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Synaptic vesicle

Synaptic vesicles are small, spherical, membrane-bound organelles located in the presynaptic terminals of neurons, primarily responsible for storing neurotransmitters and facilitating their calcium-dependent release into the synaptic cleft during neurotransmission.^[1] These vesicles, typically measuring about 40 nm in diameter, maintain a uniform size and shape essential for efficient synaptic function.^[1] Composed of a phospholipid bilayer enclosing neurotransmitters and a limited set of proteins—approximately 200 molecules per vesicle, divided into transport proteins (such as the vacuolar proton pump for neurotransmitter uptake) and trafficking proteins (including synaptophysins and synapsins for docking and fusion)—synaptic vesicles represent one of the best-characterized organelles in eukaryotic cells.^[1] Their exclusive role in neurotransmitter release underscores their critical position in the synaptic vesicle cycle, which involves biogenesis, filling, docking at the active zone, exocytosis triggered by action potentials, and subsequent endocytosis for recycling.^[2] The synaptic vesicle cycle begins with the formation and maturation of vesicles in the presynaptic terminal, where they are loaded with neurotransmitters via proton-driven transporters.^[1] Upon neuronal stimulation, an influx of calcium ions promotes the fusion of docked vesicles with the plasma membrane through the SNARE complex, releasing neurotransmitters to bind postsynaptic receptors and propagate signals.^[2] To sustain high-frequency transmission, emptied vesicle components are rapidly retrieved via clathrin-mediated endocytosis, involving adaptor proteins like AP2 and dynamin, allowing reformation and reuse of vesicles within seconds to minutes.^[3] This recycling process, which can occur through full endocytosis or transient "kiss-and-run" fusion, ensures the maintenance of vesicle pools—readily releasable, recycling, and reserve—critical for synaptic plasticity and long-term neural activity.^[4] Disruptions in synaptic vesicle function, such as mutations in associated proteins, are implicated in neurological disorders including epilepsy and Parkinson's disease, highlighting their foundational role in brain communication.^[5]

Introduction and Overview

Definition and Function

Synaptic vesicles are small, spherical organelles, typically 30–50 nm in diameter, found in the presynaptic terminals of neurons, where they store neurotransmitters for regulated release into the synaptic cleft.^[1] These membrane-bound structures enable the precise packaging and delivery of signaling molecules essential for neuronal communication.^[6] The primary function of synaptic vesicles is to facilitate chemical synaptic transmission by releasing neurotransmitters in response to arriving action potentials at the presynaptic terminal.^[7] This process allows for rapid propagation of electrical signals across synapses, either between neurons or from neurons to target cells such as muscle fibers, ensuring coordinated neural activity throughout the nervous system.^[7] Release occurs through exocytosis, where vesicles fuse with the presynaptic membrane, discharging their contents into the synaptic cleft to bind postsynaptic receptors and modulate target cell excitability.^[7] Synaptic vesicles store a variety of neurotransmitters, including excitatory types like glutamate, which promote depolarization in postsynaptic neurons, and inhibitory types like GABA, which hyperpolarize them to dampen activity; acetylcholine serves both roles depending on context, such as excitation at neuromuscular junctions.^[8] This diversity allows synaptic vesicles to support a wide range of physiological processes, from sensory processing to motor control.^[8] Each synaptic vesicle contains approximately 1,000–10,000 neurotransmitter molecules, a quantal unit that ensures discrete, reliable release events underlying the all-or-nothing nature of synaptic signaling.^[9] This quantal packaging, first conceptualized in studies of neuromuscular transmission, provides a fundamental mechanism for the graded strength of synaptic responses based on the number of vesicles released.^[9]

Historical Discovery

The discovery of synaptic vesicles began in the early 1950s with the advent of electron microscopy, which allowed visualization of subcellular structures in nerve terminals. In 1954, Eduardo De Robertis and Henry Stanley Bennett first described small, spherical organelles, approximately 200–500 Å in diameter, in electron micrographs of the frog neuromuscular junction and sympathetic ganglia, proposing they represented quanta of neurotransmitter storage. Independently, George Palade and Sanford Palay observed similar vesicles in central nervous system synapses around the same time, reinforcing the idea that these structures were integral to synaptic function. These observations marked the initial recognition of synaptic vesicles as distinct entities within presynaptic terminals. By the 1960s, biochemical approaches confirmed the role of synaptic vesicles in neurotransmitter storage. Victor P. Whittaker and colleagues pioneered subcellular fractionation techniques to isolate vesicles from brain tissue, demonstrating in 1960 that they contained acetylcholine and other transmitters. This work extended to the electric organ of Torpedo fish, where Whittaker's team in 1972 successfully purified cholinergic synaptic vesicles, showing high concentrations of acetylcholine and providing direct evidence that vesicles serve as storage organelles for neurotransmitters. These isolations established vesicles as biochemically distinct compartments, shifting understanding from morphological curiosity to functional reality. The 1970s brought insights into vesicle dynamics through advanced imaging. John Heuser and Thomas Reese utilized freeze-fracture electron microscopy in 1973 to capture synaptic vesicle exocytosis at the frog neuromuscular junction during stimulation, revealing "docked" vesicles at active zones and distinguishing them from a reserve pool, thus identifying vesicle pools based on releasability. Concurrently, Bruno Ceccarelli and colleagues demonstrated vesicle recycling in 1973, observing that prolonged stimulation depleted vesicles and formed cisternae, which reformed into new vesicles upon rest, indicating membrane reuse without net loss. These studies illuminated the active lifecycle of vesicles in neurotransmission. Advancements in the 1990s and early 2000s unraveled the molecular machinery of vesicle fusion. James Rothman and Richard Scheller, through genetic and biochemical assays, identified key SNARE proteins—such as syntaxin, SNAP-25, and synaptobrevin (VAMP)—essential for vesicle docking and fusion, with foundational work in the early 1990s demonstrating their role in regulated exocytosis. Thomas Südhof's cloning and characterization of synaptobrevin in 1989, followed by extensive studies in the 1990s and 2000s on its integration into the fusion complex, provided mechanistic details on how vesicles achieve rapid, calcium-triggered release. This molecular framework, recognized by the 2013 Nobel Prize, built on earlier discoveries to explain vesicle function at the atomic level.

Structural Features

Molecular Composition

Synaptic vesicles are composed of a phospholipid bilayer membrane enriched with specific lipids that confer properties essential for membrane curvature and fusion competence. The membrane contains approximately 40 mol% cholesterol, which stabilizes the high-curvature structure and facilitates fusion by modulating lipid packing and phase behavior.^[10] Phosphatidylserine constitutes about 6 mol% of the lipids, primarily localized to the cytosolic leaflet, where it supports interactions with fusion machinery and contributes to negative membrane curvature.^[10] The bilayer exhibits lipid asymmetry, with phosphatidylethanolamine and phosphatidylserine enriched in the inner leaflet and phosphatidylcholine and sphingomyelin in the outer leaflet, maintained by ATP-dependent translocases to ensure functional asymmetry during trafficking and exocytosis.^[10] Integral membrane proteins form the core of the vesicle's transport and acidification machinery. Neurotransmitter transporters, such as the vesicular glutamate transporters (VGLUT1-3; approximately 4-14 copies per vesicle) in glutamatergic vesicles and the vesicular inhibitory amino acid transporter (VGAT) in GABAergic vesicles, facilitate the uptake of neurotransmitters into the lumen using the proton gradient.^[11] The vesicular acetylcholine transporter (VAChT), present at about 4 copies per vesicle in cholinergic synapses, performs a similar role for acetylcholine.^[12] The vacuolar H+-ATPase (V-ATPase), with roughly 1-2 copies per vesicle, is a multi-subunit proton pump that acidifies the lumen and drives secondary active transport by generating an electrochemical proton gradient.^[13] Peripheral membrane proteins associate with the vesicle surface to aid in stabilization and regulation. Synaptophysin, the most abundant protein with about 30-32 copies per vesicle, is an integral tetrameric glycoprotein that interacts with V-ATPase and supports vesicle maturation and clustering.^[13] Synaptic vesicle protein 2 (SV2), a glycosylated integral protein with 5-8 copies per vesicle across its isoforms (SV2A-C), acts as a proteoglycan that modulates release probability and stabilizes other vesicle components.^[14] The vesicle lumen stores neurotransmitters alongside co-factors that regulate packaging and release. It maintains an acidic pH ranging from about 5.5 to 6.5 (e.g., ~5.8 in glutamatergic and ~6.4 in GABAergic vesicles) through continuous V-ATPase activity, which is crucial for proton-coupled neurotransmitter accumulation.^[15] ATP is present in millimolar concentrations, serving as an energy source for uptake processes and binding to proteoglycans within a dense matrix that sequesters up to 95% of the neurotransmitters and ATP, enabling controlled release via ionic exchange.^[16] Composition varies by neurotransmitter type, reflecting synaptic specificity. Glutamatergic vesicles predominantly express VGLUT isoforms for glutamate loading, while GABAergic vesicles rely on VGAT for GABA and glycine, and cholinergic vesicles incorporate VAChT; these transporters define vesicle identity and ensure selective filling without overlap in most synapses.^[17]

Morphology and Size

Synaptic vesicles exhibit a characteristic spherical morphology, with a typical diameter ranging from 30 to 50 nm, as determined by electron microscopy observations of presynaptic terminals.^[18] This compact, round shape facilitates their clustering near the active zone and efficient fusion during neurotransmitter release. In electron micrographs, mature, neurotransmitter-filled synaptic vesicles often display an electron-dense core, resulting from the accumulation of neurotransmitters alongside matrix proteins that stabilize the vesicular contents.^[19] This density contrasts with unfilled or recycling vesicles, which appear more translucent, underscoring the role of cargo loading in visible structural features. Morphological heterogeneity exists among synaptic vesicles, primarily distinguished by size and core composition. Small clear-core vesicles, approximately 30-50 nm in diameter, predominate in synapses releasing classical neurotransmitters such as glutamate or GABA and appear largely transparent in fixed electron microscopy preparations due to their aqueous, low-molecular-weight cargo.^[20] In contrast, larger dense-core vesicles, measuring 80-120 nm, contain neuropeptides and exhibit a prominent electron-opaque core from condensed peptide aggregates and associated proteins, enabling their identification in diverse neuronal populations.^[21] These variations in size and density reflect specialized functions, with small vesicles supporting rapid, high-frequency transmission and dense-core vesicles mediating slower, modulatory signaling. Advanced imaging techniques, particularly cryo-electron microscopy (cryo-EM) and tomography, have provided high-resolution insights into synaptic vesicle morphology, revealing transient coat structures such as clathrin lattices during vesicle formation and maturation.^[22] These studies highlight subtle differences between synaptic vesicles—tightly organized in clusters—and non-synaptic vesicles, which may lack such precise coats or exhibit irregular shapes. Such revelations emphasize the dynamic yet structured assembly of these organelles in the presynaptic compartment. The spherical morphology and size range of synaptic vesicles demonstrate remarkable evolutionary conservation, appearing similarly in vertebrates and invertebrates, from mammalian central nervous systems to Drosophila neuromuscular junctions.^[23] This preservation across phyla suggests an ancient origin for the core structural adaptations that enable vesicle-mediated neurotransmission.

Biogenesis and Maturation

Vesicle Formation

Synaptic vesicles originate through biogenesis in the neuronal cell body, where their component proteins are synthesized and assembled in the endoplasmic reticulum (ER) and processed through the Golgi apparatus. Synaptic vesicle proteins, such as synaptophysin and synaptotagmin 1, are translated from mRNA exported from the nucleus and inserted into the ER membrane, followed by trafficking to the Golgi and trans-Golgi network (TGN) for sorting into precursor vesicles (PVs) ranging from 50 to 400 nm in diameter.^[24] These PVs, which also incorporate active zone proteins like piccolo, are then transported anterogradely along axons to the synapse via microtubule-based motors, including kinesin-3 (KIF1A) and the small GTPase Arl8. Recent studies (as of 2024) emphasize the predominance of local biogenesis at synapses via endosomal intermediates, with axonal transport of precursors regulated by complexes like BORC-Arl8 for efficient delivery.^[25]^[26]^[27] This somatic biogenesis pathway ensures the delivery of essential building blocks to distal synaptic sites, with maturation potentially occurring en route or locally.^[28] At the synapse, synaptic vesicles form locally through budding from endosomal intermediates, a process driven by clathrin coats and adaptor protein complexes. Endosome-like vacuoles, generated via bulk or clathrin-independent endocytosis during high-activity conditions, serve as platforms for vesicle reformation, where clathrin assembles into coated pits to invaginate the membrane.^[29] The AP-2 complex recruits clathrin to these endosomal membranes by binding phosphoinositides and synaptic vesicle proteins like SV2, facilitating cargo selection and budding, while the AP-3 complex contributes to sorting specific transmembrane proteins (e.g., vesicular glutamate transporters) into nascent vesicles from early endosomes.^[30] Electron microscopy in hippocampal neurons and AP-2 knockout mice reveals that disrupting these adaptors results in a partial depletion of synaptic vesicles and accumulation of enlarged vacuoles, underscoring their role in local assembly.^[29] Phosphatidylinositol kinases play a crucial role in this budding process by generating phosphoinositides that promote membrane curvature essential for vesicle formation. Phosphatidylinositol 4-kinase type IIα, associated with synaptic vesicle membranes, produces phosphatidylinositol 4-phosphate (PI4P), which induces positive membrane curvature at concentrations as low as 2 mol% and recruits coat proteins to endosomal sites.^[31] Similarly, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), synthesized by type I phosphatidylinositol 4-phosphate 5-kinases, stabilizes clathrin coats on curved endosomal domains and facilitates adaptor binding, thereby driving the fission of small vesicles from larger precursors.^[32] Maturation of these newly formed vesicles involves the selective acquisition of specific lipids and proteins during sorting from recycling endosomes, transforming immature carriers into functional synaptic vesicles. As endosomes mature from early to recycling stages, proteins such as v-SNAREs (e.g., VAMP3/cellubrevin) and synaptotagmin are incorporated via Rab11- and retromer-mediated trafficking, ensuring proper docking and fusion competence.^[33] Lipids like phosphatidylinositol 3-phosphate (PI(3)P), generated by VPS34 kinase, aid in cargo partitioning, while cholesterol and sphingolipids are enriched to confer the characteristic low-curvature bilayer of mature vesicles, as revealed by proteomic analyses of isolated synaptic vesicles.^[34] This sorting refines vesicle composition, excluding degradative components destined for late endosomes. Insights from genetic models in yeast and Drosophila highlight the conservation of these budding mechanisms and the consequences of defects. In yeast, mutations in AP-3 subunits disrupt vesicle formation from endosome-like compartments analogous to synaptic pathways, leading to impaired protein sorting to lysosome-related organelles.^[35] Drosophila mutants lacking the neuronal AP-3 δ subunit (e.g., garnet gene) exhibit reduced synaptic vesicle biogenesis, with accumulation of endosomal intermediates and defective neurotransmitter transporter incorporation, phenocopying mammalian deficiencies.^[36]

Neurotransmitter Loading

Synaptic vesicles are loaded with neurotransmitters through a secondary active transport process powered by an electrochemical proton gradient established across the vesicle membrane. The vacuolar-type H⁺-ATPase (V-ATPase) hydrolyzes ATP to pump protons into the vesicle lumen, generating both a pH gradient (ΔpH, approximately 1-2 units acidic inside) and a membrane potential (Δψ, positive inside, around 40-80 mV), which together drive the uptake of neurotransmitters against their concentration gradient.^[37] This proton motive force is essential for filling vesicles to millimolar concentrations, enabling quantal release during neurotransmission.^[38] Specific vesicular neurotransmitter transporters mediate the selective uptake of different transmitters, utilizing the proton gradient via antiport or cotransport mechanisms. For monoamines such as dopamine and serotonin, the vesicular monoamine transporters (VMAT1 and VMAT2, SLC18 family) exchange two protons for each cationic monoamine molecule, with VMAT2 predominating in central neurons.^[37] In inhibitory synapses, the vesicular GABA transporter (VGAT, also known as VIAAT, SLC32A1) utilizes the proton motive force, with proposals for both proton antiport and chloride cotransport mechanisms, primarily driven by Δψ rather than ΔpH.^[38]^[39] For excitatory glutamatergic transmission, vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, SLC17 family) load glutamate via an antiporter mechanism exchanging one glutamate for two protons, with tissue-specific isoforms ensuring compartmentalized function: VGLUT1 is highly expressed in cortical and hippocampal regions, while VGLUT2 predominates in subcortical areas like the thalamus and hypothalamus.^[40] The loading capacity of synaptic vesicles is constrained by transporter stoichiometry and osmotic balance to prevent rupture during filling. For instance, VGLUT exchanges two protons per glutamate molecule, limiting accumulation to levels that maintain vesicular integrity, while chloride influx through associated channels (e.g., ClC-3) dissipates Δψ to favor transport and osmotic equilibrium, with water entry potentially facilitated by aquaporins.^[37] Regulation of loading occurs through cytosolic neurotransmitter availability, which sets the driving force for uptake, and post-translational modifications such as phosphorylation of VMAT by protein kinase C, which enhances transport activity.^[38] Variations in the proton motive force, modulated by V-ATPase activity, further fine-tune filling efficiency, linking loading to synaptic demand.^[37] Experimental evidence for these mechanisms has been obtained through vesicle patch-clamp recordings and fluorescence-based assays. Patch-clamp techniques on isolated synaptic vesicles directly measure proton-driven currents and neurotransmitter uptake rates, confirming the dependence on ΔpH and Δψ for transporters like VGLUT and VMAT, with inhibitors such as bafilomycin A1 blocking acidification and transport.^[37] Fluorescence assays using pH-sensitive dyes (e.g., acridine orange) or neurotransmitter analogs visualize loading dynamics in real-time, quantifying efficiency in cultured neurons and revealing isoform-specific differences, such as higher VGLUT1-mediated uptake in cortical terminals.^[38]

Cellular Localization and Dynamics

Vesicle Pools

Synaptic vesicles in the presynaptic terminal are categorized into distinct functional pools that determine their availability for neurotransmitter release during synaptic transmission. These pools include the readily releasable pool (RRP), the recycling pool, and the reserve pool, each characterized by differences in positioning, mobility, and responsiveness to stimulation. This organization ensures sustained neurotransmission by balancing immediate release with long-term vesicle replenishment. The readily releasable pool (RRP) comprises vesicles that are docked at the active zone and primed for rapid fusion upon calcium influx, representing approximately 5-10% of the total vesicle population in typical central nervous system synapses, such as those in hippocampal neurons where it may contain 5-20 vesicles per bouton. These vesicles are immediately available for exocytosis, enabling fast synaptic responses within milliseconds of stimulation. In contrast, the recycling pool encompasses vesicles that undergo repeated cycles of release and retrieval through endocytosis during moderate neuronal activity, overlapping substantially with the RRP and accounting for about 10-20% of total vesicles, as observed in hippocampal and calyx of Held synapses. This pool supports ongoing transmission by allowing vesicles to be reused multiple times without deep recruitment from storage. The reserve pool, often comprising 80-90% of synaptic vesicles, consists of resting vesicles that are not readily mobilized and are primarily recruited during periods of intense or prolonged stimulation to sustain release when the recycling pool is depleted. These vesicles are typically clustered away from the active zone and tethered to the actin cytoskeleton, limiting their mobility until necessary. For example, in frog neuromuscular junctions, the reserve pool can include hundreds of thousands of vesicles that are released only under high-frequency conditions. The sizes of these pools are quantified using electrophysiological methods, such as paired-pulse facilitation to assess release probability and infer RRP capacity, or prolonged stimulation trains to measure depletion and recovery rates of the recycling and reserve pools, often complemented by imaging techniques like FM dye labeling for recycling dynamics. In the calyx of Held synapse, for instance, train stimulation reveals an RRP of about 1,500-4,000 vesicles. Pool transitions are dynamically regulated by activity levels, with low-frequency stimulation maintaining the recycling pool while high activity mobilizes reserve vesicles into the recycling pool over seconds to minutes; synapsins play a key role in this process by immobilizing reserve vesicles and facilitating their recruitment upon depolarization.^[41]^[42]

Intracellular Transport

Synaptic vesicles and their precursors are transported from the neuronal soma to distal synapses via fast anterograde axonal transport, primarily driven by the microtubule-based motor protein kinesin-1, which moves cargos toward the microtubule plus ends at the synapse.^[43] This process ensures a steady supply of vesicles to maintain synaptic function over long distances, with retrograde transport back to the soma mediated by cytoplasmic dynein along microtubule minus ends.^[44] Disruptions in these motors, such as mutations in kinesin-1 subunits, lead to accumulation of vesicle precursors in the soma and synaptic depletion, contributing to neurodegenerative conditions like hereditary spastic paraplegia.^[45] Within the presynaptic terminal, short-range synaptic trafficking of vesicles relies on actin-based motility, where myosin-V motors facilitate movement along actin filaments, enabling vesicles to navigate the dense cytoskeletal network near release sites.^[46] Synapsin I plays a crucial role in this local dynamics by tethering vesicles to the actin cytoskeleton in its dephosphorylated state, thereby anchoring the reserve pool and regulating availability for recruitment.^[47] During periods of heightened neuronal activity, phosphorylation of synapsin I by kinases such as CaMKII reduces its affinity for actin and vesicles, promoting mobilization from the reserve pool to replenish the readily releasable pool and sustain neurotransmission.^[48] Pathological mutations in motor proteins, including dynein and dynactin components, impair this transport, resulting in vesicle trafficking defects that manifest as synaptic dysfunction and neuronal degeneration in disorders such as amyotrophic lateral sclerosis.^[49] Live-cell imaging techniques, including total internal reflection fluorescence microscopy, have revealed vesicle movement speeds in the terminal ranging from approximately 0.1 to 1 μm/s, highlighting the bidirectional and processive nature of this actin-myosin-dependent trafficking.^[50]

Release Mechanisms

Docking and Priming

Synaptic vesicle docking refers to the initial attachment of vesicles to the presynaptic active zone, positioning them approximately 10 nm from the plasma membrane to prepare for subsequent release events.^[51] This process is mediated by key proteins including Rab3, a small GTPase on the vesicle membrane, which interacts with Rab3-interacting molecule (RIM) to tether vesicles near the active zone.^[52] Munc13, an active zone-associated protein, further stabilizes this docking by forming a tripartite complex with RIM and Rab3, facilitating vesicle alignment and recruitment of additional components.^[53] Following docking, priming converts vesicles into a fusion-ready state through partial assembly of SNARE complexes, enabling rapid response to stimuli. Munc18 plays a central role by initially maintaining syntaxin in a closed conformation and then promoting its integration into the SNARE complex alongside synaptobrevin and SNAP-25.^[54] Complexin stabilizes this partially zippered SNARE assembly, clamping the complex to prevent premature full zippering while poising it for activation.^[55] Munc13 assists in this transition by catalyzing syntaxin release from Munc18, ensuring efficient priming. The spatial organization of docked and primed vesicles is scaffolded by large active zone proteins such as Bassoon and Piccolo, which form ribbon-like structures that cluster vesicles and maintain their proximity to release sites.^[56] These scaffolds provide structural support, organizing vesicles into ordered arrays that enhance docking efficiency and spatial precision at the active zone.^[57] Priming lowers the free energy barriers for vesicle fusion by reorganizing molecular interactions, reducing the activation energy required for SNARE-mediated membrane merging.^[58] This energetic facilitation, driven by Munc13 and Munc18, stabilizes the primed state and increases the probability of vesicles transitioning to a releasable configuration.^[59] Total internal reflection fluorescence (TIRF) microscopy serves as a primary assay for quantifying docked vesicles, offering high-resolution imaging of vesicle positions within ~100 nm of the plasma membrane.^[60] This technique visualizes fluorescently labeled vesicles in real-time, allowing precise measurement of docking numbers and dynamics, such as residence times near the active zone.^[61]

Exocytosis Process

The exocytosis of synaptic vesicles is triggered by an action potential arriving at the presynaptic terminal, which depolarizes the membrane and opens voltage-gated calcium channels, allowing a rapid influx of Ca²⁺ ions.^[62] This influx creates localized microdomains of elevated calcium concentration near the active zone, reaching 10-100 μM within microseconds, far exceeding the global cytosolic level of approximately 100 nM.^[63] These transient calcium nanodomains are essential for activating the fusion machinery with high spatiotemporal precision, ensuring that neurotransmitter release is tightly coupled to the presynaptic signal.^[64] The core fusion event is driven by the zippering of SNARE proteins, where the v-SNARE VAMP (also known as synaptobrevin) on the vesicle membrane assembles with the t-SNAREs syntaxin and SNAP-25 on the plasma membrane, forming a four-helix bundle that pulls the opposing bilayers into close apposition and overcomes the energy barrier for merger.^[65] This process is rendered calcium-dependent by synaptotagmin-1, the primary calcium sensor, which binds Ca²⁺ with its C2 domains and undergoes a conformational change to clamp or release SNARE assembly, facilitating rapid membrane fusion upon calcium elevation.^[66] The cooperative action of SNARE zippering and synaptotagmin ensures that fusion occurs only in response to the physiological calcium transient, preventing spontaneous release under resting conditions.^[67] Fusion initiates with the formation of a narrow fusion pore, approximately 1-2 nm in diameter, which connects the vesicle lumen to the extracellular space and allows initial leakage of vesicular contents.^[68] This pore rapidly expands to a larger diameter, enabling full quantal release of neurotransmitters such as glutamate or acetylcholine in discrete packets that underlie synaptic transmission.^[69] Pore expansion is modulated by the number of SNARE complexes and associated proteins, transitioning from a transient, flickering structure to a stable, irreversible merger of the vesicle and plasma membranes.^[70] The kinetics of exocytosis operate on a millisecond timescale, with synchronous release occurring within 1-5 ms of the calcium influx to support precise, phasic signaling at central synapses.^[71] In contrast, asynchronous release follows with a delay of 10-100 ms or longer, contributing to sustained or modulatory transmission, particularly during high-frequency activity.^[72] These temporal modes reflect differences in calcium sensor efficiency and residual calcium levels post-influx, with synaptotagmin-1 primarily mediating the fast synchronous component.^[73] Direct evidence for the exocytosis process comes from capacitance measurements, which detect stepwise increases in membrane surface area (approximately 0.05–0.1 fF per vesicle) as fusion adds vesicular membrane to the plasma membrane, confirming the rapidity and quantal nature of release.^[74]^[75] Complementary amperometric recordings at carbon-fiber electrodes capture the oxidative currents from released catecholamines or amperometric spikes from other transmitters, revealing the foot of the spike as the initial pore opening and the main peak as content expulsion, thus linking membrane fusion to luminal discharge.^[76] These techniques, often combined, have quantified release rates exceeding 1,000 vesicles per second during intense stimulation, underscoring the process's efficiency.^[77]

Recycling Pathways

Clathrin-Mediated Endocytosis

Clathrin-mediated endocytosis (CME) is a key mechanism for retrieving synaptic vesicle membranes following exocytosis, helping to maintain the presynaptic terminal's surface area and sustain neurotransmitter release capacity.^[78] After vesicle fusion, excess membrane components, including synaptophysin and VAMP2, are incorporated into the plasma membrane at the active zone or periactive zone, where endocytic proteins rapidly assemble to initiate retrieval.^[79] The process begins with the recruitment of clathrin adaptors, such as AP-2 and AP180, which bind to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) in the plasma membrane and interact with synaptic vesicle proteins to select cargo for internalization.^[80] These adaptors then recruit clathrin triskelions, which polymerize into a polyhedral lattice, forming a coated pit that drives membrane invagination over approximately 5-10 seconds.^[81] Dynamin, a large GTPase, assembles into helical polymers around the neck of the invaginated pit, and its GTP hydrolysis provides the mechanical force for membrane constriction and fission, completing vesicle scission within 1-2 seconds.^[82] Following scission, the clathrin-coated vesicle undergoes uncoating, mediated by the accessory protein auxilin, which recruits the ATP-dependent chaperone HSC70 (heat shock cognate 70) to disassemble the clathrin lattice, allowing the vesicle to mature and refill with neurotransmitter via V-ATPase proton pumps.^[83] This uncoating step, powered by ATP hydrolysis, occurs rapidly post-scission and is essential for recycling clathrin and adaptors for subsequent cycles.^[84] Throughout the process, adaptors like AP180 and stonin 2 ensure selective sorting of synaptic vesicle proteins, excluding plasma membrane components to preserve vesicle identity.^[85] A single CME cycle typically takes 10-20 seconds, enabling efficient recycling during moderate synaptic activity but becoming rate-limiting under sustained stimulation.^[86] To handle intense neuronal firing, when membrane retrieval demand exceeds standard CME capacity, bulk endocytosis emerges as a variant, rapidly internalizing large plasma membrane invaginations (tubule- or cistern-like structures) in a partially clathrin-dependent manner, from which new synaptic vesicles bud via CME.^[87] This pathway, triggered by high calcium influx, supplements CME to prevent synaptic fatigue.^[88] In contrast to faster, transient modes like kiss-and-run and ultrafast endocytosis, CME involves complete membrane mixing and slower, more comprehensive retrieval. Recent studies as of 2025 suggest CME may be less predominant under physiological conditions compared to ultrafast endocytosis.^[89]

Kiss-and-Run Fusion

Kiss-and-run fusion represents an alternative mode of synaptic vesicle exocytosis and endocytosis, characterized by the transient opening of a narrow fusion pore that permits neurotransmitter release without the vesicle fully collapsing into the plasma membrane. In this process, the vesicle briefly "kisses" the plasma membrane, allowing small molecules like neurotransmitters to efflux through the pore, which measures approximately 2.3–4.6 nm in diameter, before closing and retrieving the intact vesicle.^[90] The closure of this fusion pore is mediated by dynamin, a GTPase that constricts and fissions the neck of the pore, enabling rapid vesicle retrieval and reuse.^[91] This mechanism contrasts with full fusion, where the vesicle membrane completely merges with the plasma membrane, requiring subsequent endocytosis for retrieval.^[92] One key advantage of kiss-and-run fusion is its speed, with the entire exo-endocytosis cycle completing in approximately 50 ms, facilitating quicker recovery of vesicles compared to clathrin-mediated pathways.^[91] This rapid kinetics preserves the structural identity and protein composition of the vesicle, minimizing the need for resorted components and reducing disruption to the active zone during low-frequency synaptic activity.^[92] It is particularly prevalent in central nervous system synapses, such as hippocampal neurons, where it supports efficient transmission under moderate stimulation, whereas full fusion predominates at high-activity neuromuscular junctions. Evidence for kiss-and-run fusion has been established through multiple experimental approaches, including the use of pH-sensitive dyes like acridine orange and FM1-43, which demonstrate incomplete content mixing and rapid reacidification of retrieved vesicles, indicating limited intermixing with the plasma membrane.^[93] Capacitance measurements in synaptic terminals reveal transient "flickers" corresponding to brief pore openings, while total internal reflection fluorescence microscopy (TIRFM) in hippocampal cultures shows that 50–70% of fusion events involve kiss-and-run, with vesicles retaining their fluorescence post-release.^[90] Seminal studies in cultured hippocampal neurons confirmed these modes by tracking single-vesicle dynamics during evoked release.^[92] The prevalence and execution of kiss-and-run fusion are regulated by intracellular calcium levels and lipid composition. Lower Ca²⁺ concentrations favor this mode by slowing fusion pore expansion, with pore dilation being 13 times slower without sufficient Ca²⁺, thereby promoting transient closure over full collapse. Specific lipids, such as phosphatidylinositol 4,5-bisphosphate (PIP₂) and cholesterol in the vesicle membrane, influence pore stability and dynamin recruitment, enhancing the efficiency of fission in low-Ca²⁺ conditions.^[90] This regulation allows kiss-and-run to be selectively engaged during physiological signaling with submicromolar Ca²⁺ transients, supporting vesicle reuse without extensive protein sorting. Despite its advantages, kiss-and-run fusion has limitations, including reduced efficiency for releasing larger cargo molecules due to the restricted pore size, which may hinder complete emptying in certain synaptic contexts.^[91] Its prevalence in vivo remains debated, with estimates varying from 5% to over 70% of events depending on synapse type and stimulation paradigm, and some studies questioning its dominance in mature central synapses under intense activity.

Ultrafast Endocytosis

Ultrafast endocytosis (UFE) is a clathrin-independent mechanism of synaptic vesicle retrieval that operates on a timescale of 50-100 ms following exocytosis, making it suitable for physiological stimulation rates.^[89] This pathway involves the rapid invagination and fission of membrane lateral to the active zone, driven by mechanical forces and curvature-inducing proteins such as endophilin A1 and a specialized form of dynamin (dynamin 1xA). It retrieves membrane in proportion to the amount added during exocytosis, preserving vesicle pools without the need for clathrin coats. UFE predominates under moderate calcium levels (around 1.2 mM), complementing slower CME during high-frequency activity and bulk endocytosis during intense stimulation. Recent molecular studies as of 2025 have elucidated its components, confirming its role as a major recycling mode in central synapses.^[89]

Regulation and Modulation

Calcium-Dependent Control

Calcium ions (Ca²⁺) play a pivotal role in regulating the synaptic vesicle cycle by controlling the transition from priming to exocytosis. Under resting conditions, intracellular Ca²⁺ concentration in the presynaptic terminal is maintained at approximately 100 nM through active extrusion mechanisms, preventing premature vesicle fusion.^[94] Upon action potential arrival, voltage-gated Ca²⁺ channels open, allowing influx that elevates local Ca²⁺ to peaks of around 10 μM within nanodomains near the channels, sufficient to trigger rapid neurotransmitter release while global concentrations remain lower.^[95] The primary Ca²⁺ sensor for synchronous synaptic vesicle exocytosis is synaptotagmin-1 (Syt1), a vesicle-associated protein with two C2 domains that bind Ca²⁺ with high affinity. The C2A domain of Syt1 exhibits a dissociation constant (K_D) of approximately 20 μM for the first Ca²⁺ ion, enabling it to detect the transient elevation in Ca²⁺ and undergo conformational changes that promote membrane penetration and interaction with phospholipids such as phosphatidylserine.^[96] This Ca²⁺ binding clamps the vesicle in a fusion-ready state prior to influx and, upon elevation, releases the clamp to accelerate SNARE-mediated fusion, ensuring millisecond-precision timing.^[97] Ca²⁺ microdomains, formed by the close proximity (∼20-50 nm) of synaptic vesicles to voltage-gated Ca²⁺ channels like Ca_v2.1, confine high Ca²⁺ concentrations to nanoscale volumes, preventing diffusion and enabling precise spatiotemporal control of release. These nanodomains ensure that only vesicles docked near open channels experience the requisite Ca²⁺ levels for Syt1 activation, contributing to the reliability of synaptic transmission.^[98] Beyond triggering exocytosis, Ca²⁺ exerts feedback regulation on the vesicle cycle. Low micromolar Ca²⁺ promotes vesicle priming by activating proteins like Munc13, enhancing the readily releasable pool, while higher levels during intense activity stimulate endocytosis through calcineurin, a Ca²⁺/calmodulin-dependent phosphatase that dephosphorylates dynamin and synaptojanin to accelerate membrane retrieval.^[99]^[100] This dual action balances release and recycling to sustain synaptic function. Dysregulation of Ca²⁺-dependent control contributes to neurological disorders such as epilepsy, where mutations in Ca_v2.1 channels (e.g., in CACNA1A) reduce Ca²⁺ influx, impairing vesicle priming and exocytosis, leading to altered neurotransmitter release and hyperexcitability.^[101]

Protein Interactions and SNAREs

The SNARE complex plays a pivotal role in mediating synaptic vesicle fusion by forming a stable four-helix bundle that bridges the vesicle and plasma membranes. This complex comprises the v-SNARE vesicle-associated membrane protein 2 (VAMP-2, also known as synaptobrevin-2) anchored in the synaptic vesicle membrane, and the t-SNAREs syntaxin-1 and synaptosome-associated protein of 25 kDa (SNAP-25) located on the presynaptic plasma membrane. Assembly occurs through sequential zippering of their SNARE motifs from the N-terminus to the C-terminus, generating a mechanical force estimated at approximately 65 kT to drive membrane fusion.^[102]^[103]^[104] Accessory proteins regulate SNARE complex dynamics during vesicle priming, fusion clamping, and post-fusion disassembly. Munc13 facilitates priming by catalyzing the transition of syntaxin-1 from an inhibitory closed conformation with Munc18-1 into an open state competent for SNARE complex formation. Complexin binds to the assembled SNARE complex, clamping it in a partially zippered state to inhibit spontaneous exocytosis while poised for triggered release. Following fusion, the cis-SNARE complex is disassembled by N-ethylmaleimide-sensitive factor (NSF), an ATPase that hydrolyzes ATP to disrupt the bundle and recycle SNARE proteins for subsequent cycles.^[105]^[106]^[107] Rab GTPases contribute to vesicle docking and pool maintenance through interactions with SNARE-associated effectors. Rab3, in its GTP-bound form, promotes synaptic vesicle docking at the active zone by recruiting effectors that tether vesicles near SNARE proteins. Rab27, particularly Rab27b, regulates the reserve pool of synaptic vesicles, facilitating their mobilization and recruitment to docked positions via interactions with proteins like exophilin.^[108]^[109] Cryo-electron microscopy (cryo-EM) studies have revealed structural arrangements of SNARE complexes as rosettes or rings beneath docked vesicles, comprising multiple SNARE pins that coordinate fusion. Mutations at specific sites within SNARE motifs, such as those targeted by botulinum neurotoxins (e.g., the Q197-R198 bond in SNAP-25 or Q76-F77 in VAMP-2), disrupt complex assembly and stability, underscoring the precision of these interactions.^[110]^[111] SNARE protein diversity arises from isoforms tailored to synapse-specific functions, enhancing adaptability in vesicle dynamics. For instance, syntaxin-3, an isoform prevalent in hippocampal neurons, localizes to the axonal plasma membrane and supports targeted exocytosis in polarized trafficking pathways, differing from the ubiquitous role of syntaxin-1 in central synapses. Recent structural studies (as of 2025) have also revealed roles for protein condensates, such as those formed by intersectin and endophilin, in priming synaptic vesicles for fusion.^[112]^[113]^[114]

Pathological Aspects

Effects of Neurotoxins

Neurotoxins such as botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) disrupt synaptic vesicle exocytosis by cleaving essential SNARE proteins required for vesicle fusion with the presynaptic membrane. BoNTs, produced by Clostridium botulinum, include serotypes like BoNT/A, which specifically cleaves SNAP-25 at a site between residues 197 and 198, thereby preventing the formation of the SNARE complex and inhibiting neurotransmitter release, leading to flaccid paralysis. Similarly, TeNT, produced by Clostridium tetani, cleaves synaptobrevin/VAMP2 at the bond between residues 76 and 77, blocking vesicle fusion and causing spastic paralysis through disinhibition in the central nervous system. These cleavages occur intracellularly after toxin uptake via synaptic vesicle recycling, selectively targeting primed vesicles at active zones.^[115]^[116]^[117]^[117]^[118] α-Latrotoxin, the primary neurotoxin from black widow spider (Latrodectus spp.) venom, induces massive calcium influx through formation of cation-permeable pores in the presynaptic membrane, triggering uncontrolled exocytosis of synaptic vesicles and subsequent depletion of vesicular stores. This leads to excessive neurotransmitter release followed by synaptic fatigue and vesicle exhaustion, as observed in neuromuscular junctions where vesicle density decreases dramatically post-exposure. The toxin's action involves binding to neurexins and latrophilins, activating both calcium-dependent and independent pathways for vesicle fusion.^[119]^[120]^[121] Conotoxins from cone snail (Conus spp.) venoms, particularly ω-conotoxins, selectively block N-type voltage-gated calcium channels (Ca_v2.2), preventing calcium entry necessary for synaptic vesicle exocytosis and thereby inhibiting neurotransmitter release at presynaptic terminals. For instance, ω-conotoxin MVIIA (ziconotide), binds with high affinity to these channels, reducing evoked release without affecting vesicle docking or priming. This toxin is clinically used as an intrathecal analgesic for severe chronic pain, where it modulates pain signaling by limiting calcium-dependent transmitter release in the spinal cord.^[122]^[123]^[124] β-Bungarotoxin, a presynaptic neurotoxin from krait (Bungarus spp.) venom, possesses phospholipase A₂ activity that hydrolyzes phospholipids in synaptic vesicle membranes, causing vesicle swelling, leakage of contents, and depletion of the vesicular pool, which disrupts both exocytosis and recycling processes. This enzymatic action leads to punctate swellings along neurites and progressive failure of neuromuscular transmission, with electron microscopy revealing reduced vesicle numbers and altered morphology at nerve terminals.^[125]^[126]^[127] In experimental settings, neurotoxins like α-latrotoxin serve as valuable tools for dissecting synaptic vesicle pools, as it mobilizes vesicles from both the readily releasable pool and the reserve pool, enabling researchers to quantify pool sizes and study exocytosis dynamics in isolated nerve terminals or cultured neurons.^[128]^[120]

Role in Neurological Disorders

Synaptic vesicle dysfunction plays a central role in various neurological disorders, where impairments in vesicle trafficking, docking, priming, or release contribute to synaptic failure and neuronal circuit disruptions. In Alzheimer's disease, amyloid-β (Aβ) oligomers impair synaptic vesicle endocytosis and recycling in hippocampal neurons, leading to depletion of the readily releasable pool and reduced neurotransmitter release, which underlies early synaptic loss. ^[129] This disruption is exacerbated by Aβ's interference with dynamin-dependent fission during vesicle retrieval, resulting in accumulation of unfused vesicles and diminished synaptic plasticity. ^[130] In Parkinson's disease, pathological α-synuclein aggregates bind to synaptic vesicles, inhibiting their trafficking and clustering, which depletes the reserve pool and impairs evoked release at dopaminergic terminals. ^[131] Overexpression or fibrillization of α-synuclein further blocks endocytosis, causing synaptic vesicle accumulation and reduced dopamine secretion, contributing to motor deficits. ^[132] Mutations in synaptotagmin-1 (Syt1) and SNARE proteins like SNAP25 are implicated in epilepsy, where they lower the energy barrier for SNARE-mediated fusion, increasing spontaneous release probability and leading to hyperexcitability. ^[133] For instance, SNAP25 mutations enhance Ca²⁺-triggered exocytosis while disrupting synchronized release, promoting seizure susceptibility through altered vesicle priming dynamics. ^[134] In autism spectrum disorders, mutations in SHANK3 disrupt postsynaptic scaffolding, indirectly impairing presynaptic vesicle docking and trans-synaptic signaling via neurexin-neuroligin interactions, resulting in weakened synaptic transmission and spine morphology alterations. ^[135] These genetic variants reduce synaptic vesicle recruitment efficiency, contributing to imbalances in excitatory-inhibitory neurotransmission observed in affected individuals. ^[136] Lambert-Eaton myasthenic syndrome involves autoantibodies targeting presynaptic P/Q-type voltage-gated calcium channels, which reduce Ca²⁺ influx and thereby diminish synaptic vesicle exocytosis, leading to decreased quantal content and muscle weakness. ^[137] This antibody-mediated blockade specifically impairs high-frequency release while sparing basal vesicle pools. ^[138] In major depressive disorder, decreased levels of presynaptic neurotransmitter vesicle-associated proteins have been reported in brain regions such as the dorsolateral prefrontal cortex and hippocampus.^[139]

References

[1]
Composition of Synaptic Vesicles - Basic Neurochemistry - NCBI - NIH
The only known function of synaptic vesicles is neurotransmitter release · The proteins of synaptic vesicles are divided into two classes based on function · Most ...
[2]
Synaptic vesicle morphology: a case of protein sorting? - PMC
Oct 8, 2013 · Synaptic vesicles (SVs) are tiny membrane-enclosed organelles that store neurotransmitters at presynaptic terminals. These vesicles undergo Ca2 ...
[3]
Synaptic vesicle recycling: steps and principles | The EMBO Journal
These fuse with the plasma membrane and release their contents of neurotransmitter molecules (exocytosis). The molecules diffuse across the gap between the pre‐ ...
[4]
The Synaptic Vesicle Cycle Revisited: New Insights into the Modes ...
Oct 16, 2019 · Upon stimulation, these endocytic proteins translocate to the periactive zone, thus coupling the processes of exocytosis and endocytosis ( ...
[5]
Synaptic Vesicle Proteins and Active Zone Plasticity - Frontiers
Apr 17, 2016 · Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ).
[6]
Synaptic Vesicle - an overview | ScienceDirect Topics
Synaptic vesicles are intracellular trafficking organelles that mediate the fast release of neurotransmitters by rapidly fusing with the plasma membrane in ...Synaptic Vesicle Cycle... · Synaptic Vesicle Dynamics in...
[7]
The Synaptic Vesicle Cycle in the Nerve Terminal - NCBI - NIH
Synaptic vesicles undergo a membrane-trafficking cycle in the presynaptic nerve terminal that prepares them for neurotransmitter release.Missing: definition | Show results with:definition
[8]
Synaptic Transmission - Basic Neurochemistry - NCBI Bookshelf - NIH
... neurotransmitters. The predominant excitatory neurotransmitter in the brain, glutamate, and the inhibitory neurotransmitter in the spinal cord, glycine, are ...
[9]
Release of Transmitters from Synaptic Vesicles - Neuroscience - NCBI
The discovery of the quantal release of packets of neurotransmitter immediately raised the question of how such quanta are formed and discharged into the ...
[10]
An overview of the synaptic vesicle lipid composition - ScienceDirect
Sep 30, 2021 · In this short review, we summarize the current knowledge about the composition and role of synaptic vesicle lipids, starting from their biogenesis up to their ...
[11]
Recent insights into the building and cycling of synaptic vesicles
### Summary of Synaptic Vesicle (SV) Building: Molecular Composition
[12]
Structure and topography of the synaptic V-ATPase–synaptophysin ...
Jun 5, 2024 · Synaptic vesicles are organelles with a precisely defined protein and lipid composition1,2, yet the molecular mechanisms for the biogenesis ...
[13]
Synaptic Vesicle Protein 2: a multi-faceted regulator of secretion - PMC
SV2 is, to date, the only synaptic vesicle protein that is a viable therapeutic target in the treatment of nervous system diseases.Sv2 Affects Calcium... · Sv2 Binds Adenine... · Sv2 As A Therapeutic Target
[14]
The Synaptic Vesicle Glycoprotein 2: Structure, Function, and ...
This proteoglycan matrix binds 95% of the neurotransmitter and ATP within the vesicle, requiring ionic exchange for release and thereby regulating ...
[15]
Co-existence of Functionally Different Vesicular Neurotransmitter ...
The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes.
[16]
Automated Detection and Localization of Synaptic Vesicles in ...
Jan 19, 2022 · Nevertheless, since synaptic vesicles are very small organelles, having a diameter of 30–40 nm, electron microscopy (EM) is the state-of-the-art ...
[17]
Packaging Neurotransmitters - Neuroscience - NCBI Bookshelf - NIH
These vesicles are electron-dense in electron micrographs—hence, they are referred to as large dense-core vesicles (Figure 6.7B). Finally, the biogenic ...
[18]
Release mode of large and small dense-core vesicles specified by ...
Small, clear synaptic vesicles (SVs) generally contain low–molecular weight neurotransmitters, whereas neuropeptides are packaged in larger, dense-core vesicles ...
[19]
Dense core vesicles resemble active-zone transport ... - PubMed
Large dense core vesicles (approximately 100 nm) contain neuroactive peptides and other co-transmitters. Smaller dense core vesicles (approximately 80 nm) ...
[20]
Molecular architecture of synaptic vesicles - PMC - PubMed Central
Employing cryoelectron tomography, the study characterizes a diversity of SV proteins, including small proteins on the SV surface, elongated proteins inside, ...
[21]
Presynaptic active zones in invertebrates and vertebrates - PMC
The regulated release of neurotransmitter occurs via the fusion of synaptic vesicles (SVs) at specialized regions of the presynaptic membrane called active ...
[22]
Biogenesis and reformation of synaptic vesicles - PMC
Oct 5, 2024 · B, somatic biogenesis may occur via nuclear export of mRNA coding for SV proteins, its ribosomal translation and insertion into the endoplasmic ...
[23]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4552486/
[24]
https://pmc.ncbi.nlm.nih.gov/articles/PMC12559975/
[25]
https://doi.org/10.1016/j.neuron.2018.08.004
[26]
Synaptic Vesicle Endocytosis - PMC - PubMed Central - NIH
Although auxilin binds clathrin and AP-2, its recruitment to budding coated vesicles ... A function for the AP3 coat complex in synaptic vesicle formation from ...Figure 1 · Core Components And... · Table 1
[27]
Mammalian phosphatidylinositol 4-kinases as modulators of ...
Additionally, PI4P, at physiologically relevant concentrations as low as 2 mol%, can induce curvature in model membranes [56]. Therefore, PI4P can contribute to ...
[28]
Phosphatidylinositol 4,5-bisphosphate stimulates vesicle formation ...
These results suggest that PtdIns(4,5)P2 plays a critical role in the early step of vesicle formation, possibly in the recruitment of coats and fission factors ...
[29]
https://doi.org/10.1016/j.neuron.2014.05.007
[30]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3428771/
[31]
Adaptor Complex-independent Clathrin Function in Yeast - PMC
AP-3, which is associated with endosomes and/or the TGN, plays a role in membrane protein sorting to lysosomes and synaptic vesicle formation (Le Borgne and ...
[32]
Characterization of the Adaptor-related Protein Complex, AP-3 - PMC
An AP-3 Mutant in Drosophila. When the database was searched for homologues of the AP-3 subunits, we found that δ is closely related to the protein product ...
[33]
https://doi.org/10.3389/fnsyn.2022.826098
[34]
https://doi.org/10.1016/j.cell.2006.10.030
[35]
https://pmc.ncbi.nlm.nih.gov/articles/PMC25654/
[36]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2139840/
[37]
Axonal transport: Driving synaptic function - Science
Oct 11, 2019 · Vesicles formed in the cell body are actively transported by kinesin motors along axonal microtubules to presynaptic sites that can be located ...Axonal Transport: Driving... · Axonal Microtubule... · Axonal Microtubule Diversity
[38]
Axonal Transport: Cargo-Specific Mechanisms of Motility and ...
Oct 22, 2014 · Microtubule motor proteins kinesin and dynein drive the movement of organelles, vesicles, RNA granules, and proteins along the axon. Kinesins ...Molecular Motors Drive... · Kinesin And Dynein Motors... · Synaptic Vesicle Precursors...
[39]
Disruption of axonal transport in neurodegeneration - JCI
Jun 1, 2023 · Underscoring impaired axonal transport as a pathogenic mechanism is that mutations in genes encoding multiple motor proteins, including the ...
[40]
Synaptic vesicle traffic is supported by transient actin filaments and ...
Oct 21, 2020 · We find that the axonal traffic of recycling vesicles is not supported by ubiquitous microtubule-based motility but relies on actin instead.
[41]
Dephosphorylated synapsin I anchors synaptic vesicles to actin ...
The data indicate that synapsin I markedly affects synaptic vesicle traffic and cytoskeleton assembly in the nerve terminal and provide a molecular basis for ...
[42]
Synaptic Vesicle Mobilization Is Regulated by Distinct Synapsin I ...
The dynamic balance between activity-dependent phosphorylation and dephosphorylation of synapsin Ia may underlie general mechanisms involved in molecular ...
[43]
Axonal transport defects in neurodevelopmental disorders | Journal ...
Apr 3, 2024 · A growing number of mutations in genes encoding the transport machinery have been linked to neurodevelopmental disorders. Emerging lines of ...
[44]
Recently recycled synaptic vesicles use multi-cytoskeletal transport ...
Nov 6, 2023 · Each SV is selected to have either a slow velocity (80% having 0.5 μm/s) or fast velocity (20% having 1.5 μm/s). Slow-velocity SVs are ...
[45]
RIM determines Ca2+ channel density and vesicle docking at the ...
Defining "docked" vesicles as those that are located within 10 nm of the active zone membrane, we found 7.0 ± 4.6 docked vesicles in control synapses (n = 17 ...
[46]
A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity?
Our results suggest a model whereby the Munc13/α‐RIM/Rab3 complex tethers docked vesicles in the active zone, facilitating priming and making them substrates ...Missing: distance | Show results with:distance
[47]
Disentangling the Roles of RIM and Munc13 in Synaptic Vesicle ...
Dec 2, 2020 · We found that RIM modulates synaptic vesicle localization in the proximity of the active zone membrane independent of Munc13-1.
[48]
Neuronal SNARE complex assembly guided by Munc18‐1 and ...
Priming of synaptic vesicles is believed to be a hallmark of synaptic vesicle exocytosis, which involves activation and regulation of SNARE complex assembly.
[49]
Munc13 activates the Munc18‐1/syntaxin‐1 complex and enables ...
Jul 9, 2020 · Our data suggest a mechanism by which Munc13 activates the Munc18‐1/syntaxin‐1 complex and enables Munc18‐1 to prime SNARE assembly.Missing: Rab3 bassoon piccolo
[50]
Role of Bassoon and Piccolo in Assembly and Molecular ... - Frontiers
Bassoon and Piccolo are two very large scaffolding proteins of the cytomatrix assembled at the active zone (CAZ) where neurotransmitter is released.
[51]
Article Bassoon and the Synaptic Ribbon Organize Ca 2+ Channels ...
Nov 18, 2010 · We conclude that Bassoon and the ribbon (1) create a large number of release sites by organizing Ca 2+ channels and vesicles, and (2) promote vesicle ...
[52]
Additive effects on the energy barrier for synaptic vesicle fusion ...
The energy required to fuse synaptic vesicles with the plasma membrane ('activation energy') is considered a major determinant in synaptic efficacy.
[53]
Additive effects on the energy barrier for synaptic vesicle fusion ...
Apr 14, 2015 · Exposing neurons to hypertonic solution induces vesicle fusion selectively from the readily releasable pool (primed state) (Rosenmund and ...
[54]
The docking of synaptic vesicles on the presynaptic membrane ...
Feb 10, 2021 · Three TIRF videos per sample condition were recorded and analyzed to quantify the number of docked vesicles and their residence time (d, e ...
[55]
Direct imaging of rapid tethering of synaptic vesicles accompanying ...
Jun 8, 2020 · Here, we visualize SV movements near presynaptic membrane using total internal reflection fluorescence (TIRF) microscopy. Upon stimulation, SVs ...
[56]
The release of inhibition model reproduces kinetics and plasticity of ...
Oct 27, 2023 · When an AP reaches the presynaptic terminal, it depolarises the presynaptic membrane and transiently activates voltage-gated Ca2+ channels ( ...
[57]
and trans-membrane interactions of synaptotagmin-1 - Nature
Dec 27, 2022 · Ca2+ is a triggering factor of vesicle fusion and intracellular Ca2+ concentration ([Ca2+]i) is typically ~ 100 nM, but local [Ca2+]i and Ca2+ ...
[58]
Ca2+ channel nanodomains boost local Ca2+ amplitude - PNAS
We discovered an unexpected and dramatic boost in nanodomain Ca 2+ amplitude, ten-fold higher than predicted on theoretical grounds.Missing: seminal | Show results with:seminal
[59]
SNARE zippering - PMC - PubMed Central - NIH
May 6, 2016 · In this review, we describe some recent progress in understanding SNARE zippering and the characterization of the half-zippered intermediate.
[60]
Synaptotagmin Interaction with SNAP-25 Governs Vesicle Docking ...
Abstract. SNARE complex assembly constitutes a key step in exocytosis that is rendered Ca2+-dependent by interactions with synaptotagmin-1.Missing: seminal | Show results with:seminal
[61]
The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins ...
Jun 30, 2021 · Here, we show that the neuronal/exocytic calcium sensor Synaptotagmin-1 (Syt1) promotes expansion of fusion pores induced by SNARE proteins.Missing: seminal | Show results with:seminal
[62]
Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding ...
ANF-GFP is a moderate-sized molecule (∼6 nm) whose release by exocytosis requires expansion of a fusion pore that is initially 1–2 nm in diameter (Breckenridge ...
[63]
Fusion pore formation and expansion induced by Ca2+ and ... - PNAS
During this process, an initial fusion pore between two membranes can either close back or expand to a larger pore.
[64]
The fusion pore, 60 years after the first cartoon - Sharma - FEBS Press
Jun 14, 2018 · Neurotransmitter release occurs in the form of quantal events by fusion of secretory vesicles with the plasma membrane, and begins with the ...
[65]
Molecular Mechanisms for Synchronous, Asynchronous, and ...
When an action potential invades a presynaptic bouton, voltage-gated Ca2+ channels open briefly, which results in a sharp, local rise of the intraterminal Ca2+.
[66]
Two forms of asynchronous release with distinctive spatiotemporal ...
May 11, 2023 · Asynchronous release is a ubiquitous form of neurotransmitter release that persists for tens to hundreds of milliseconds after an action ...
[67]
Differential regulation of synchronous versus asynchronous ... - PNAS
Most synchronous release occurs within 10 ms of stimulation (9). The ... ms, with 95% of asynchronous release occurring within 300 msec after stimulation.Sign Up For Pnas Alerts · Results · Discussion
[68]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2592635/
[69]
https://www.pnas.org/doi/10.1073/pnas.1218818110
[70]
Fast Kinetics of Exocytosis Revealed by Simultaneous ...
Knowing the number of vesicles per unit capacitance jump, we determined the size of the releasable pool and the rate of release by capacitance measurements.
[71]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4503208/
[72]
https://elifesciences.org/articles/84041
[73]
https://www.pnas.org/doi/10.1073/pnas.1000606107
[74]
https://www.cell.com/trends/neurosciences/fulltext/S0166-2236%2897%2901083-7
[75]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4002768/
[76]
https://pmc.ncbi.nlm.nih.gov/articles/PMC5748430
[77]
https://www.sciencedirect.com/science/article/pii/S0896627301002719
[78]
https://doi.org/10.1083/jcb.57.2.315
[79]
https://doi.org/10.1016/S0896-6273(00)80664-9
[80]
https://doi.org/10.1038/nrm3151
[81]
https://doi.org/10.1016/j.neuron.2005.05.004
[82]
https://doi.org/10.1038/374186a0
[83]
https://doi.org/10.1016/S0896-6273(03)00644-5
[84]
https://doi.org/10.1016/0092-8674(86)90852-4
[85]
https://doi.org/10.1016/j.neuron.2006.05.027
[86]
Complexity of calcium signaling in synaptic spines - PubMed Central
For example, a 50 nm resting [Ca2+]i in a dendritic spine (0.1 μm3) entails an average of only three free Ca2+ ions. Similarly, a [Ca2+]i of 1 μM, a high level ...
[87]
Single Calcium Channel Nanodomains Drive Presynaptic Calcium ...
Mar 23, 2022 · Efficient and reliable neurotransmission requires precise coupling between action potentials (APs), Ca2+ entry and neurotransmitter release.
[88]
Calcium Binding by Synaptotagmin's C2A Domain is an Essential ...
Jan 25, 2012 · Synaptotagmin is the major calcium sensor for fast synaptic transmission that requires the synchronous fusion of synaptic vesicles.
[89]
Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian ...
Sep 9, 2019 · We postulate that the C2B domain of syt1, independent of complexin, is the molecular clamp that arrests SVs prior to Ca 2+ -triggered fusion.
[90]
Nanodomain coupling between Ca2+ channels and sensors of ...
If several open Ca2+ channels jointly trigger the release of a synaptic vesicle, the progressive reduction of Ca2+ inflow will lead to a supralinear ...
[91]
Vesicle Priming and Recruitment by ubMunc13-2 Are Differentially ...
Feb 20, 2008 · Ca2+ regulates multiple processes in nerve terminals, including synaptic vesicle recruitment, priming, and fusion. Munc13s, the mammalian ...
[92]
Calcium triggers calcineurin-dependent synaptic vesicle recycling in ...
Jun 18, 1998 · Our results suggest that dynamin-dependent synaptic vesicle endocytosis is triggered by calcium influx occurring upon nerve-terminal depolarisation.
[93]
The Role of Calcium Channels in Epilepsy - PMC - PubMed Central
The coupling between synaptic vesicles and Ca2+ channels determines fast neurotransmitter release. Neuron 53: 563–575. [DOI] [PubMed] [Google Scholar] ...
[94]
SNARE-mediated membrane fusion is a two-stage process driven ...
A common view is that some or all of the ~ 65 kT of zippering energy [23] is transduced into membrane energy sufficient to fuse the membranes. In this ...
[95]
Entropic forces drive self-organization and membrane fusion ... - PNAS
May 10, 2017 · Thus, the ∼65 kT of SNARE motif zippering energy does not drive membrane fusion: Only a small fraction is stored, as LD stretching energy (∼2 kT) ...
[96]
SNARE zippering | Bioscience Reports - Portland Press
VAMP2 and syntaxin 1A both contain one SNARE motif each connected to the C-terminal single transmembrane (TM) helix by a short linker regions whereas SNAP-25 ...
[97]
Molecular mechanisms of synaptic vesicle priming by Munc13 and ...
SUMMARY. Munc13 catalyzes the transit of syntaxin from a closed complex with Munc18 into the ternary SNARE complex. Here we report a new function of Munc13, ...
[98]
Focused clamping of a single neuronal SNARE complex by ... - Nature
Sep 7, 2018 · Complexin (Cpx) is the only presynaptic protein that tightly binds to SNAREs and regulates membrane fusion, but how it modulates the energy ...
[99]
SNARE-complex disassembly by NSF follows synaptic-vesicle fusion
Characterization of 16 comatose mutations demonstrates that NSF mediates disassembly of SNARE complexes after synaptic-vesicle fusion.
[100]
Quantitative Analysis of Synaptic Vesicle Rabs Uncovers Distinct Yet ...
Oct 6, 2010 · Rab3a and Rab27b reside on distinct yet overlapping SV pools. Rab27 proteins (Rab27a/b) have recently emerged as key regulators of exocytotic ...Rab3a And Rab27b Reside On... · Rab3a And Rab27b Exhibit... · Rab27b Regulates Sv...<|control11|><|separator|>
[101]
Distinct Actions of Rab3 and Rab27 GTPases on Late Stages of ...
Jun 6, 2014 · Not surprisingly, Rab3 and, more recently, Rab27 GTPases have been reported as central to targeting and docking secretory vesicles in β-cells 19 ...Abstract · Results · Discussion · Materials and Methods
[102]
The neuronal porosome complex in health and disease - PMC
Besides vesicle size, vesicle composition is also known to influences the size of SNARE rosette. (A color version of this figure is available in the online ...
[103]
Botulinum neurotoxin E-insensitive mutants of SNAP-25 fail to bind ...
Neurotransmitter release from synaptic vesicles is mediated by complex machinery, which includes the v- and t-SNAP receptors (SNAREs), vesicle-associated ...
[104]
Syntaxin-3 is dispensable for basal neurotransmission and synaptic ...
Jan 20, 2020 · Our data suggest that syntaxin-3 is dispensable for hippocampal basal neurotransmission and synaptic plasticity, and further supports the notion that syntaxin- ...
[105]
The SNARE Protein Syntaxin 3 Confers Specificity for Polarized ...
Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons.
[106]
Botulinum Toxins A and E Inflict Dynamic Destabilization on t ...
Nov 7, 2017 · Botulinum toxins (BoNTs) A and E block neurotransmitter release by specifically cleaving the C- terminal ends of SNAP-25, a plasma membrane ...
[107]
Association of Botulinum Neurotoxins With Synaptic Vesicle Protein ...
Botulinum neurotoxins (BoNTs) elicit flaccid paralysis by cleaving SNARE proteins within peripheral neurons. BoNTs are classified into seven serotypes, ...
[108]
Tetanus toxin blocks the exocytosis of synaptic vesicles clustered at ...
Aug 15, 1999 · Tetanus toxin blocks the exocytosis of synaptic vesicles clustered at synapses but not of synaptic vesicles in isolated axons · Authors.
[109]
A post-docking role for synaptobrevin in synaptic vesicle fusion
Injection of either toxin into squid nerve terminals caused a slow, irreversible inhibition of release without affecting the Ca2+ signal which triggers release.
[110]
alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins
alpha-Latrotoxin, a potent neurotoxin from black widow spider venom, triggers synaptic vesicle exocytosis from presynaptic nerve terminals. alpha-Latrotoxin ...
[111]
Mechanisms of alpha-latrotoxin action - PubMed
The major component of black widow spider venom, alpha-latrotoxin, triggers massive exocytosis in a variety of neurosecretory cells.
[112]
Release of Neurotransmitters and Depletion of Synaptic Vesicles in ...
The results suggest that the release of neurotransmitter and the depletion of synaptic vesicle in boutons are manifestations of a single action of the toxin.
[113]
Ziconotide for treatment of severe chronic pain - PubMed
May 1, 2010 · The ziconotide-induced blockade of N-type calcium channels in the spinal cord inhibits release of pain-relevant neurotransmitters from central ...
[114]
A comprehensive review on ziconotide - PubMed
May 11, 2024 · Ziconotide produces powerful analgesia by blocking N-type calcium channels in the spinal cord, which inhibits the release of pain-relevant neurotransmitters.
[115]
Pharmacological characterisation of voltage-sensitive calcium ...
Nifedipine and omega-agatoxin IVA dose dependently (IC50 values of 10 nM and 0.7 nM, respectively) blocked most of the release, whereas omega-conotoxin MVIIA ( ...
[116]
Beta-bungarotoxin-induced depletion of synaptic vesicles at the ...
The neurotoxic phospholipase A(2), beta-bungarotoxin, caused the failure of the mechanical response of the indirectly stimulated rat diaphragm.
[117]
Snake presynaptic neurotoxins with phospholipase A2 ... - PubMed
Snake presynaptic neurotoxins with phospholipase A2 activity induce punctate swellings of neurites and exocytosis of synaptic vesicles ... beta-bungarotoxin ...
[118]
Nerve terminal damage by beta-bungarotoxin: its clinical significance
We report here original data on the biological basis of prolonged neuromuscular paralysis caused by the toxic phospholipase A2 beta-bungarotoxin.
[119]
Structural basis of α-latrotoxin transition to a cation-selective pore
Oct 3, 2024 · α-LTX has been widely used as a molecular tool to study the exocytosis of synaptic vesicles and its actions are considered precisely the ...
[120]
Beta-amyloid disrupted synaptic vesicle endocytosis in cultured ...
Jun 15, 2007 · In the present study, we analyzed beta-amyloid (Abeta)-induced changes in synaptic vesicle recycling in rat cultured hippocampal neurons. Our ...
[121]
Aβ DISRUPTED SYNAPTIC VESICLE ENDOCYTOSIS IN ...
In the present study, we analyzed beta-amyloid (Aβ)-induced changes in synaptic vesicle recycling in cultured hippocampal neurons.
[122]
Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's ...
Feb 19, 2018 · α-Syn affects synaptic vesicle pools and their trafficking in the presynaptic terminal ... Fusion competent synaptic vesicles persist upon active ...
[123]
Acute increase of α-synuclein inhibits synaptic vesicle recycling ...
This is the first study to show the direct effects of α-synuclein on synaptic vesicle trafficking and to elucidate the underlying structural mechanisms.
[124]
SNAP25 disease mutations change the energy landscape ... - PubMed
Feb 27, 2024 · These mutations lowered the energy barrier for fusion and increased the release probability ... SNARE complex and synaptotagmin-1, while ...
[125]
SNAP25 disease mutations change the energy landscape for ...
These mutations lowered the energy barrier for fusion and increased the release probability, which are gain-of-function features not found in Syt1 knockout (KO) ...
[126]
Autism-associated mutations in ProSAP2/Shank3 impair synaptic ...
Oct 24, 2012 · Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders ( ...Missing: dysfunction | Show results with:dysfunction
[127]
Shank3 mutation in a mouse model of autism leads to changes in ...
Jul 9, 2018 · Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan- ...
[128]
Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q ...
Our presynaptic imaging data directly show that LEMS IgG decreases action potential–dependent synaptic vesicle release in rat and wild-type mouse neurons. We ...
[129]
Synaptic pathophysiology and treatment of Lambert-Eaton ...
This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca2+ channels involved with neurotransmitter release.
[130]
How antidepressant drugs act: A primer on neuroplasticity as ... - NIH
Antidepressant drugs inhibit the breakdown of monoamines (such as serotonin, noradrenaline and dopamine) in the storage vesicles of the presynaptic neuron.
[131]
Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Oct 5, 2012 · Evidence that typical antidepressants, such as the highly prescribed SSRIs, could influence synaptic plasticity is provided by ...