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PubMed2006

The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves.

Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by selectively cleaving core components of the vesicular fusion machinery. The synaptic vesicle proteins Synaptotagmin-I and -II act as receptors for BoNT/B and BoNT/G. Here we show that BoNT/A also interacts with a synaptic vesicle protein, the synaptic vesicle glycoprotein 2C (SV2C), but not with the homologous proteins SV2A and SV2B. Binding of BoNT/A occurs at the membrane juxtaposed region preceding transmembrane domain 8. A peptide comprising the intravesicular domain between transmembrane domains 7 and 8 specifically reduces the neurotoxicity of BoNT/A at phrenic nerve preparations demonstrating the physiological relevance of this interaction.

Animals↗

PubMed1993

Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein.

Tetanus toxin inhibits neurotransmitter release by selectively blocking fusion of synaptic vesicles. Recently tetanus toxin was shown to proteolytically degrade synaptobrevin II (also named VAMP-2), a synaptic vesicle-specific protein, in vitro and in nerve terminals. As targets of tetanus toxin, synaptobrevins probably function in the exocytotic fusion of synaptic vesicles. Here we describe a new synaptobrevin homologue, cellubrevin, that is present in all cells and tissues tested and demonstrate that it is a membrane trafficking protein of a constitutively recycling pathway. Like synaptobrevin II, cellubrevin is proteolysed by tetanus toxin light chain in vitro and after transfection. Our results suggest that constitutive and regulated vesicular pathways use homologous proteins for membrane trafficking, probably for membrane fusion at the plasma membrane, indicating a greater mechanistic and evolutionary similarity between these pathways than previously thought.

Amino Acid Sequence↗

PubMed1973

A semiquantitative theory of synaptic vesicle movements.

Under the assumption that vesicles are the anatomic correlate of quantal release, the forces governing the movement of synaptic vesicles inside neurons are analyzed. Semiquantitative calculations are presented to show that a diffuse layer field penetrates a few Debye lengths into the axoplasm. This field binds tightly a monolayer of water to the membrane forming the potential barrier for miniature end-plate potential (mepp) release. The action potential destroys the monolayer and pulls the vesicle to the membrane. The vesicles are brought to the synaptic zone and held there by a Na(+) leak in the synaptic membrane. A stochastic theory of synaptic vesicle release is presented to explain experimental results. The rate of vesicle release is fractionated into a rate of membrane contacts by a vesicle and a rate of vesicle discharge per contact.

Action Potentials↗

PubMed2001

The synaptic vesicle priming protein Munc13-1 is absent from tonically active ribbon synapses of the rat retina.

Ribbon synapses, for example of the retina, are specialized synapses that differ from conventional, phasically active synapses in several aspects. Ribbon synapses can tonically and yet very rapidly release neurotransmitter via synaptic vesicle exocytosis. This requires an optimization of the synaptic machinery and is at least partly due to the presence of synaptic ribbons that bind large numbers of synaptic vesicles and which are believed to participate in priming synaptic vesicles for exocytosis. In this paper we analyzed whether ribbon synapses of the retina employ similar priming factors, i.e. Munc13-1, as do conventional, non-ribbon containing phasically active synapses. We found that though present in conventional synapses of the retina Munc13-1 was completely absent from ribbon-containing synapses of the retina, both in the outer as well as in the inner plexiform layer. This indicates that ribbon synapses of the retina employ other, possibly more potent priming factors than phasically active conventional synapses.

Animals↗

PubMed1989

Membrane proteins of synaptic vesicles and cytoskeletal specializations at the node of Ranvier in electric ray and rat.

Binding sites for antibodies against membrane proteins of synaptic vesicles have been shown to be enhanced at nodes of Ranvier in electromotor axons of the electric ray Torpedo marmorata and sciatic nerve axons of the rat, using indirect immunofluorescence and monoclonal antibodies against the synaptic vesicle transmembrane proteins SV2 and synaptophysin (rat) or SV2 (Torpedo). In the electric lobe of Torpedo, vesicle-membrane constituents occurred at higher density in the proximal axon segments covered by oligodendroglia cells than in the distal axon segments where myelin is formed by Schwann cells. Antibody binding sites were enhanced at nodes forming the borderline of the central and peripheral nervous systems. Filamentous actin was present in the Schwann-cell processes covering both the nodal and the paranodal axon segments as suggested by the pattern of phalloidin labelling. Furthermore, in rat sciatic nerve, Schmidt-Lanterman incisures were intensely labelled by phalloidin. A similar nodal distribution was found for binding sites of antibodies against actin and myosin. Binding of antibodies to tubulin was enhanced at nodes in Torpedo electromotor axons. The apparent nodal accumulation of constituents of synaptic vesicle membranes and the presence of filamentous actin and of myosin are discussed in relation to the substantial constriction of the axoplasm at nodes of Ranvier.

Animals↗

PubMedDate not supplied

Effect of phosphomonoesters, phosphodiesters, and phosphocreatine on glutamate uptake by synaptic vesicles.

L-Glutamate, a major excitatory amino acid, plays an important role in learning and memory. L-Glutamate uptake into synaptic vesicles is an ATP-dependent process. Exposure of neurons to high, sustained extracellular concentrations of glutamate results in excitotoxicity. Elevated levels of phosphomonoesters (PMEs), phosphodiesters (PDEs), and phosphocreatine (PCr) have been reported in Alzheimer disease (AD). In this article, the effects of selected PMEs, PDEs, and PCr on vesicular L-[3H]glutamate uptake into isolated bovine synaptic vesicles are investigated. D-myo-Inositol-1-monophosphate (I1P), D-myo-inositol-2-monophosphate (I2P), sn-glycero-3-phosphate, (alpha-GP) and PCr significantly stimulated L-[3H]glutamate uptake into synaptic vesicles. Phosphoethanolamine (PE), phosphocholine (PC), L-phosphoserine (L-PS) sn-glycero-3-phosphocholine (GPC), and sn-glycero-3-phosphoethanolamine (GPE) had little or no effect on vesicular L-glutamate uptake. These observations suggested that the vesicular uptake of glutamate can be regulated by endogenous PMEs and PCr. The mechanism of activation by I1P, I2P, and alpha-GP appears to be stimulation of Mg(2+)-ATPase activity. These effects on vesicular glutamate uptake may be important in diseases in which the levels of these metabolites are altered, as they are in AD.

Amino Acids↗

PubMed1980

ATP-stimulated Ca2+ transport into cholinergic Torpedo synaptic vesicles.

Activation of the Ca2+/Mg2+ ATPase associated with highly purified Torpedo synaptic vesicles results in 45Ca2+ uptake. The accumulated 45Ca2+ is released by hypoosmotic buffer and by the Ca2+ ionophore A23187. Density-gradient centrifugation and permeation chromatography reveal that vesicular acetylcholine and the membrane-bound 45Ca2+ co-migrate, thus implying that 45Ca2+ is transported into cholinergic vesicles. ATP-dependent 45Ca2+ uptake follows saturation kinetics, with KmCa2+ = 50 microM, and Vmax = 3 +/- 0.3 nmol Ca2+/mg protein/min. Treatment of the vesicles with mersalyl, dicyclohexylcarbodiimide, and quercetin leads to inactivation of the Ca2+/Mg2+ ATPase and to comparable inhibition of 45Ca2+ transport. Ruthenium red and ouabain have no effect on either of these activities. Nigericin in the presence of external K+ is a potent inhibitor of 45Ca2+ translocation, whereas gramicidin activates transport. The proton translocator carbonylcyanide p-trifluoromethoxy-phenylhydrazone (FCCP) and FCCP + the ionophore valinomycin partially inhibit 45Ca2+ transport. By contrast, the above ionophores do not affect Ca2+/Mg2+ ATPase activity. Tentative mechanisms for ATP-dependent Ca2+ transport into cholinergic synaptic vesicles and the physiological significance of this process are discussed.

Acetylcholine↗

PubMed1986

The density and free water of cholinergic synaptic vesicles as a function of osmotic pressure.

Synaptic vesicles from the cholinergic electromotor nerve terminals of Torpedo marmorata are among the most uniform subcellular organelles known and are osmotically sensitive. Changes in density accompanying osmotic perturbation have enabled changes in water content to be calculated; when referred to a standard state of known volume and water content, fractional and absolute water contents could be calculated for the perturbed states and compared with the fractional free water content as measured by the glycerol space. Under hyperosmotic conditions, discrepancies were found between these two estimates, the glycerol space falling more rapidly than the water space predicted from the density change. This is attributed to a failure of glycerol to displace water imbibed by the membrane as it collapses round an aqueous core of decreasing volume. 'Reserve' vesicles obeyed a relationship between density, osmotic load and osmolality derived for a perfect osmometer, and independent estimates of fractional free water content under standard conditions and osmotic load were made. The former of these agreed well with the glycerol space under standard conditions and the latter agreed with previous estimates of the osmotic load using morphological and analytical data and an assumed activity coefficient of 0.65. Finally, it was possible to model the interconversion of reserve and recycling vesicles more accurately than in previous work.

Acetylcholine↗

PubMed1990

Uptake of glycine into synaptic vesicles isolated from rat spinal cord.

Glycine was taken up by a synaptic vesicle fraction from spinal cord in a Mg-ATP-dependent manner. The accumulation of glycine was inhibited by carbonyl cyanide-m-chlorophenylhydrazone (CCCP) and nigericin, agents known to destroy the proton gradient across the vesicle membrane. Vesicular uptake of glycine was clearly different from synaptosomal uptake, with respect to both the affinity constant and the effect of Na+, ATP, CCCP, and temperature. Oligomycin and strychnine did not inhibit the vesicular uptake, showing that neither mitochondrial H(+)-ATPase nor binding to strychnine-sensitive glycine receptors was involved. It is suggested that the vesicular uptake of glycine is driven by a proton gradient generated by a Mg2(+)-ATPase. A low concentration of Cl- had little effect on the uptake of glycine, whereas the uptake of glutamate in the same experiment was highly stimulated. High concentrations of gamma-amino-n-butyric acid and beta-alanine inhibited vesicular glycine uptake, but glutamate did not. Accumulation of glycine was found to be fourfold higher in a spinal cord synaptic vesicle fraction than in a vesicle fraction from cerebral cortex.

Adenosine Triphosphate↗

PubMed1989

Ionic channels in synaptic vesicles: are they involved in transmitter release?

Synaptic vesicles were isolated from the nerve terminals of Torpedo electric organ. After fusion, 'giant' vesicles were formed which could be examined by the patch clamp technique. One of the cationic channels, the P channel, shows a small preference for K+ compared to Na+ and has multiple conductance levels. Its rate of opening is voltage and calcium dependent. Fractal analysis of the P channels reveals that its behaviour does not seem to be fractal in nature. At voltages where only one conductance level is observed, fractal analysis shows at least one discrete open state and at least two discrete closed states. There are considerable similarities between the P channel and channels found in granules from the hypophysis. These channels resemble, in turn, the channels found in gap junctions. Therefore, it is not unwarranted to speculate that a gap-junction-like communication between the secretory vesicle and the extracellular space may occur during exocytosis.

Animals↗

PubMed1994

Intermediates in synaptic vesicle recycling revealed by optical imaging of Drosophila neuromuscular junctions.

We show that uptake and release of the styryl dye FM1-43 may be used to monitor synaptic vesicle exocytosis and recycling at Drosophila larval neuromuscular junctions. At Drosophila nerve terminals, FM1-43 specifically labels subsynaptic domains enriched in synaptotagmin, in a manner that requires Ca2+, membrane depolarization, and shibire (shi) function. Endocytosis rates, very low in unstimulated synapses, are induced severalfold by the exocytosis of synaptic vesicles. Using shi(ts)1 mutant synapses to separate synaptic vesicle fusion and recycling temporally, we show that recycling events subsequent to the shi block do not require extracellular Ca2+. We suggest that two distinct intermediate stages in vesicle recycling may be trapped and analyzed at Drosophila neuromuscular junctions.

Animals↗

PubMed1987

Synapsin I: a regulated synaptic vesicle organizing protein.

Synapsin is a protein initially discovered and characterized as a target for cyclic AMP and Ca/calmodulin-regulated protein kinases that is concentrated in nerve endings and is localized on the surface of small synaptic vesicles. Synapsin shares antigenic sites and some local regions of homology with erythrocyte protein 4.1, although these proteins in general are quite different in sequence. Protein 4.1 and synapsin share several local regions of homology with erythrocyte spectrin alpha subunit. Protein 4.1 and synapsin may be related to each other through a common relationship with spectrin. Synapsin binds to synaptic vesicles and membrane sites with a Kd of 0.01-0.02 microM and associates with a Kd of 0.5-4 microM to spectrin, microtubules and neurofilaments in in vitro assays. Synapsin interconnects synaptic vesicles to membranes, and this activity is inhibited by phosphorylation with Ca/calmodulin-dependent protein kinase. Synapsin may have a role in neurons as a structural protein capable of interconnecting small synaptic vesicles with a number of proteins, including spectrin, microtubules, neurofilaments, and membrane sites. A physiological function of synapsin could be as a vesicle-organizing protein that mediates calcium-regulated association of vesicles with cytoskeletal proteins during axonal transport and attaches vesicles to active zones in nerve endings.

Animals↗

PubMed2002

The core membrane fusion complex governs the probability of synaptic vesicle fusion but not transmitter release kinetics.

Synaptic vesicle fusion is driven by the formation of a four-helical bundle composed of soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptors (SNAREs). Exactly how the structural interactions that lead to the formation of this complex relate to neurotransmitter release is not well understood. To address this question, we used a strategy to "rescue" synaptic transmission after proteolytic cleavage of the synaptosome-associated protein of 25 kDa (SNAP-25) by botulinum neurotoxin E (BoNtE). Transfection of CA3 hippocampal pyramidal cells with BoNtE-resistant SNAP-25 restored synaptic transmission. Additional mutations that alter the interaction between SNAP-25 C-terminal coil and the other SNARE coils dramatically reduce transmitter release probability but leave the kinetics of synaptic responses unaltered. These data indicate that at synapses, SNARE interactions are necessary for fusion but are not the rate-limiting step of neurotransmission.

Animals↗

PubMed1994

Purification of the N-type calcium channel associated with syntaxin and synaptotagmin. A complex implicated in synaptic vesicle exocytosis.

omega-Conotoxin-sensitive N-type calcium channels control neurotransmitter release at the nerve terminal and interact with proteins implicated in secretion. Solubilized omega-conotoxin receptors from rat brain synaptic membrane were immunoprecipitated by antibodies against calcium channel alpha 1 subunits, syntaxin, and a 105-kDa plasma membrane protein. A multimeric complex, composed of calcium channel subunits, and synaptic proteins that showed varying degrees of association, was purified by a procedure involving anti-syntaxin immunoaffinity chromatography. A 250-kDa N-type alpha 1 subunit, containing cAMP-dependent phosphorylation site(s), was identified by photoaffinity labeling with 125I-azidonitrobenzoyl omega-conotoxin and immunoblotting with sequence-directed antibodies. An immunologically related 210-kDa form of the alpha 1 subunit was detected that displayed different pharmacological and regulatory properties. Protein bands of 140, 70, 58, and 35 kDa comigrated with purified alpha 1 subunits upon sucrose gradient centrifugation, whereas the 105-kDa protein was removed. The 58- and 35-kDa bands contained, respectively, the synaptic vesicle protein synaptotagmin and syntaxin, a plasma membrane protein that binds synaptic vesicle proteins. Purified omega-contoxin receptors were quantitatively immunoprecipitated by anti-syntaxin antibodies. These proteins may constitute an isolated exocytotic complex in which the N-type calcium channel tightly interacts with a synaptic vesicle docking site.

Amino Acid Sequence↗

PubMed2003

Estrogen decreases zinc transporter 3 expression and synaptic vesicle zinc levels in mouse brain.

Previous studies suggest that female sex hormones modulate synaptic zinc levels, which may influence amyloid plaque formation and Alzheimer's disease progression. We examined the effects of ovariectomy and estrogen supplement on the levels of synaptic zinc and zinc transporter protein Znt3 in the brain. Ovariectomy was performed on 5-month-old mice, and 2 weeks later, pellets containing vehicle, low (0.18 mg/pellet), or high dose (0.72 mg) 17beta-estradiol were implanted. After 4 weeks, animals were decapitated, and blood and brain were collected for analysis. Blood analysis indicated that estrogen implants altered plasma estrogen levels in a dose-dependent manner. Analysis of brain tissue showed that ovariectomy raised hippocampal synaptic vesicle zinc levels, whereas estrogen replacement lowered these zinc levels. Western blots revealed that Znt3 levels in the brain were modulated in parallel with synaptic zinc levels, whereas no change was detected in the levels of Znt3 mRNA, as determined by Northern blot and reverse transcriptase-PCR analysis. However, mRNA levels of the delta subunit of adaptor protein complex (AP)-3, which modulates the level of Znt3 levels, were altered by estrogen depletion or replacement. These data demonstrate that estrogen alters the levels of Znt3 and synaptic vesicle zinc in female mice, probably through changing AP-3 delta expression. Since synaptic zinc may play a key role in neuronal death in acute brain injury as well as in plaque formation in Alzheimer's disease, and since estrogen may be beneficial in both conditions, our results may provide new insights into the effects of estrogen on the brain.

Adaptor Protein Complex 3↗

PubMed1989

Comparison of the properties of gamma-aminobutyric acid and L-glutamate uptake into synaptic vesicles isolated from rat brain.

Rat brain synaptic vesicles exhibit ATP-dependent uptake of gamma-[3H]amino-n-butyric acid ([3H]GABA) and L-[3H]glutamate. After hypotonic shock, the highest specific activities of uptake of both L-glutamate and GABA were recovered in the 0.4 M fraction of a sucrose gradient. The uptakes of L-glutamate and GABA were inhibited by similar, but not identical, concentrations of the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone and the ionophores nigericin and gramicidin, but they were not inhibited by the K+ carrier valinomycin. N,N'-Dicyclohexyl-carbodiimide and N-ethylmaleimide, Mg2+-ATPase inhibitors, inhibited the GABA and L-glutamate uptakes similarly. Low concentrations of Cl- stimulated the vesicular uptake of L-glutamate but not that of GABA. The uptakes of both L-glutamate and GABA were inhibited by high concentrations of Cl-. These results indicate that the vesicular GABA and L-glutamate uptakes are driven by an electrochemical proton gradient generated by a similar Mg2+-ATPase. The vesicular uptake mechanisms are discussed in relation to other vesicle uptake systems.

Adenosine Triphosphate↗

PubMed2001

Visualizing postendocytic traffic of synaptic vesicles at hippocampal synapses.

We have investigated mechanisms in postendocytic processing of synaptic vesicles at hippocampal synapses, using synaptobrevin/vesicle-associated membrane protein (VAMP) tagged with variants of the green fluorescent protein. Following exocytosis, VAMP is retrieved at synaptic and adjoining axonal regions. Retrieved VAMP-containing vesicles return to synaptic vesicle clusters at a rate slower than endocytosis. Vesicles containing a different protein, synaptophysin, recluster at a similar rate, suggesting common vesicular intermediates for the two proteins. Activity prolongs the time taken by endocytosed vesicles to return to synapses. Exogenous calcium buffers slow endocytosis but have no additional effect on the time course of reclustering. In contrast, the protein kinase inhibitor staurosporine does not affect endocytosis but slows reclustering. Finally, since VAMP can move freely on surface membranes, sustained synaptic activity leads to mixing of this vesicular component between adjacent synapses.

Animals↗

PubMed1982

Appearance and distribution of neuronal cell surface and synaptic vesicle antigens in the developing rat superior cervical ganglion.

Monoclonal antibodies directed against a neuronal cell surface heparan sulfate proteoglycan and against a synaptic vesicle protein were used to study the postnatal development of ganglionic neurons and synapses in the rat superior cervical ganglion. Antigen levels in developing ganglia were quantitated by radioimmune assays. Localization of antigens in adult and developing ganglia was carried out using peroxidase-antiperoxidase immunocytochemistry at the light microscopic level. Ultrastructural staining patterns in adult ganglia also were studied. The time course of antigen increases parallels those in previous reports on the accumulation of neurotransmitter enzymes within the ganglion. Both synaptic and surface antigens increase postnatally, with the most rapid changes occurring during the 2nd week. Antibodies stain adult tissue in patterns consistent with the expected distribution of antigens: antibodies directed against synaptic vesicles stain synaptic terminals and cell cytoplasm and those directed against surface proteoglycan stain the plasma membranes of neuronal cell bodies and processes. Variable staining of the cell cytoplasm also is observed. No apparent changes in antigen distribution are observed with the light microscope during development. Variations in the time course of the development of antigens associated with different portions of the proteoglycan molecule suggest that the intracellular processing of the molecule may vary during development.

Aging↗