Synaptic vesicle

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Synaptic vesicle
Synapse diag1.svg
Neuron A (transmitting) to neuron B (receiving).
1.  Mitochondrion;
2. Synaptic vesicle with 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
A-dynamin-1--dynamin-3--and-clathrin-independent-pathway-of-synaptic-vesicle-recycling-mediated-by-elife01621fs001.jpg
MeSH D013572
TH H2.00.06.2.00004
Anatomical terms of microanatomy

In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. [1] In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5  nanometers (nm) with a standard deviation of 5.1 nm. [2]

Contents

Structure

Primary hippocampal neurons observed at 10 days in vitro by confocal microscopy. In both images neurons are stained with a somatodendritic marker, microtubule associated protein (red). In the right image, synaptic vesicles are stained in green (yellow where the green and red overlap). Scale bar = 25 mm. Hippocampal neurons.jpg
Primary hippocampal neurons observed at 10 days in vitro by confocal microscopy. In both images neurons are stained with a somatodendritic marker, microtubule associated protein (red). In the right image, synaptic vesicles are stained in green (yellow where the green and red overlap). Scale bar = 25 μm.

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 involved in neurotransmitter uptake, and trafficking proteins that participate in synaptic vesicle exocytosis, endocytosis, and recycling.

The stoichiometry for the movement of different neurotransmitters into a vesicle is given in the following table.

Neurotransmitter type(s)Inward movementOutward movement
norepinephrine, dopamine, histamine, serotonin and acetylcholine neurotransmitter+2 H+
GABA and glycine neurotransmitter1 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 neurotoxins, such as batrachotoxin, are known to destroy synaptic vesicles. The tetanus toxin damages vesicle-associated membrane proteins (VAMP), a type of v-SNARE, while botulinum toxins damage t-SNARES and v-SNARES and thus inhibit synaptic transmission. [6] A spider toxin called alpha-Latrotoxin binds to neurexins, damaging vesicles and causing massive release of neurotransmitters.[ citation needed ]

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 acetylcholine transporter and vesicular GABA transporter have been described to date. [13]

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 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. [10]

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 action potential, Ca2+ floods to the presynaptic membrane. Ca2+ 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 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. [22]

The mechanism behind full collapse fusion has been shown to be the target of the 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. [23] 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 neurotoxins prevent synaptic vesicles from completing full collapse fusion. Without this mechanism in effect, muscle spasms, paralysis, and death can occur.[ citation needed ]

"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 electron microscope in the early 1950s, nerve endings were found to contain a large number of electron-lucent (transparent to electrons) vesicles. [27] [28] The term synaptic vesicle was first introduced by De Robertis and Bennett in 1954. [29] This was shortly after transmitter release at the frog neuromuscular junction was found to induce postsynaptic miniature end-plate potentials that were ascribed to the release of discrete packages of neurotransmitter (quanta) from the presynaptic nerve terminal. [30] [31] It was thus reasonable to hypothesize that the transmitter substance (acetylcholine) was contained in such vesicles, which by a secretory mechanism would release their contents into the synaptic cleft (vesicle hypothesis). [32] [33]

The missing link was the demonstration that the neurotransmitter acetylcholine is actually contained in synaptic vesicles. About ten years later, the application of subcellular fractionation techniques to brain tissue permitted the isolation first of nerve endings (synaptosomes), [34] and subsequently of synaptic vesicles from mammalian brain. Two competing laboratories were involved in this work, that of Victor P. Whittaker at the Institute of Animal Physiology, Agricultural Research Council, Babraham, Cambridge, UK and that of Eduardo de Robertis at the Instituto de Anatomía General y Embriología, Facultad de Medicina, Universidad de Buenos Aires, Argentina. [35] Whittaker's work demonstrating acetylcholine in vesicle fractions from guinea-pig brain was first published in abstract form in 1960 and then in more detail in 1963 and 1964, [36] [37] and the paper of the de Robertis group demonstrating an enrichment of bound acetylcholine in synaptic vesicle fractions from rat brain appeared in 1963. [38] Both groups released synaptic vesicles from isolated synaptosomes by osmotic shock. The content of acetylcholine in a vesicle was originally estimated to be 1000–2000 molecules. [39] Subsequent work identified the vesicular localization of other neurotransmitters, such as amino acids, catecholamines, serotonin, and ATP. Later, synaptic vesicles could also be isolated from other tissues such as the superior cervical ganglion, [40] or the octopus brain. [41] The isolation of highly purified fractions of cholinergic synaptic vesicles from the ray Torpedo electric organ [42] [43] was an important step forward in the study of vesicle biochemistry and function.

See also

Related Research Articles

<span class="mw-page-title-main">Chemical synapse</span> Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

<span class="mw-page-title-main">Exocytosis</span> Active transport and bulk transport in which a cell transports molecules out of the cell

Exocytosis is a form of active transport and bulk transport in which a cell transports molecules out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive means. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">End-plate potential</span>

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

<span class="mw-page-title-main">SNARE protein</span> Protein family

SNARE proteins – "SNAPREceptors" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells, and some numbers in plants. The primary role of SNARE proteins is to mediate the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments. The best studied SNAREs are those that mediate the release of synaptic vesicles containing neurotransmitters in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

<span class="mw-page-title-main">Neurotransmission</span> Impulse transmission between neurons

Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

<span class="mw-page-title-main">Synaptotagmin</span>

Synaptotagmins (SYTs) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 isoforms in the mammalian synaptotagmin family. There are several C2-domain containing protein families that are related to synaptotagmins, including transmembrane (Ferlins, Extended-Synaptotagmin (E-Syt) membrane proteins, and MCTPs) and soluble (RIMS1 and RIMS2, UNC13D, synaptotagmin-related proteins and B/K) proteins. The family includes synaptotagmin 1, a Ca2+ sensor in the membrane of the pre-synaptic axon terminal, coded by gene SYT1.

<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Complexin</span>

Complexin (also known as synaphin) refers to a one of a small set of eukaryotic cytoplasmic neuronal proteins which binds to the SNARE protein complex (SNAREpin) with a high affinity. These are called synaphin 1 and 2. In the presence of Ca2+, the transport vesicle protein synaptotagmin displaces complexin, allowing the SNARE protein complex to bind the transport vesicle to the presynaptic membrane.

Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

<span class="mw-page-title-main">Axon terminal</span> Nerve fiber part

Axon terminals are distal terminations of the branches of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell that conducts electrical impulses called action potentials away from the neuron's cell body in order to transmit those impulses to other neurons, muscle cells or glands. In the central nervous system, most presynaptic terminals are actually formed along the axons, not at their ends.

The ribbon synapse is a type of neuronal synapse characterized by the presence of an electron-dense structure, the synaptic ribbon, that holds vesicles close to the active zone. It is characterized by a tight vesicle-calcium channel coupling that promotes rapid neurotransmitter release and sustained signal transmission. Ribbon synapses undergo a cycle of exocytosis and endocytosis in response to graded changes of membrane potential. It has been proposed that most ribbon synapses undergo a special type of exocytosis based on coordinated multivesicular release. This interpretation has recently been questioned at the inner hair cell ribbon synapse, where it has been instead proposed that exocytosis is described by uniquantal release shaped by a flickering vesicle fusion pore.

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.

Munc-18 proteins are the mammalian homologue of UNC-18 and are a member of the Sec1/Munc18-like (SM) protein family. Munc-18 proteins have been identified as essential components of the synaptic vesicle fusion protein complex and are crucial for the regulated exocytosis of neurons and neuroendocrine cells.

<span class="mw-page-title-main">Thomas C. Südhof</span> German-American biochemist

Thomas Christian Südhof, ForMemRS, is a German-American biochemist known for his study of synaptic transmission. Currently, he is a professor in the school of medicine in the department of molecular and cellular physiology, and by courtesy in neurology, and in psychiatry and behavioral sciences at Stanford University.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

Kiss-and-run fusion is a type of synaptic vesicle release where the vesicle opens and closes transiently. In this form of exocytosis, the vesicle docks and transiently fuses at the presynaptic membrane and releases its neurotransmitters across the synapse, after which the vesicle can then be reused.

<span class="mw-page-title-main">Soluble NSF attachment protein</span> Protein family

Soluble N-ethylmaleimide-Sensitive Factor Attachment Proteins are a family of cytosolic adaptor proteins involved in vesicular fusion at membranes during intracellular transport and exocytosis. SNAPs interact with proteins of the SNARE complex and NSF to play a key role in recycling the components of the fusion complex. SNAPs are involved in the priming of the vesicle fusion complex during assembly, as well as in the disassembly following a vesicle fusion event. Following membrane fusion, the tethering SNARE proteins complex disassembles in response to steric changes originating from the ATPase NSF. The energy provided by NSF is transferred throughout the SNARE complex and SNAP, allowing the proteins to untangle, and recycled for future fusion events. Mammals have three SNAP genes: α-SNAP, β-SNAP, and γ-SNAP. α- and γ-SNAP are expressed throughout the body, while β-SNAP is specific to the brain. The yeast homolog of the human SNAP is Sec17, the structural diagram of which is included on this page.

References

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