Editing Synaptic vesicle (section)

=== 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}}