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PubMed1993

A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs.

A human vesicular monoamine transporter cDNA has been identified by screening a human brainstem library using sequences from the rat brain synaptic vesicle monoamine transporter (SVMT) [(1992) Cell 70, 539-551; (1992) Proc. Natl. Acad. Sci. USA 89, 10993-10997]. The hSVMT shares 92% amino acid identity with the rat sequence, but displays one less consensus site for asparagine N-linked glycosylation and one more consensus site for phosphorylation by protein kinase C. The human SVMT gene maps to chromosome 10q25 using Southern blotting analysis of human/rodent hybrid cell lines and fluorescent in situ hybridization approaches. The cDNA, and a subclone, recognize TaqI polymorphisms that may prove useful to assess this gene's involvement in neuropsychiatric disorders involving monoaminergic brain systems.

Amino Acid Sequence↗
PubMed1987

Synaptic vesicles in electromotoneurones. II. Heterogeneity of populations is expressed in uptake properties; exocytosis and insertion of a core proteoglycan into the extracellular matrix.

The three populations of synaptic vesicles in electromotor nerve terminals were analysed quantitatively. Empty vesicles (VP0), fully charged vesicles (VP1) and charged but smaller VP2-type vesicles are present in approximately equal amounts in the nerve terminal. The populations show differences in the kinetics of in vitro uptake of acetylcholine, ATP and Ca2+. VP0 and VP2 accumulate acetylcholine and ATP but no Ca2+, whereas VP1 shows negligible acetylcholine and ATP but high Ca2+ uptake. Thus the expression of uptake properties of this secretory organelle depend on the stage it has reached in its life cycle and might constitute a signal for processing. VP2 was found to contain much less core proteoglycan than VP0 and VP1 indicating that part of it has been lost by exocytosis. In synaptic extracellular matrix containing fractions an antigen is detectable that cross-reacts with an antiserum against the vesicle proteoglycan. This material elutes upon gel filtration in a position similar to a smaller form of proteoglycan found in vesicles. We conclude that the electromotor nerve terminal releases a proteoglycan by the regulated secretory pathway that is deposited in the extracellular matrix. It might have a function in keeping pre- and postsynaptic structures in alignment constituting a transsynaptic signal. Based on the findings described, a model of the vesicles' life-cycle is discussed, whereby the VP2 population is the major source of quantal release of acetylcholine.

Animals↗
PubMed1977

A newly designed decantation for purified synaptic vesicle.

A new decanting device of fine stainless steel needles has been developed, which can remove a layer from a gradient with little contamination from the adjacent upper or lower layers. This new apparatus can be used for removal of a very narrow band from a density gradient and has been successfully used in the fractionation of synaptic vesicles from brain homogenates.

Cell Separation↗
PubMed1996

Synaptic vesicle biogenesis, docking, and fusion: a molecular description.

Secretion of neurotransmitter is the primary means of intercellular communication within the nervous system. This process is regulated by a highly orchestrated cycle of membrane trafficking within the presynaptic nerve terminal. Characterization of proteins localized to the synaptic vesicle and the subsequent studies of their properties have led to a model for the biochemical pathway that underlies vesicle docking, activation, and fusion. The proteins found to function in the synapse are related to those in yeast and other organisms, demonstrating that the mechanisms that mediate vesicle trafficking are conserved in all eukaryotic species.

Animals↗
PubMed2005

The effect of psychostimulants on [3H]dopamine uptake and release in rat brain synaptic vesicles.

Amphetamine and its derivatives are psychostimulants active at the plasma membrane monoamine transporters. In the present study we assessed the interaction of parachloroamphetamine, D-amphetamine, fenfluramine and methylendioxymethamphetamine with brain vesicular monoamine transporter using purified rat striatal synaptic vesicles. All four psychostimulants inhibited vesicular [(3)H]dopamine uptake in a competitive and dose-dependent manner and had no effect on [(3)H]dihydrotetrabenazine binding. At higher concentrations the drugs enhanced [(3)H]dopamine vesicular efflux. Parachloroamphetamine was the most potent agent while methylendioxymethamphetamine was the weakest one. The vesicular activities may be relevant to their neurotoxicity.

Animals↗
PubMed1972

The isolation of pure cholinergic synaptic vesicles from the electric organs of elasmobranch fish of the family Torpedinidae.

1. Zonal centrifuging permitted the separation, on the milligram scale and in a form largely free from contamination by soluble cytoplasmic protein or membrane fragments derived from other structures, of synaptic vesicles from the purely cholinergic terminals of the electric organ of Torpedo. Up to 100g of tissue could be processed in a single run. 2. As much as 46% of the bound acetylcholine from the original tissue preparation was recovered as a single peak of density equivalent to 0.38m-sucrose-0.21m-NaCl and with a concentration of up to 680nmol of acetylcholine/mg of protein. 3. The limiting concentration of acetylcholine in isolated vesicles when allowance had been made for non-vesicular protein appeared to be about 600nmol/mg of protein. 4. Vesicle counts by a ;bead-tagging' procedure indicated an acetylcholine content of about 360mumol/ml of vesicles; thus the vesicle protein content would be about 60% (w/v). 5. Calculations showed that the core of the vesicle, accounting for about 55% of the vesicle volume, could be largely filled with acetylcholine and protein.

Acetylcholine↗
PubMed1987

Deafferentation-induced increases in a synaptic vesicle protein in the adult rat superior cervical ganglion are associated with new protein synthesis.

Previous studies have shown that deafferentation of the adult rat superior cervical ganglion results in a transient increase in levels of a 65 kDa synaptic vesicle membrane protein (SV). The present study indicates that the observed increase in SV after deafferentation is the result of new protein synthesis. Treatment with cycloheximide, a protein synthesis inhibitor, for 8 h at selected times after surgery produces decreases in SV which are greater than that observed after treatment of unoperated animals. The results suggest that an increased rate of synthesis of this protein is induced by deafferentation. Transsynaptic factors may play important roles in regulation of protein synthesis in sympathetic ganglia.

Afferent Pathways↗
PubMed2005

Lipid regulation of the synaptic vesicle cycle.

Membrane vesicle cycling is orchestrated through the combined actions of proteins and lipids. At neuronal synapses, this orchestration must meet the stringent demands of speed, fidelity and sustainability of the synaptic vesicle cycle that mediates neurotransmission. Historically, the lion's share of the attention has been focused on the proteins that are involved in this cycle; but, in recent years, it has become clear that the previously unheralded plasma membrane and vesicle lipids are also key regulators of this cycle. This article reviews recent insights into the roles of lipid-modifying enzymes and lipids in the acute modulation of neurotransmission.

Animals↗
PubMed1988

Synaptic vesicle redistribution during hippocampal frequency potentiation and depression in young and aged rats.

Technical complexities associated with studies of defined synapses in the mammalian CNS have made it difficult to determine whether CNS synaptic vesicles respond to repetitive monosynaptic activation in the same ways as do PNS vesicles. Moreover, even in the PNS, the specific ultrastructural correlates of short-term synaptic potentiation are not well characterized. In the present studies, therefore, the Schaffer collateral-commissural fiber projection to field CA1 of the hippocampus was used as a model brain system in which to assess quantitative relations between dynamic vesicle patterns and frequency potentiation and depression. Anesthetized rats were perfused with aldehyde fixative during stimulation trains and concomitant microelectrode recording in order to study temporal correlations between physiology and synaptic structure. In addition, young and aged animals were compared to determine whether there are ultrastructural correlates of a previously described age-related impairment of hippocampal frequency potentiation. After 1 min of 10 Hz synaptic stimulation (stim), frequency potentiation of the population spike was correlated with increases in local vesicles (LV; within 150 nm of the active zone) and in vesicles directly apposed (AV) to the active zone membrane of CA 1 synapses. In addition, the ratio LVD: DVD of local-to-distant vesicle (DV; beyond 150 nm) densities was increased under all stimulation conditions. After 10 min of 10 Hz stim, or 1 min of 40 Hz stim, some vesicle depletion (approximately 25%) was present, as was some spike depression or decline from peak potentiation. However, LV depletion was not well correlated with degree of spike depression. Mean dendritic spine area was also increased in association with potentiation (at 1 min of 10 Hz stim) in young rats. Membrane infoldings similar to the cisternae described in other systems were seen with repetitive stimulation, providing evidence of vesicle recycling in these CNS terminals. In comparison to young control animals, terminals in non-stimulated aged group control rats exhibited a higher LVD:DVD ratio and a reduced DVD. In addition, the stimulation-induced increase in AV at 1 min of 10 Hz stim was not present in aged rat synapses. However, no age-related differences in vesicle-density measures were found at any stimulation point.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1993

Optical monitoring of transmitter release and synaptic vesicle recycling at the frog neuromuscular junction.

1. Frog cutaneous pectoris motor nerve terminals were loaded with the fluorescent dye FM1-43, which produced a series of discrete spots along the length of terminals, each spot evidently marking a cluster of synaptic vesicles. Terminals were imaged for 2-10 min as they destained during repetitive nerve stimulation. Endplate potentials (EPPs) were recorded simultaneously from the muscle fibres innervated by these terminals; their summed amplitudes provided a measure of cumulative transmitter release. 2. Individual fluorescent spots in any one terminal varied in initial brightness but destained at similar fractional rates. 3. The rates of cumulative transmitter release and destaining increased with stimulus frequency in the range 2-30 Hz. At 40 Hz, however, both transmitter release and destaining were slower than at 30 Hz. 4. In twenty-six experiments, rates of dye loss and transmitter release were compared quantitatively. When the time course of summed EPPs was scaled to fit the time course of dye loss during the first 30-60 s of destaining, the two curves usually diverged at later times, the dye loss curve falling below the summed EPP curve. Thus, assuming that dye loss and transmitter release are proportional at early times, at later times the rate of dye loss decreases relative to the rate of transmitter release. 5. At stimulus frequencies from 2 to 30 Hz, the results could be fitted by a simple model in which vesicles lose their dye during exocytosis and, after a fixed recycle 'dead time', they re-enter the vesicle pool, mixing randomly with other vesicles. 6. Unlike stimulation at lower frequencies, at 40 Hz dye loss and summed EPP amplitude curves did not significantly diverge. Stimulation periods lasted up to about 2 min. Interpreted according to the model of vesicle recycling, this suggests that vesicle recycling is inhibited at 40 Hz. 7. The model led to predictions about the relative number, N, of vesicles (labelled and unlabelled) in the terminal at any time during stimulation. The calculated value of N decreased at times less than the recycle 'dead time', and then increased, reflecting the appearance of recycled vesicles in the vesicle pool. 8. From estimates of N and recorded EPP amplitudes, the fraction of vesicles released per shock, F, could be calculated during the entire stimulation period. At low stimulus frequencies (2-5 Hz), after an initial rapid fall, F decreased slowly and monotonically by about 50% in 6 min. At higher stimulus frequencies, a different process was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Optical detection of synaptic vesicle exocytosis and endocytosis.

Recent advances in optical methods have catalyzed a detailed study of individual visualized synapses in several model systems. Quantal events at small central synapses, as well as single granule exocytosis in secretory cells, have been detected using quantitative fluorescence imaging. Sensitive detection of exocytosis and endocytosis at individual synapses has advanced our knowledge of synaptic vesicle trafficking.

Animals↗
PubMed2004

Ceramidase regulates synaptic vesicle exocytosis and trafficking.

A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed (slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed embryos with severely reduced movement. The SLAB protein is widely expressed in different tissues but enriched in neurons at all stages of development. Targeted neuronal expression of slab rescues mutant lethality, demonstrating the essential neuronal function of the protein. C(5)-ceramide applied to living preparations is rapidly accumulated at neuromuscular junction (NMJ) synapses dependent on the SLAB expression level, indicating that synaptic sphingolipid trafficking and distribution is regulated by SLAB function. Evoked synaptic currents at slab mutant NMJs are reduced by 50-70%, whereas postsynaptic glutamate-gated currents are normal, demonstrating a specific presynaptic impairment. Hypertonic saline-evoked synaptic vesicle fusion is similarly impaired by 50-70%, demonstrating a loss of readily releasable vesicles. In addition, FM1-43 dye uptake is reduced in slab mutant presynaptic terminals, indicating a smaller cycling vesicle pool. Ultrastructural analyses of mutants reveal a normal vesicle distribution clustered and docked at active zones, but fewer vesicles in reserve regions, and a twofold to threefold increased incidence of vesicles linked together and tethered at the plasma membrane. These results indicate that SLAB ceramidase function controls presynaptic terminal sphingolipid composition to regulate vesicle fusion and trafficking, and thus the strength and reliability of synaptic transmission.

Animals↗
PubMed1985

The effect of nerve activity on the distribution of synaptic vesicles.

Certain gymnotid fish (apteronotids) continuously emit a high-frequency electric-organ discharge and thus continuously drive their electroreceptor afferents at high rates. Electroreceptor afferents terminate in one lamina of the electrosensory lateral line lobe (ELL) and can be readily sampled. Normally these terminals have many small vesicles clustered adjacent to the presynaptic membrane. When afferent activity is blocked for 24 hr by an injection of tetrodotoxin (TTX) into the electroreceptor nerve, the density of vesicles adjacent to the synaptic membrane declines; the volume of the remaining vesicles increases. If the nerve of a TTX-treated fish is stimulated proximal to the injection site, these changes can be reversed. These results imply that the migration of vesicles toward the presynaptic membrane is influenced by the level of activity in the nerve.

Animals↗
PubMed1988

Synaptic vesicle relationships with the presynaptic membrane as shown by a new method of fast chemical fixation.

Brief vascular perfusion of the rat brain with a mixture of concentrated aldehydes completely insolubilized the brain protein in less than 30 s and yielded excellent ultrastructural preservation. Abundant synaptic vesicles closely and specifically attached to the presynaptic membrane were constantly detected. These vesicles appeared to undergo progressive transformation into amorphous, electron-dense material. No evidence of vesicle exocytosis was detected in the brains perfused in vivo but fixations performed 1 h after death showed abundant exocytotic-like images. The results suggest that the vesicles may not be exocytotically released to the intersynaptic cleft but disintegrate intracytoplasmically in the immediate vicinity of the presynaptic membrane.

Animals↗
PubMed2001

Effect of polychlorinated biphenyls on the uptake of dopamine into rat brain synaptic vesicles: a structure-activity study.

PCBs are neurotoxic compounds that have a known effect on the dopaminergic system in the brain. In a previous work it was established that PCBs are potent inhibitors of the uptake of dopamine into rat brain synaptic vesicles. In this work we further investigated the vesicular dopamine uptake in response to different PCBs to explore the structure-activity relationship involved in this effect. Twenty PCB congeners were selected, based on multivariate chemical characterization, to cover the chemical variation within tetra- to hepta-chlorinated PCBs. PCBs of large structural variation were tested and the general finding was that only the ortho-substituted PCBs inhibited the dopamine uptake. The most active congeners were the penta- and hexa-chlorinated PCBs. Furthermore, the uptake was correlated with parameters describing the absolute hardness, the octanol-water partition coefficient, and the Henry's law constant. These parameters are correlated to the number of chlorine atoms in ortho positions and to the size of the molecule. Notably the most active PCBs are highly prevalent in the environment and are disposed to bioaccumulate in wildlife. Thus, these neurotoxic effects should be included in the risk assessment of PCBs.

Animals↗
PubMed2000

Binding of Rab3A to synaptic vesicles.

Prenylated Rab GTPases cycle between membrane-bound and soluble forms. Membrane-bound GDP-Rabs interact with GDP dissociation inhibitor (GDI), resulting in the dissociation of a Rab.GDI complex, which in turn serves as a precursor for the membrane re-association of Rabs. We have now characterized the binding of Rab3A to synaptic vesicles in vitro using either purified complexes or rat brain cytosol as source for GDI.Rab3A. Binding of Rab3A results in the immediate release of GDI from the membrane. Furthermore, binding does not require the presence of additional guanine nucleotides (GDP or GTP) or of cytosolic factors. Although nucleotide exchange follows binding, binding is initially reversible, suggesting that binding of GDP-Rab3A and nucleotide exchange are separate and independent events. Comparison with the binding of Rab1B revealed that both Rab proteins bind preferentially to their respective resident membranes although some promiscuity was observable. Binding is saturable and involves a protease-sensitive binding site that is tightly associated with the vesicle membrane.

Animals↗
PubMed1991

Inhibition of gamma-aminobutyrate and glycine uptake into synaptic vesicles.

The substrate specificity of vesicular GABA and glycine uptake was studied in vesicle fractions from brain and spinal cord, respectively. Glycine, beta-alanine and gamma-vinyl-GABA were competitive inhibitors of the GABA uptake were competitive inhibitors of the GABA uptake by synaptic vesicles in brain. Likewise GABA and beta-alanine turned out to be competitive inhibitors of vesicular uptake of glycine in spinal cord. The apparent K1 values were in the same range as the respective Km values for the transport systems. Accumulation of different amino acids were examined, and the structurally related amino acids GABA, beta-alanine and glycine were all taken up by both vesicle fractions. In the present study, we suggest that there are similarities in the vesicular transporters for GABA and glycine, and the two amino acids are probably taken up into the same vesicle population. The key factor in differentiating between GABA and glycine as transmitters in the terminals could be the synthesis and the high-affinity synaptosomal uptake.

Alanine↗
PubMed1979

Isolation of synaptosomal plasma membranes from cholinergic nerve terminals and a comparison of their proteins with those of synaptic vesicles.

Plasma membranes were purified from purely cholinergic nerve endings (synaptosomes) isolated from the electric organ of Torpedo marmorata. Synaptosomes were lysed, membranes recovered and further separated by density gradient centrifugation. A fraction was obtained enriched in 5'-nucleotidase, Na+, K+-activated ATPase and acetylcholine esterase. Morphological examination showed abundant membrane fragments of the size range of synaptosomes and few of vesicle size. The fraction has a characteristic protein composition upon gel electrophoresis. Five reproducible major bands with apparent Mr of 100000, 75000, 52000, 42000 and 35000--33000 are found. A gel-electrophoretic comparison with proteins from synaptic vesicles from the same source (major bands Mr 160000, 147000, 34000 and 25000) was made. Comigration of major bands was detected in one-dimensional gel electrophoresis with the 42000-Mr, 35000--33000-Mr and 34000-Mr components. Upon two-dimensional gel electrophoresis the 42000-Mr component comigrates with a similar component in vesicles, recently characterized as actin; the other components are different. The presence of tubulin-like polypeptides is unlikely. Beside actin, all major vesicle proteins are often detected in small amounts in the plasma membrane preparation. It cannot be decided if they result from fused or contaminating vesicle membranes, but since they are essentially absent in some preparations, it seems that the plasma membrane does not contain vesicle proteins.

Animals↗