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PubMed1999

Styrene and styrene oxide affect the transport of dopamine in purified rat striatal synaptic vesicles.

Animal and human studies suggest a dopamine-mediated effect of styrene neurotoxicity. To date, mechanisms of cerebral membrane transport of neurotransmitter amines in the presence of styrene in relation to its neurotoxicity have not been addressed properly. So, the present study has examined to test the hypothesis that dopaminergic malfunction in vesicular transport is a critical component in styrene-induced neurotoxicity in rats. Both styrene and its intermediate reactive metabolite, styrene oxide antagonized the in vitro striatal binding of [3H] tyramine, a putative marker of the vesicular transporter for dopamine. Both styrene and styrene oxide potently inhibited the uptake of [3H] dopamine in purified synaptic vesicles prepared from rat brain striata, in a dose-related manner, with inhibitory constants (Ki) 2.5 and 2.2 microM respectively. However, neither styrene nor styrene oxide significantly increased the basal efflux of [3H] dopamine that has been preloaded into striatal vesicles in vitro. On the other hand, both styrene and styrene oxide have failed to significantly inhibit the uptake of either [3H] norepinephrine, or [3H] serotonin into striatal synaptic vesicles. It is concluded that both styrene and styrene oxide are capable of producing impairments in dopaminergic transport in purified striatal synaptic vesicles, an effect which may be a critical component in styrene-induced neurotoxicity.

Animals↗
PubMed1980

Antibodies to synaptic vesicles purified from Narcine electric organ bind a subclass of mammalian nerve terminals.

Antibodies were raised in rabbits to synaptic vesicles purified to homogeneity from the electric organ of Narcine brasiliensis, a marine electric ray. These antibodies were shown by indirect immunofluorescence techniques to bind a wide variety of nerve terminals in the mammalian nervous system, both peripheral and central. The shared antigenic determinants are found in cholinergic terminals, including the neuromuscular junction, sympathetic ganglionic and parasympathetic postganglionic terminals, and in those synaptic areas of the hippocampus and cerebellum that stain with acetylcholinesterase. They are also found in some noncholinergic regions, including adrenergic sympathetic postganglionic terminals, the peptidergic terminals in the posterior pituitary, and adrenal chromaffin cells. They are, however, not found in many noncholinergic synapse-rich regions. Such regions include the molecular layer of the cerebellum and those laminae of the dentate gyrus that receive hippocampal associational and commissural input. We conclude that one or more of the relatively small number of antigenic determinants in pure electric fish synaptic vesicles have been conserved during evolution, and are found in some but not all nerve terminals of the mammalian nervous system. The pattern of antibody binding in the central nervous system suggests unexpected biochemical similarities between nerve terminals heretofore regarded as unrelated.

Adrenal Medulla↗
PubMed1980

Free amino acids in the synaptosome and synaptic vesicle fractions of different bovine brain areas.

Free amino acids were quantitatively estimated in intact tissues and isolated synaptosome and synaptic vesicle fractions of the bovine brain regions with the aid of a sensitive amino acid analyzer. The brain areas studied were frontal, parietal and occipital cerebral cortices, cerebellar cortex, caudate and lenticular nuclei, superior colliculi, thalamus, pons and medulla. The most abundant amino acid in tissue samples and synaptosome fractions was glutamic acid, followed by glutamine, aspartic acid, GABA and taurine. The dominatating amino acid in all isolated synaptic vesicle fractions was taurine. The concentrations of glutamic acid, glutamine, GABA and aspartic acid were generally much lower. The 5 transmitter candidates, viz. GABA, glycine, glutamic acid, as particaid and taurine, comprised about one-half of the total amino acids in all samples. Taurine was the only amino acid highly enriched in the vesicle fractions. This enrichment was discernible in all brain areas. It is suggested therefore that taurine is rather a ubiquitous associate of synaptic membrane structures than a specific inhibitory transmitter.

Amino Acids↗
PubMed2000

Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease.

Maple syrup urine disease is an inherited metabolic disorder characterized by tissue accumulation of branched-chain amino acids and their corresponding keto acids in the affected children. Although this disorder is predominantly characterized by neurological symptoms, only few studies were carried out to investigate its neuropathology. In this study we investigated the effect of the metabolites accumulating in maple syrup urine disease on the in vitro uptake of [3H]glutamate by synaptic vesicles of rat brain. Synaptic vesicle preparations from whole brain of male adult Wistar rats (200-250 g) were incubated with the branched-chain amino acids and their corresponding keto acids at final concentrations ranging from 0.25 to 10 mM for the determination of glutamate uptake. Glutamate uptake was significantly inhibited by L-leucine, L-isoleucine, L-2-ketoisocaproic acid and L-2-keto-3-methylvaleric acid by approximately 60%, whereas L-valine and L-2-ketoisovaleric acid showed no effect. We also verified that the metabolites probably act by competitive inhibition. Therefore, it is possible that extracellular glutamate levels may be increased in maple syrup urine disease and that excitotoxicity may be involved in the neuropathology of this disorder.

Animals↗
PubMed1983

Number of synaptic vesicles in rat cortex immediately after cessation of the self-sustained afterdischarge during kindling.

The sensorimotor area of rat cerebral cortex was subjected to repetitive electrical stimulation at 10-min intervals; this led to progressive lengthening of self-sustained afterdischarges (SSADs). At 50-60 s after cessation of the third SSAD the brains of the animals were perfused transaortally with fixing fluid, and a quantitative electron microscopic analysis of type I synapses in the second cortical layer of the sensorimotor area of the contralateral hemisphere was carried out. In a zone 0.1 micron wide adjacent to the presynaptic membrane in the active zone, the number of synaptic vesicles (converted to the number per 0.01 micron2 area) in the experimental animals fell by 64.6%. In a zone of the same width 0.1 micron distant from the presynaptic membrane, it fell by 67.6%. The mean absolute synaptic vesicle count per presynaptic bag section fell by 66.6%. The number of synapses showing signs of exocytosis rose in the experimental animals from 3.8 to 5.9%, while the number with clearly demonstrable exocytosis rose from 0.7 to 11.4%. The proportion of synapses with signs of (clearly demonstrable) endocytosis rose from 2.8% (2.1%) in the controls to 7.1% (3.7%) in the experimental rats. In the experimental and control animals we demonstrated complex vesicle formation in 4.3 and 3.8%, respectively, of the synapses and dense-cored vesicles in 7.7 and 2.8%, respectively, of the synapses. We consider changes in the number and formation of synaptic vesicles to be signs of exhaustion of the synapses caused by the previous epileptic seizure, which simultaneously activates mechanisms of vesicle formation.

Animals↗
PubMed1989

A synaptic vesicle membrane protein is conserved from mammals to Drosophila.

The structure of synaptobrevin, an intrinsic membrane protein of small synaptic vesicles from mammalian brain, was studied by purification and molecular cloning. Its message in bovine brain encodes a 116 amino acid protein whose sequence reveals it to be the mammalian homolog of Torpedo VAMP-1. Antibody probing demonstrates that the protein is also present in Drosophila, and its Drosophila homolog was cloned. Alignment of the sequences of synaptobrevin/VAMP-1 from the three species shows it to contain four domains, including a highly conserved central region of 63 amino acids that contains 75% invariant residues. The finding that a membrane protein from vertebrate synaptic vesicles is conserved in Drosophila points toward a central role of this protein in neurotransmission and should allow a genetic approach to neurotransmitter release.

Amino Acid Sequence↗
PubMed1987

Redistribution of synaptic vesicles during long-term potentiation in the hippocampus.

Synaptic vesicles were quantified 20 min after the induction of long-term potentiation (LTP) in the Schaffer-commissural system of the hippocampus. With LTP, significant increases were found in vesicles attached to the active zone membrane, and in the percentage of vesicles adjacent to the active zone. In addition, as others have reported, overall vesicle density was decreased and spine area was increased. These results suggest that an increased probability of vesicle release may contribute to brain LTP.

Animals↗
PubMed1990

Chloride ion increases [3H]dopamine accumulation by synaptic vesicles purified from rat striatum: inhibition by thiocyanate ion.

The effect of chloride ion on the transport of [3H]dopamine into synaptic vesicles purified from rat striatum has been evaluated. The inclusion of 10 mM chloride ion in the incubation medium produced a 100% increase in temperature-sensitive [3H]dopamine uptake into synaptic vesicles from approximately 1800 pmol/mg to 3600 pmol/mg of protein. Half-maximal effects were observed with chloride ion at 4 mM concentration. The anion selectivity of stimulation supports the presence of anion channels within the membranes of dopaminergic storage organelles. Low concentrations of thiocyanate ion (less than 10 mM), 4-acetamido-4'-isothiocyano-2-2'-disulfonic acid stilbene (100 microM), and duramycin (5 micrograms/ml) selectively blocked the chloride ion stimulated accumulation of [3H]dopamine. Higher concentrations of these agents are required to significantly reduce [3H]dopamine uptake in the absence of chloride ion. These results suggest that both components of the proton electrochemical gradient (delta psi and delta pH) are important for dopamine uptake by brain vesicles. This article presents the first demonstration that chloride ion plays a role in the transport of dopamine into vesicles isolated from the CNS.

Animals↗
PubMed1996

Selective depletion of clear synaptic vesicles and enhanced quantal transmitter release at frog motor nerve endings produced by trachynilysin, a protein toxin isolated from stonefish (Synanceia trachynis) venom.

Our previous observation that low concentrations of stonefish (Synanceia trachynis) venom elicit spontaneous quantal acetylcholine release from vertebrate motor nerve terminals prompted our present study to purify the quantal transmitter-releasing toxin present in the venom and to characterize the toxin's ability to alter the ultrastructure and immunoreactivity of frog motor nerve terminals. Fractionation of S. trachynis venom by sequential anion exchange fast protein-liquid chromatography (FPLC) and size-exclusion FPLC yielded a highly purified preparation of a membrane-perturbing (haemolytic) protein toxin, named trachynilysin. Trachynilysin (2-20 micrograms/ml) significantly increased spontaneous quantal acetylcholine release from motor endings, as detected by recording miniature endplate potentials from isolated frog cutaneous pectoris neuromuscular preparations. Ultrastructural analysis of nerve terminals in which quantal acetylcholine release was stimulated to exhaustion by 3 h exposure to trachynilysin revealed swelling of nerve terminals and marked depletion of small clear synaptic vesicles. However, trachynilysin did not induce a parallel depletion of large dense-core vesicles. Large dense core vesicles contained calcitonin gene-related peptide (CGRP), as revealed by colloidal gold immunostaining, and trachynilysin-treated nerve endings exhibited CGRP-like immunofluorescence similar to that of untreated terminals. Our results indicate that the ability of stonefish venom to elicit spontaneous quantal acetylcholine release from vertebrate motor nerve terminals is a function of trachynilysin, which selectively stimulates the release of small clear synaptic vesicles and impairs the recycling of small clear synaptic vesicles but does not affect the release of large dense-core vesicles. Trachynilysin may be a valuable tool for use in other secretory terminals to discriminate between neurotransmitter and neuropeptide release.

Acetylcholine↗
PubMed1998

The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons.

A transporter thought to mediate accumulation of GABA into synaptic vesicles has recently been cloned (McIntire et al., 1997). This vesicular GABA transporter (VGAT), the first vesicular amino acid transporter to be molecularly identified, differs in structure from previously cloned vesicular neurotransmitter transporters and defines a novel gene family. Here we use antibodies specific for N- and C-terminal epitopes of VGAT to localize the protein in the rat CNS. VGAT is highly concentrated in the nerve endings of GABAergic neurons in the brain and spinal cord but also in glycinergic nerve endings. In contrast, hippocampal mossy fiber boutons, which although glutamatergic are known to contain GABA, lack VGAT immunoreactivity. Post-embedding immunogold quantification shows that the protein specifically associates with synaptic vesicles. Triple labeling for VGAT, GABA, and glycine in the lateral oliva superior revealed a higher expression of VGAT in nerve endings rich in GABA, with or without glycine, than in others rich in glycine only. Although the great majority of nerve terminals containing GABA or glycine are immunopositive for VGAT, subpopulations of nerve endings rich in GABA or glycine appear to lack the protein. Additional vesicular transporters or alternative modes of release may therefore contribute to the inhibitory neurotransmission mediated by these two amino acids.

Animals↗
PubMed2003

Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies.

During action potential firing, the rate of synapsin dissociation from synaptic vesicles and dispersion into axons controls the rate of vesicle availability for exocytosis at the plasma membrane. Here we show that synapsin Ia's dispersion rate tracks the synaptic vesicle pool turnover rate linearly over the range 5-20 Hz and that the molecular basis for this lies in regulation at both the calcium-calmodulin-dependent kinase (CaM kinase) and the mitogen-activated protein (MAP) kinase/calcineurin sites. Our results show that CaM kinase sites control vesicle mobilization at low stimulus frequency, while MAP kinase/calcineurin sites are critical at both lower and higher stimulus frequencies. Thus, multiple signaling pathways serve to allow synapsin's control of vesicle mobilization over different stimulus frequencies.

Animals↗
PubMed1978

Chemical composition of cholinergic synaptic vesicles from Torpedo marmorata based on improved purification.

Cholinergic synaptic vesicles from the electric organ of Torpedo marmorata have been purified to a constant composition and a higher transmitter content than previously reported. By optimising the extraction conditions and using a two-step purification on discontinuous and continuous sucrose density gradients, 10-fold higher acetylcholine and ATP values per weight of protein were obtained. The purity of the vesicle preparation was confirmed by electronmicroscopy, absence of marker enzymes, behaviour in density gradient centrifugation, as well as by a specific and reproducible protein composition. Vesicles contain 6.9 mumol acetylcholine and 1.0 mumol ATP per mg protein. The lipid/protein ratio of 3.5 (w/w) indicates a lipid-rich membrane. The value suggests the absence of a proteinaceous core. Upon dodecylsulphate gel electrophoresis a distinct protein pattern is obtained with components ranging from 20000 to 160000 in molecular weight. Vesiculin, reported earlier to be a low-molecular-weight vesicle protein, is not detected. One of the major bands comigrates with muscle actin from the same animal. Further characterisation of this protein by two-dimensional gel electrophoresis suggested that it is an actin-like polypeptide. Evidence for a specific association of this actin-like protein with vesicles and its possible involvement in the neurosecretory process is discussed.

Acetylcholine↗
PubMed2004

Beta-bungarotoxin-induced depletion of synaptic vesicles at the mammalian neuromuscular junction.

The neurotoxic phospholipase A(2), beta-bungarotoxin, caused the failure of the mechanical response of the indirectly stimulated rat diaphragm. Exposure to beta-bungarotoxin had no effect on the response of the muscle to direct stimulation. Resting membrane potentials of muscle fibres exposed to the toxin were similar to control values, and the binding of FITC-labelled alpha-bungarotoxin to nAChR at the neuromuscular junction was unchanged. Motor nerve terminal boutons at a third of cell junctions were destroyed by exposure to beta-bungarotoxin leaving only a synaptic gutter filled with Schwann cell processes and debris. At other junctions, some or all boutons survived exposure to the toxin. Synaptic vesicle density in surviving terminal boutons was reduced by 80% and synaptophysin immunoreactivity by >60% in preparations exposed to beta-bungarotoxin, but syntaxin and SNAP-25 immunoreactivity was largely unchanged. Terminal bouton area was also unchanged. The depletion of synaptic vesicles was completely prevented by prior exposure to botulinum toxin C and significantly reduced by prior exposure to conotoxin omega-MVIIC. The data suggest that synaptic vesicle depletion is caused primarily by a toxin-induced entry of Ca(2+) into motor nerve terminals via voltage gated Ca(2+) channels and an enhanced exocytosis via the formation of t- and v-SNARE complexes.

Acetylcholinesterase↗
PubMed2004

Choline acetyltransferase: regulation and coupling with protein kinase and vesicular acetylcholine transporter on synaptic vesicles.

Both the membrane-bound choline acetyltransferase (MChAT) and soluble ChAT (SChAT) were found to be activated by ATP-mediated protein phosphorylation. ATP activation of MChAT but not SChAT was found to depend on the integrity of proton gradient of synaptic vesicles because conditions disrupting the proton gradient also abolished the activation of MChAT by ATP. Among the kinases studied, Ca2+/calmodulin kinase II is most effective in activation of MChAT. Transport of ACh into synaptic vesicles by vesicular acetylcholine transporter (VAChT) is also proton gradient-dependent; therefore we proposed that there is a functional coupling between ACh synthesis and its packaging into synaptic vesicles. This notion is supported by the following findings: first, the newly synthesized [3H]-ACh from [3H]-choline was taken up much more efficiently than the pre-existing ACh; second, ATP-activation of MChAT was abolished when VAChT was inhibited by the specific inhibitor vesamicol; third, the activity of ChAT was found to be markedly increased when neurons are under depolarizing conditions.

Adenosine Triphosphate↗
PubMed1999

Distribution of synaptic vesicle proteins in the mammalian retina identifies obligatory and facultative components of ribbon synapses.

The mammalian retina contains two synaptic layers. The outer plexiform layer (OPL) is primarily composed of ribbon synapses while the inner plexiform layer (IPL) comprises largely conventional synapses. In presynaptic terminals of ribbon synapses, electron-dense projections called ribbons are present at the synaptic plasma membranes. Ribbons bind synaptic vesicles and guide them to the synaptic membrane for fusion. In this manner, ribbons are thought to accelerate the delivery of vesicles for continuous exocytosis. In recent years, a large number of synaptic proteins has been described but it is not known if these protein colocalize in the same types of synapses. In previous studies, several proteins essential for synaptic function were not detected in ribbon synapses, suggesting that the mechanism of synaptic vesicle exocytosis may be very different in ribbon and conventional synapses. Using confocal laser scanning microscopy, we have now systematically investigated the protein composition of ribbon synapses. Our results show that, of the 19 synaptic proteins investigated, all except synapsin and rabphilin are obligatorily present in ribbon synapses. For example, rab3 which was reported to be absent from ribbon synapses, was found in bovine, rat and mouse ribbon synapses using multiple independent antibodies. In addition, we found staining in these synapses for PSD-95 and NMDA receptors, which suggested a similar design for the postsynaptic component in ribbon and conventional synapses. Our data show that ribbon synapses are more conventional in composition than reported, that most synaptic proteins are colocalized to the same type of synapse, and that synapsin and rabphilin are likely to be dispensible for basic synaptic functions.

Animals↗
PubMed1988

Antibodies against GABA and glutamate label neurons with morphologically distinct synaptic vesicles in the locust central nervous system.

Antibodies raised against GABA and glutamate were used to stain sections through locust thoracic ganglia for light and electron microscopy. Using a peroxidase-antiperoxidase method for light microscopy, the GABA antibody was shown to label inhibitory motor neurons thought to use GABA as their neurotransmitter, and the glutamate antibody to label excitatory motor neurons thought to use glutamate. An immunogold method was used to reveal labelled neuropilar processes in the electron microscope. Each antibody specifically labels a particular population of processes. With the GABA antibody, labelling is equally clear whether the processes concerned contain synaptic vesicles or not and is strongly contrasted against very low background levels. With the glutamate antibody, most processes show some affinity for the antibody, probably reflecting the presence of metabolic glutamate, however one population can be clearly distinguished by the presence of a much greater density of gold particles over synaptic vesicles. In the locust it appears, therefore, that the antibody can distinguish clearly between the metabolic and neurotransmitter pools of glutamate. It has been proposed that synaptic vesicles in GABAergic neurons have a different shape to those in glutamatergic neurons. This was supported by the electron microscope immunocytochemistry. Those showing GABA-like immunoreactivity contain predominantly pleomorphic agranular vesicles approximately 21 x 30 nm in diameter. Those showing glutamate-like immunoreactivity contain round agranular vesicles of about 38 nm in diameter. The GABA antibody appears to label all processes containing pleomorphic agranular vesicles. By contrast, some processes containing round agranular vesicles are not labelled by the glutamate antibody, even though the vesicles they contain are statistically identical in size to those in labelled profiles. With neither antibody was the labelling of glial cells greater than the background level.

Animals↗
PubMed1989

[Inhibition by local anesthetics and barbiturates of the active transport of H+ in the synaptic vesicle membranes of the brain].

The effects of local anesthetics and barbiturates on the ATP-dependent H+ transport in synaptic vesicle membranes from rat brain were studied using a fluorescent probe, acridine orange. Local anesthetics depressed the active H+ transport with the following order of potencies: tetracaine trimecaine lidocaine procaine. Respective IC50 values were 0.07, 0.28, 0.46 and 0.60 mM. The local anesthetics also disrupted the endogenous pH gradient seen in the absence of ATP. Barbiturates inhibited the active H+ transport showing IC50 values in the range of 2-5 mM except for benzobarbital and barbital characterized by IC50 values of 0.5 and 20 mM, respectively. The order of potencies was benzobarbital hexobarbital amobarbital pentobarbital phenobarbital barbital. The endogenous pH gradient was not affected by the barbiturates. The results show that local anesthetics disrupt the H+ transport by acting as permeable weak bases (uncouplers) whereas barbiturates are likely to block and anion channel which maintains electroneutrality of the H+ transport in the membrane of synaptic vesicles.

Acridine Orange↗