Editing Synaptic vesicle (section)

== Physiology ==
=== Synaptic vesicle cycle ===
The events of the synaptic vesicle cycle can be divided into a few key steps:<ref name=2synapse>{{Cite journal | last1 = Südhof | first1 = T. C. | doi = 10.1146/annurev.neuro.26.041002.131412 | title = The Synaptic Vesicle Cycle | journal = Annual Review of Neuroscience | volume = 27 | pages = 509–547 | year = 2004 | issue = 1 | pmid = 15217342 | s2cid = 917924 }}</ref>

;1. Trafficking to the synapse

Synaptic vesicle components in the presynaptic neuron are initially trafficked to the synapse using members of the [[kinesin]] motor family. In ''[[Caenorhabditis elegans|C. elegans]]'' the major motor for synaptic vesicles is UNC-104.<ref>{{Cite journal | last1 = Tien | first1 = N. W. | last2 = Wu | first2 = G. H. | last3 = Hsu | first3 = C. C. | last4 = Chang | first4 = C. Y. | last5 = Wagner | first5 = O. I. | title = Tau/PTL-1 associates with kinesin-3 KIF1A/UNC-104 and affects the motor's motility characteristics in C. Elegans neurons | doi = 10.1016/j.nbd.2011.04.023 | journal = Neurobiology of Disease | volume = 43 | issue = 2 | pages = 495–506 | year = 2011 | pmid = 21569846 | s2cid = 9712304 }}</ref> There is also evidence that other proteins such as UNC-16/Sunday Driver regulate the use of motors for transport of synaptic vesicles.<ref>{{Cite journal | last1 = Arimoto | first1 = M. | last2 = Koushika | first2 = S. P. | last3 = Choudhary | first3 = B. C. | last4 = Li | first4 = C. | last5 = Matsumoto | first5 = K. | last6 = Hisamoto | first6 = N. | doi = 10.1523/JNEUROSCI.2653-10.2011 | title = The Caenorhabditis elegans JIP3 Protein UNC-16 Functions As an Adaptor to Link Kinesin-1 with Cytoplasmic Dynein | journal = Journal of Neuroscience | volume = 31 | issue = 6 | pages = 2216–2224 | year = 2011 | pmid = 21307258 | pmc = 6633058}}</ref>

;2. Transmitter loading

Once at the synapse, synaptic vesicles are loaded with a neurotransmitter. Loading of transmitter is an active process requiring a neurotransmitter transporter and a proton pump ATPase that provides an electrochemical gradient. These transporters are selective for different classes of transmitters. Characterization of unc-17 and unc-47, which encode the vesicular [[acetylcholine]] transporter and [[vesicular GABA transporter]] have been described to date.<ref>{{Cite journal | last1 = Sandoval | first1 = G. M. | last2 = Duerr | first2 = J. S. | last3 = Hodgkin | first3 = J. | last4 = Rand | first4 = J. B. | last5 = Ruvkun | first5 = G. | title = A genetic interaction between the vesicular acetylcholine transporter VAChT/UNC-17 and synaptobrevin/SNB-1 in C. Elegans | doi = 10.1038/nn1685 | journal = Nature Neuroscience | volume = 9 | issue = 5 | pages = 599–601 | year = 2006 | pmid = 16604067 | s2cid = 11812089 }}</ref>

;3. Docking

The loaded synaptic vesicles must dock near release sites, however docking is a step of the cycle that we know little about. Many proteins on synaptic vesicles and at release sites have been identified, however none of the identified protein interactions between the vesicle proteins and release site proteins can account for the docking phase of the cycle. Mutants in rab-3 and munc-18 alter vesicle docking or vesicle organization at release sites, but they do not completely disrupt docking.<ref>{{Cite journal | last1 = Abraham | first1 = C. | last2 = Bai | first2 = L. | last3 = Leube | first3 = R. E. | title = Synaptogyrin-dependent modulation of synaptic neurotransmission in Caenorhabditis elegans | doi = 10.1016/j.neuroscience.2011.05.069 | journal = Neuroscience | volume = 190 | pages = 75–88 | year = 2011 | pmid = 21689733 | s2cid = 14547322 }}</ref> SNARE proteins, now also appear to be involved in the docking step of the cycle.<ref>{{Cite journal|last1=Hammarlund|first1=Marc|last2=Palfreyman|first2=Mark T|last3=Watanabe|first3=Shigeki|last4=Olsen|first4=Shawn|last5=Jorgensen|first5=Erik M|date=August 2007|title=Open Syntaxin Docks Synaptic Vesicles|journal=PLOS Biology|volume=5|issue=8|pages=e198|doi=10.1371/journal.pbio.0050198|issn=1544-9173|pmc=1914072|pmid=17645391 |doi-access=free }}</ref>

;4. Priming

After the synaptic vesicles initially dock, they must be primed before they can begin fusion. Priming prepares the synaptic vesicle so that they are able to fuse rapidly in response to a calcium influx. This priming step is thought to involve the formation of partially assembled SNARE complexes. The proteins [[UNC13B|Munc13]], [[RIMS1|RIM]], and RIM-BP participate in this event.<ref>{{cite journal|last1=Kaeser|first1=Pascal S.|last2=Deng|first2=Lunbin|last3=Wang|first3=Yun|last4=Dulubova|first4=Irina|last5=Liu|first5=Xinran|last6=Rizo|first6=Josep|last7=Südhof|first7=Thomas C.|title=RIM Proteins Tether Ca2+ Channels to Presynaptic Active Zones via a Direct PDZ-Domain Interaction|journal=Cell|volume=144|issue=2|pages=282–295|doi=10.1016/j.cell.2010.12.029|pmid=21241895|year=2011|pmc=3063406}}</ref> Munc13 is thought to stimulate the change of the t-SNARE syntaxin from a closed conformation to an open conformation, which stimulates the assembly of v-SNARE /t-SNARE complexes.<ref>{{Cite journal | last1 = Lin | first1 = X. G. | last2 = Ming | first2 = M. | last3 = Chen | first3 = M. R. | last4 = Niu | first4 = W. P. | last5 = Zhang | first5 = Y. D. | last6 = Liu | first6 = B. | last7 = Jiu | first7 = Y. M. | last8 = Yu | first8 = J. W. | last9 = Xu | first9 = T. | doi = 10.1016/j.bbrc.2010.05.148 | last10 = Wu | first10 = Z. X. | title = UNC-31/CAPS docks and primes dense core vesicles in C. Elegans neurons | journal = Biochemical and Biophysical Research Communications | volume = 397 | issue = 3 | pages = 526–531 | year = 2010 | pmid = 20515653 }}</ref> RIM also appears to regulate priming, but is not essential for the step.{{cn|date=December 2022}}

;5. Fusion

Primed vesicles fuse very quickly with the cell membrane in response to calcium elevations in the cytoplasm. This releases the stored neurotransmitter into the [[synaptic cleft]]. The fusion event is thought to be mediated directly by the SNAREs and driven by the energy provided from SNARE assembly. The calcium-sensing trigger for this event is the calcium-binding synaptic vesicle protein synaptotagmin. The ability of SNAREs to mediate fusion in a calcium-dependent manner recently has been reconstituted in vitro. Consistent with SNAREs being essential for the fusion process, v-SNARE and t-SNARE mutants of ''C. elegans'' are lethal. Similarly, mutants in ''[[Drosophila]]'' and knockouts in mice indicate that these SNARES play a critical role in synaptic exocytosis.<ref name=2synapse/>

;6. Endocytosis

This accounts for the re-uptake of synaptic vesicles in the full contact fusion model. However, other studies have been compiling evidence suggesting that this type of fusion and endocytosis is not always the case.{{cn|date=December 2022}}

=== Vesicle recycling ===
Two leading mechanisms of action are thought to be responsible for synaptic vesicle recycling: full collapse fusion and the "kiss-and-run" method. Both mechanisms begin with the formation of the synaptic pore that releases transmitter to the extracellular space. After release of the neurotransmitter, the pore can either dilate fully so that the vesicle collapses completely into the synaptic membrane, or it can close rapidly and pinch off the membrane to generate kiss-and-run fusion.<ref name=3synapse>{{Cite journal | last1 = Breckenridge | first1 = L. J. | last2 = Almers | first2 = W. | doi = 10.1038/328814a0 | title = Currents through the fusion pore that forms during exocytosis of a secretory vesicle | journal = Nature | volume = 328 | issue = 6133 | pages = 814–817 | year = 1987 | pmid = 2442614 | bibcode = 1987Natur.328..814B | s2cid = 4255296 }}</ref>

==== Full collapse fusion ====
It has been shown that periods of intense stimulation at neural synapses deplete vesicle count as well as increase cellular capacitance and surface area.<ref>{{Cite journal | doi = 10.1083/jcb.57.2.315 | last1 = Heuser | first1 = J. E. | title = Evidence for Recycling of Synaptic Vesicle Membrane During Transmitter Release at the Frog Neuromuscular Junction | last2 = Reese | first2 = T. S. | journal = The Journal of Cell Biology | volume = 57 | issue = 2 | pages = 315–344 | year = 1973 | pmid = 4348786 | pmc = 2108984}}</ref> This indicates that after synaptic vesicles release their neurotransmitter payload, they merge with and become part of, the cellular membrane. After tagging synaptic vesicles with HRP ([[horseradish peroxidase]]), Heuser and Reese found that portions of the cellular membrane at the frog [[neuromuscular junction]] were taken up by the cell and converted back into synaptic vesicles.<ref>{{Cite journal | last1 = Miller | first1 = T. M. | last2 = Heuser | first2 = J. E. | title = Endocytosis of synaptic vesicle membrane at the frog neuromuscular junction | journal = The Journal of Cell Biology | volume = 98 | issue = 2 | pages = 685–698 | year = 1984 | pmid = 6607255 | pmc = 2113115 | doi=10.1083/jcb.98.2.685}}</ref> Studies suggest that the entire cycle of exocytosis, retrieval, and reformation of the synaptic vesicles requires less than 1 minute.<ref>{{Cite journal | last1 = Ryan | first1 = T. A. | last2 = Smith | first2 = S. J. | last3 = Reuter | first3 = H. | title = The timing of synaptic vesicle endocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5567–5571 | year = 1996 | pmid = 8643616 | pmc = 39287 | doi=10.1073/pnas.93.11.5567| bibcode = 1996PNAS...93.5567R | doi-access = free }}</ref>

In full collapse fusion, the synaptic vesicle merges and becomes incorporated into the cell membrane. The formation of the new membrane is a protein mediated process and can only occur under certain conditions. After an [[action potential]], Ca<sup>2+</sup> floods to the presynaptic membrane. Ca<sup>2+</sup> binds to specific proteins in the cytoplasm, one of which is [[synaptotagmin]], which in turn trigger the complete fusion of the synaptic vesicle with the cellular membrane. This complete fusion of the pore is assisted by [[SNARE (protein)|SNARE]] proteins. This large family of proteins mediate docking of synaptic vesicles in an ATP-dependent manner. With the help of [[synaptobrevin]] on the synaptic vesicle, the t-SNARE complex on the membrane, made up of [[syntaxin]] and [[SNAP-25]], can dock, prime, and fuse the synaptic vesicle into the membrane.<ref>{{Cite journal | last1 = Xu | first1 = H. | last2 = Zick | first2 = M. | last3 = Wickner | first3 = W. T. | last4 = Jun | first4 = Y. | title = A lipid-anchored SNARE supports membrane fusion | doi = 10.1073/pnas.1113888108 | journal = Proceedings of the National Academy of Sciences | volume = 108 | issue = 42 | pages = 17325–17330 | year = 2011 | pmid = 21987819 | pmc =3198343 | bibcode = 2011PNAS..10817325X | doi-access = free }}</ref>

The mechanism behind full collapse fusion has been shown to be the target of the [[Botulinum toxin|botulinum]] and [[tetanus]] toxins. The botulinum toxin has [[protease]] activity which degrades the [[SNAP-25]] protein. The [[SNAP-25]] protein is required for vesicle fusion that releases neurotransmitters, in particular acetylcholine.<ref>{{Cite journal | last1 = Foran | first1 = P. G. | last2 = Mohammed | first2 = N. | last3 = Lisk | first3 = G. O. | last4 = Nagwaney | first4 = S. | last5 = Lawrence | first5 = G. W. | last6 = Johnson | first6 = E. | last7 = Smith | first7 = L. | last8 = Aoki | first8 = K. R. | last9 = Dolly | first9 = J. O. | title = Evaluation of the Therapeutic Usefulness of Botulinum Neurotoxin B, C1, E, and F Compared with the Long Lasting Type A. BASIS FOR DISTINCT DURATIONS OF INHIBITION OF EXOCYTOSIS IN CENTRAL NEURONS | doi = 10.1074/jbc.M209821200 | journal = Journal of Biological Chemistry | volume = 278 | issue = 2 | pages = 1363–1371 | year = 2002 | pmid = 12381720 | doi-access = free }}</ref> Botulinum toxin essentially cleaves these SNARE proteins, and in doing so, prevents synaptic vesicles from fusing with the cellular synaptic membrane and releasing their neurotransmitters. Tetanus toxin follows a similar pathway, but instead attacks the protein [[synaptobrevin]] on the synaptic vesicle. In turn, these [[neurotoxin]]s prevent synaptic vesicles from completing full collapse fusion. Without this mechanism in effect, muscle spasms, paralysis, and death can occur.{{cn|date=December 2022}}

===="Kiss-and-run"====
The second mechanism by which synaptic vesicles are recycled is known as [[kiss-and-run fusion]]. In this case, the synaptic vesicle "kisses" the cellular membrane, opening a small pore for its neurotransmitter payload to be released through, then closes the pore and is recycled back into the cell.<ref name=3synapse/> The kiss-and-run mechanism has been a hotly debated topic. Its effects have been observed and recorded; however the reason behind its use as opposed to full collapse fusion is still being explored. It has been speculated that kiss-and-run is often employed to conserve scarce vesicular resources as well as being utilized to respond to high-frequency inputs.<ref name=4synapse>{{Cite journal | last1 = Harata | first1 = N. C. | last2 = Aravanis | first2 = A. M. | last3 = Tsien | first3 = R. W. | doi = 10.1111/j.1471-4159.2006.03987.x | title = Kiss-and-run and full-collapse fusion as modes of exo-endocytosis in neurosecretion | journal = Journal of Neurochemistry | volume = 97 | issue = 6 | pages = 1546–1570 | year = 2006 | pmid = 16805768 | s2cid = 36749378 }}</ref> Experiments have shown that kiss-and-run events do occur. First observed by [[Bernard Katz|Katz]] and del Castillo, it was later observed that the kiss-and-run mechanism was different from full collapse fusion in that cellular [[capacitance]] did not increase in kiss-and-run events.<ref name=4synapse/> This reinforces the idea of a kiss-and-run fashion, the synaptic vesicle releases its payload and then separates from the membrane.

==== Modulation ====
Cells thus appear to have at least two mechanisms to follow for membrane recycling. Under certain conditions, cells can switch from one mechanism to the other. Slow, conventional, full collapse fusion predominates the synaptic membrane when Ca<sup>2+</sup> levels are low, and the fast kiss-and-run mechanism is followed when Ca<sup>2+</sup> levels are high.{{cn|date=December 2022}}

Ales ''et al.'' showed that raised concentrations of extracellular calcium ions shift the preferred mode of recycling and synaptic vesicle release to the kiss-and-run mechanism in a calcium-concentration-dependent manner. It has been proposed that during secretion of neurotransmitters at synapses, the mode of exocytosis is modulated by calcium to attain optimal conditions for coupled exocytosis and endocytosis according to synaptic activity.<ref>{{Cite journal | last1 = Alvarez De Toledo | first1 = G. | last2 = Alés | first2 = E. | last3 = Tabares | first3 = L. A. | last4 = Poyato | first4 = J. M. | last5 = Valero | first5 = V. | last6 = Lindau | first6 = M. | title = High calcium concentrations shift the mode of exocytosis to the kiss-and-run mechanism | journal = Nature Cell Biology | volume = 1 | issue = 1 | pages = 40–44 | doi = 10.1038/9012 | year = 1999 | pmid = 10559862 | s2cid = 17624473 }}</ref>

Experimental evidence suggests that kiss-and-run is the dominant mode of synaptic release at the beginning of stimulus trains. In this context, kiss-and-run reflects a high vesicle release probability. The incidence of kiss-and-run is also increased by rapid firing and stimulation of the neuron, suggesting that the kinetics of this type of release is faster than other forms of vesicle release.<ref>{{Cite journal | last1 = Zhang | first1 = Q. | last2 = Li | first2 = Y. | last3 = Tsien | first3 = R. W. | doi = 10.1126/science.1167373 | title = The Dynamic Control of Kiss-And-Run and Vesicular Reuse Probed with Single Nanoparticles | journal = Science | volume = 323 | issue = 5920 | pages = 1448–1453 | year = 2009 | pmc = 2696197 | pmid = 19213879| bibcode = 2009Sci...323.1448Z }}</ref>