Synaptic vesicle
Synaptic vesicle | |
---|---|
neurotransmitters; 3. Autoreceptor 4. Synapse with neurotransmitter released (serotonin); 5. Postsynaptic receptors activated by neurotransmitter (induction of a postsynaptic potential); 6. Calcium channel; 7. Exocytosis of a vesicle; 8. Recaptured neurotransmitter. | |
Details | |
System | Nervous system |
Identifiers | |
Latin | vesicula synaptica |
MeSH | D013572 |
TH | H2.00.06.2.00004 |
Anatomical terms of microanatomy |
In a
Structure
Synaptic vesicles are relatively simple because only a limited number of proteins fit into a sphere of 40 nm diameter. Purified vesicles have a protein:phospholipid ratio of 1:3 with a lipid composition of 40% phosphatidylcholine, 32% phosphatidylethanolamine, 12% phosphatidylserine, 5% phosphatidylinositol, and 10% cholesterol.[4]
Synaptic vesicles contain two classes of obligatory components:
- Transport proteins are composed of proton pumps that generate electrochemical gradients, which allow for neurotransmitter uptake, and neurotransmitter transporters that regulate the actual uptake of neurotransmitters. The necessary proton gradient is created by V-ATPase, which breaks down ATP for energy. Vesicular transporters move neurotransmitters from the cells' cytoplasm into the synaptic vesicles. Vesicular glutamate transporters, for example, sequester glutamate into vesicles by this process.
- Trafficking proteins are more complex. They include intrinsic SNAREs. These proteins do not share a characteristic that would make them identifiable as synaptic vesicle proteins, and little is known about how these proteins are specifically deposited into synaptic vesicles. Many but not all of the known synaptic vesicle proteins interact with non-vesicular proteins and are linked to specific functions.[4]
The stoichiometry for the movement of different neurotransmitters into a vesicle is given in the following table.
Neurotransmitter type(s) | Inward movement | Outward movement |
---|---|---|
norepinephrine, dopamine, histamine, serotonin and acetylcholine | neurotransmitter+ | 2 H+ |
GABA and glycine |
neurotransmitter | 1 H+ |
glutamate |
neurotransmitter− + Cl− | 1 H+ |
Recently, it has been discovered that synaptic vesicles also contain small RNA molecules, including transfer RNA fragments, Y RNA fragments and mirRNAs.[5] This discovery is believed to have broad impact on studying chemical synapses.
Effects of neurotoxins
Some
Vesicle pools
Vesicles in the nerve terminal are grouped into three pools: the readily releasable pool, the recycling pool, and the reserve pool.[7] These pools are distinguished by their function and position in the nerve terminal. The readily releasable pool are docked to the cell membrane, making these the first group of vesicles to be released on stimulation. The readily releasable pool is small and is quickly exhausted. The recycling pool is proximate to the cell membrane, and tend to be cycled at moderate stimulation, so that the rate of vesicle release is the same as, or lower than, the rate of vesicle formation. This pool is larger than the readily releasable pool, but it takes longer to become mobilised. The reserve pool contains vesicles that are not released under normal conditions. This reserve pool can be quite large (~50%) in neurons grown on a glass substrate, but is very small or absent at mature synapses in intact brain tissue.[8][9]
Physiology
The synaptic vesicle cycle
The events of the synaptic vesicle cycle can be divided into a few key steps:[10]
- 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 C. elegans the major motor for synaptic vesicles is UNC-104.[11] There is also evidence that other proteins such as UNC-16/Sunday Driver regulate the use of motors for transport of synaptic vesicles.[12]
- 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
- 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.[14] SNARE proteins, now also appear to be involved in the docking step of the cycle.[15]
- 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 Munc13, RIM, and RIM-BP participate in this event.[16] 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.[17] RIM also appears to regulate priming, but is not essential for the step.[citation needed]
- 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
- 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.[citation needed]
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.[18]
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.[19] 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.[20] Studies suggest that the entire cycle of exocytosis, retrieval, and reformation of the synaptic vesicles requires less than 1 minute.[21]
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
The mechanism behind full collapse fusion has been shown to be the target of the
"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.[18] 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.[24] Experiments have shown that kiss-and-run events do occur. First observed by 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.[24] 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 Ca2+ levels are low, and the fast kiss-and-run mechanism is followed when Ca2+ levels are high.[citation needed]
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.[25]
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.[26]
History
With the advent of the
The missing link was the demonstration that the neurotransmitter
was an important step forward in the study of vesicle biochemistry and function.See also
References
- PMID 19202060.
- S2CID 23965024. Archived from the originalon 2013-01-05.
- PMID 27877708.
- ^ PMID 2497105.
- PMID 26446566.
- ISBN 978-0-8385-7701-1.
- S2CID 7473893.
- PMID 23522046.
- PMID 23678124.
- ^ S2CID 917924.
- S2CID 9712304.
- PMID 21307258.
- S2CID 11812089.
- S2CID 14547322.
- PMID 17645391.
- PMID 21241895.
- PMID 20515653.
- ^ S2CID 4255296.
- PMID 4348786.
- PMID 6607255.
- PMID 8643616.
- PMID 21987819.
- PMID 12381720.
- ^ S2CID 36749378.
- S2CID 17624473.
- PMID 19213879.
- ^ Palay, Sanford L.; Palade, George E. (1954). "Electron microscope study of the cytoplasm of neurons". The Anatomical Record (Oral presentation). 118: 336. .
- PMID 14381427.)
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: CS1 maint: multiple names: authors list (link - ^ De Robertis EDP, Bennett HS (1954). "Submicroscopic vesicular component in the synapse". Fed Proc. 13: 35.
- S2CID 9117892.
- PMID 14946732. Archived from the original(PDF) on 2 February 2014. Retrieved 1 February 2014.
- PMID 13175199.
- PMID 13420190.
- PMID 13901297.
- .
- PMID 14000416.
- PMID 5834239.
- S2CID 33266876.
- S2CID 5746357.
- S2CID 6157415.
- PMID 5412681.
- S2CID 8087195.
- PMID 4638794.