs.[11] 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.
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- ^ Pigino, Gustavo; Morfini, Gerardo; Brady, Scott (2006). "Chapter 9: Intracellular Trafficking". In Siegal, George J.; Albers, R. Wayne; Brady, Scott T.; et al. (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (Textbook) (7th ed.). Burlington, MA: Elsevier Academic Press. p. 143. ISBN 0-12-088397-X.
- ^ Pigino et al. p 158
- ^ Pigino et al. p.143
- ^ Georgiev, Danko D .; James F . Glazebrook (2007). "Subneuronal processing of information by solitary waves and stochastic processes". In Lyshevski, Sergey Edward (ed.). Nano and Molecular Electronics Handbook. Nano and Microengineering Series. CRC Press. pp. 17-1–17-41. ISBN 978-0-8493-8528-5.
- ^ a b Kümmel, D.; Krishnakumar, S. S.; Radoff, D. T.; Li, F.; Giraudo, C. G.; Pincet, F.; Rothman, J. E.; Reinisch, K. M. (2011). "Complexin cross-links prefusion SNAREs into a zigzag array". Nature Structural & Molecular Biology. 18 (8): 927–933. doi:10.1038/nsmb.2101. PMC 3410656. PMID 21785414.
- ^ Richmond, Janet. "Synapse Function".
- ^ Jackson, Meyer B.; Chapman, Edwin R. "FUSION PORES AND FUSION MACHINES IN CA 2+ -TRIGGERED EXOCYTOSIS". Annual Review of Biophysics and Biomolecular Structure. 35 (1): 135–160. doi:10.1146/annurev.biophys.35.040405.101958.
- ^ Marrink, Siewert J.; Mark, Alan E. (2003-09-01). "The Mechanism of Vesicle Fusion as Revealed by Molecular Dynamics Simulations". Journal of the American Chemical Society. 125 (37): 11144–11145. doi:10.1021/ja036138+. ISSN 0002-7863.
- ^ a b Nanavati, C; Markin, V S; Oberhauser, A F; Fernandez, J M (1992-10-01). "The exocytotic fusion pore modeled as a lipidic pore". Biophysical Journal. 63 (4): 1118–1132. ISSN 0006-3495. PMC 1262250. PMID 1420930.
- ^ a b c Chang, Che-Wei; Hui, Enfu; Bai, Jihong; Bruns, Dieter; Chapman, Edwin R.; Jackson, Meyer B. (2015-04-08). "A Structural Role for the Synaptobrevin 2 Transmembrane Domain in Dense-Core Vesicle Fusion Pores". The Journal of Neuroscience. 35 (14): 5772–5780. doi:10.1523/JNEUROSCI.3983-14.2015. ISSN 0270-6474. PMC 4388931. PMID 25855187.
- ^ Woodbury DJ, Rognlien K (2000). "The t-SNARE syntaxin is sufficient for spontaneous fusion of synaptic vesivles to planar membranes" (PDF). Cell Biology International. 24 (11): 809–818. doi:10.1006/cbir.2000.0631. PMID 11067766.