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PubMed1985

Measurement of quantal secretion induced by ouabain and its correlation with depletion of synaptic vesicles.

Ouabain (0.1 and 0.05 mM) was applied to frog cutaneous pectoris nerve-muscle preparations bathed in modified Ringer's solution containing either 1.8 mM Ca2+ (and 4 mM Mg2+) or no added Ca2+ (4 mM Mg2+ and 1 mM EGTA). During the intense quantal release of acetylcholine (ACh) induced by ouabain, the parameters of the miniature endplate potentials (mepps) were deduced from the variance, skew, and power spectra of the endplate recordings by applying a recently described modification of classical fluctuation analysis. Often the high frequency of mepps is not stationary; therefore, the signal was high-pass filtered (time constant of the resistance-capacitance filter of 2 ms) to remove the errors introduced by nonstationarity. When ouabain was applied in the presence of Ca2+, mepp frequency started to rise exponentially after a lag of 1.5-2 h, reached an average peak frequency of 1,300/s in approximately 30 min, and then suddenly subsided to low level (10/s). In Ca2+-free solution, after a shorter lag (1-1.5 h), mepp frequency rose to peak rate of 700/s in approximately 20 min and then gradually subsided. In spite of the different time course of secretion in the two experimental conditions, the cumulative quantal release was not significantly different (7.4 +/- 1.3 X 10(5) in Ca2+-containing and 8.8 +/- 2.7 X 10(5) in Ca2+-free solutions). 60 min after the peak secretion, the muscles were fixed for observation in the electron microscope. Morphometric analysis on micrographs of neuromuscular junctions revealed in both cases a profound depletion of synaptic vesicles and deep infoldings of presynaptic membrane. This rapid depletion and the lack of uptake of horseradish peroxidase suggest that ouabain impairs the recycling process that tends to conserve the vesicle population during intense secretion of neurotransmitter. The good correlation observed between the reduction in the store of synaptic vesicles and the total number of quanta of ACh secreted in the absence of a vigorous membrane recycling strongly supports the view that the secretion of a quantum of ACh requires the fusion of a synaptic vesicle with the axolemma.

Acetylcholine↗
PubMed1987

Differentiation of the cerebellar granule cell: expression of a synaptic vesicle protein and the microtubule-associated protein MAP1A.

The expression of the microtubule-associated protein MAP1A and the synaptic vesicle protein p65 by rat cerebellar granule cells developing in vivo and in vitro was examined. MAP1A in common with a series of previously described cytoskeletal proteins was present in immature parallel fibres and began to disappear from parallel fibres around P15. From the earliest age (P6) at which the molecular layer could be identified parallel fibres throughout the molecular layer expressed p65 with no evidence of any gradient of expression from young to mature axons. Granule cells in culture did not express p65 until later than 1 day in vitro. By 7 days in vitro numerous p65 containing varicosities were present on granule cell processes though MAP1A was still expressed. The results show that transport of synaptic vesicles and formation of varicosities is an early event in granule cell differentiation and precedes a major reorganisation of the axonal cytoskeleton.

Animals↗
PubMed1994

A post-docking role for synaptobrevin in synaptic vesicle fusion.

We have used the squid giant synapse to determine the role of synaptobrevin, integral membrane proteins of small synaptic vesicles, in neurotransmitter release. The sequence of squid synaptobrevin, deduced by cDNA cloning, is 65%-68% identical to mammalian isoforms and includes the conserved cleavage site for tetanus and botulinum B toxins. Injection of either toxin into squid nerve terminals caused a slow, irreversible inhibition of release without affecting the Ca2+ signal which triggers release. Microinjection of a recombinant protein corresponding to the cytoplasmic domain of synaptobrevin produced a more rapid and reversible inhibition of release, whereas two smaller peptide fragments were without effect. Electron microscopy of tetanus-injected terminals revealed an increased number of both docked and undocked synaptic vesicles. These data indicate that synaptobrevin participates in neurotransmitter release at a step between vesicle docking and fusion.

Amino Acid Sequence↗
PubMed1999

Proteins involved in synaptic vesicle trafficking.

Neurotransmitter release relies on a series of synaptic vesicle trafficking reactions. We have determined the molecular basis of these reactions by microinjecting, into 'giant' nerve terminals of squid, probes that interfere with presynaptic proteins. These probes affect neurotransmitter release and disrupt nerve terminal structure. From the nature of these lesions, it is possible to deduce the roles of individual proteins in specific vesicle trafficking reactions. This approach has revealed the function of more than a dozen presynaptic proteins and we hypothesize that neurotransmitter release requires the coordinated action of perhaps 50-100 proteins.

Animals↗
PubMed1993

Transient increase of calcium in synaptic vesicles after stimulation.

Function-dependent changes of calcium distribution were studied in the nerve-electroplaque synapses of Torpedo marmorata before and after the transmission of a nerve impulse. For the cytochemical demonstration of calcium at the ultrastructural level the oxalate-pyroantimonate technique was combined with electron spectroscopic imaging. Cholinergic synapses of the electric organ were stimulated in the presence of 4-aminopyridine, a drug which powerfully potentiates transmitter release. A single stimulus evoked a giant electrical discharge, which was followed by a long refractory period. Calcium cytochemistry was performed by fixing the tissue at four well defined functional states: (i) before and (ii) immediately after the giant discharge, and (iii) at 1 min or (iv) at 30 min of subsequent rest, corresponding to partial and complete functional recovery, respectively. In the non-stimulated synapses about 20% of synaptic vesicles contained small electron-dense precipitates. The element specific mapping by electron spectroscopic imaging clearly showed that calcium was present in the vesicular granules. The volume density of synaptic vesicles did not change among the four experimental states, but we detected a significant increase in the proportion of calcium containing vesicles at 1 min after the giant discharge. The vesicular calcium accumulation was transient: it returned to the control value at the end of the recovery period. Our data suggest that the synaptic vesicles play a role in sequestering the excess calcium which enters the nerve terminal during stimulation.

4-Aminopyridine↗
PubMed1998

NSF function in neurotransmitter release involves rearrangement of the SNARE complex downstream of synaptic vesicle docking.

The SNARE hypothesis has been proposed to explain both constitutive and regulated vesicular transport in eukaryotic cells, including release of neurotransmitter at synapses. According to this model, a vesicle targeting/docking complex consisting primarily of vesicle- and target-membrane proteins, known as SNAREs, serves as a receptor for the cytosolic N-ethylmaleimide-sensitive fusion protein (NSF). NSF-dependent hydrolysis of ATP disassembles the SNARE complex in a step postulated to initiate membrane fusion. While features of this model remain tenable, recent studies have challenged fundamental aspects of the SNARE hypothesis, indicating that further analysis of these components is needed to fully understand their roles in neurotransmitter release. We have addressed this issue by using the temperature-sensitive Drosophila NSF mutant comatose (comt) to study the function of NSF in neurotransmitter release in vivo. Synaptic electrophysiology and ultrastructure in comt mutants have recently defined a role for NSF after docking in the priming of synaptic vesicles for fast calcium-triggered fusion. Here we report that an SDS-resistant neural SNARE complex, composed of the SNARE polypeptides syntaxin, n-synaptobrevin, and SNAP-25, accumulates in comt mutants at restrictive temperature. Subcellular fractionation experiments indicate that these SNARE complexes are distributed predominantly in fractions containing plasma membrane and docked synaptic vesicles. Together with the electrophysiological and ultrastructural analyses of comt mutants, these results indicate that NSF functions to disassemble or otherwise rearrange a SNARE complex after vesicle docking and that this rearrangement is required to maintain the readily releasable pool of synaptic vesicles.

Adenosine Triphosphatases↗
PubMed1979

ZIO staining in synaptic vesicles of the rat pineal nerves after inhibition of serotonin and noradrenaline synthesizing enzymes.

Two compartments have been defined in monoaminergic synaptic vesicles: the core or central compartment, storage site for monoamines, and the matrix or outer compartment, of unknown function. The outer compartment reacts with the mixture of zinc iodide-osmium tetroxide (ZIO). This reaction is temperature and time dependent and may be abolished by -SH reagents. The effect of drugs inhibiting the synthesis of serotonin and noradrenaline (stored in the core) on the ZIO reaction in the matrix was studied in synaptic vesicles of rat pineal nerves. The inhibitors of monoamine synthesis abolish or decrease the ZIO reaction directly or in combination with the administration of tyramine. This effect is temperature dependent suggesting that the drugs act on different components of the matrix that react with ZIO at different temperatures. A comparison of the present results with those obtained with -SH reagents seems to indicate that the drugs assayed act, at least in part, by changing the accessibility of -SH groups in vesicle proteins. (An abstract of this paper was presented at the 7th International Congress of Pharmacology, Paris, 1978.)

Animals↗
PubMed1996

Distributions of two homologous synaptic vesicle proteins, synaptoporin and synaptophysin, in the mammalian retina.

Synaptophysin and synaptoporin are homologous proteins that are among the most abundant synaptic vesicle proteins. Despite their high degree of sequence similarity, they are differentially distributed in the brain. The distribution of synaptophysin and synaptoporin was examined in the adult rat and rabbit retina by using single- and double- labeling immunocytochemistry with conventional light microscopy and confocal laser scanning microscopy. In the rat retina, synaptophysin immunoreactivity was found in the outer plexiform layer in terminals of photoreceptors and was homogeneously distributed throughout the inner plexiform layer. Synaptoporin immunoreactivity, however, was restricted to the inner plexiform layer. Labeling was most prominent in three distinct bands of the inner plexiform layer separated by two bands of very low synaptoporin immunoreactivity. In the rabbit retina, synaptophysin and synaptoporin immunoreactivity were found in the inner and outer plexiform layers. In the inner plexiform layer, labeling for both vesicle proteins was homogeneous, with no detectable stratification. In the outer plexiform layer, synaptophysin was present in photoreceptor terminals, and synaptoporin was present in horizontal cells. Staining of isolated rabbit retinal cells confirmed that both the axonless A type and the axon-bearing B type horizontal cells are immunoreactive for synaptoporin. In addition, electron microscopy of synaptoporin-immunostained rabbit retinas revealed no labeling of photoreceptor terminals but of putative synaptic sites in horizontal cells in the outer plexiform layer. No functional correlation was found in the expression of either synaptic vesicle protein with the type of neuron or synapse (ribbon or conventional).

Animals↗
PubMed1990

Mapping of a dominant immunogenic region of synaptophysin, a major membrane protein of synaptic vesicles.

Synaptophysin is a major integral membrane protein of synaptic vesicles. Its transmembrane topology deduced from the cDNA sequence predicts 4 transmembrane regions and a carboxy-terminal cytoplasmic tail containing a characteristic pentapeptide repeat structure. The monoclonal antibody (mAb), SY38, binds to a cytoplasmic domain of synaptophysin. By using fusion proteins corresponding to truncated forms of the cytoplasmic tail, its epitope was located to a flexible segment in the center of the repeat structure. Four other mAbs (c7.1, c7.2, c7.3, c7.4) share the same epitope, which thus emerges as the major immunogenic region of this membrane protein.

Amino Acid Sequence↗
PubMed1996

Regulation of glutamate transport into synaptic vesicles by chloride and proton gradient.

Glutamate uptake into synaptic vesicles is driven by an electrochemical proton gradient formed across the membrane by a vacuolar H+-ATPase. Chloride has a biphasic effect on glutamate transport, which it activates at low concentrations (2-8 mM) and inhibits at high concentrations (>20 mM). Stimulation with 4 mM chloride was due to an increase in the Vmax of transport, whereas inhibition by high chloride concentrations was related to an increase in Km to glutamate. Both stimulation and inhibition by Cl- were observed in the presence of A23187 or (NH4)2SO4, two substances that dissipate the proton gradient (deltapH). With the use of these agents, we show that the transmembrane potential regulates the apparent affinity for glutamate, whereas the deltapH antagonizes the effect of high chloride concentrations and is important for retaining glutamate inside the vesicles. Selective dissipation of deltapH in the presence of chloride led to a significant glutamate efflux from the vesicles and promoted a decrease in the velocity of glutamate uptake. The H+-ATPase activity was stimulated when the deltapH component was dissipated. Glutamate efflux induced by chloride was saturable, and half-maximal effect was attained in the presence of 30 mM Cl-. The results indicate that: (i) both transmembrane potential and deltapH modulate the glutamate uptake at different levels and (ii) chloride affects glutamate transport by two different mechanisms. One is related to a change of the proportions between the transmembrane potential and the deltapH components of the electrochemical proton gradient, and the other involves a direct interaction of the anion with the glutamate transporter.

Ammonium Sulfate↗
PubMed1997

GABA(B)-mediated presynaptic inhibition of excitatory transmission and synaptic vesicle dynamics in cultured hippocampal neurons.

Local recycling of synaptic vesicle membrane at nerve terminals is necessary to maintain a readily releasable pool of transmitter. To what extent are the dynamics of vesicle recycling subject to modulation? We examined the influence of presynaptic GABA(B) receptors on vesicle dynamics at single synapses using optical imaging of FM1-43 in cultured rat hippocampal neurons. The kinetics of FM1-43 destaining indicate that synapses from a single neuron have a unimodal distribution of release probabilities, and GABA(B)-mediated inhibition occurs uniformly at all sites. Electrical and optical recordings from single cells show that the inhibition of excitatory transmission is entirely accounted for by a rapidly reversible reduction of exocytosis. In contrast, GABA(B) receptors do not alter the rate or extent of endocytosis.

2-Amino-5-phosphonovalerate↗
PubMed1988

[Electrogenic character of the functioning of H+-ATPase of synaptic vesicles in the rat brain].

Transmembrane potential (TMP) of synaptic vesicles (SV) from the rat brain was registered by means of potential-sensitive fluorescent probe 3,3' dipropylthiocarbocyanine iodide (dis-C3-(5)). It was found that Mg-ATP generates TMP on the SV membrane suspended in sucrose-buffer medium. TMP did not appear if 0.25 M sucrose medium was replaced by 0.125 M KCl medium or 0.125 NaCl medium, or if the SV membrane was disrupted by triton X-100 or alamethicin, or if there was protonophore m-chlorophenylhydrazone or N-ethylmaleimide influence on SV. The data obtained indicate that functioning of SV proton pump is electrogenic and the level of TMP depends on the presence of anion Cl- in the incubation medium.

Adenosine Triphosphate↗
PubMed1998

Control of the calcium concentration involved in acetylcholine release and its facilitation: an additional role for synaptic vesicles?

2,5-Diterbutyl-1,4-benzohydroquinone, a specific blocker of Ca2+-ATPase pumps, increased acetylcholine release from an identified synapse of Aplysia, as well as from Torpedo and mouse caudate nucleus synaptosomes. Because 2,5-diterbutyl-1,4-benzohydroquinone does not change the presynaptic Ca2+ influx, the enhancement of acetylcholine release could be due to an accumulation of Ca2+ in the terminal. This possibility was further checked by studying the effects of 2,5-diterbutyl-1,4-benzohydroquinone on twin pulse facilitation, classically attributed to residual Ca2+. While preventing the fast sequestration of Ca2+ by presynaptic organelles, 2,5-diterbutyl-1,4-benzohydroquinone magnified both twin pulse facilitation observed under low extracellular Ca2+ concentration and twin pulse dysfacilitation observed under high extracellular Ca2+ concentration. Thus, it is concluded that 2,5-diterbutyl-1,4-benzohydroquinone, by preventing Ca2+ buffering near transmitter release sites, modulates acetylcholine release. As 2,5-diterbutyl-1,4-benzohydroquinone was also shown to decrease by 50% the uptake of 45Ca2+ by isolated synaptic vesicles, we propose that synaptic vesicles can control the presynaptic Ca2+ concentration triggering the release of neurotransmitter.

Acetylcholine↗
PubMedDate not supplied

[Neuromediator content in the synaptic vesicles of rat adrenergic nerves in some pharmacological actions].

Cytochemical electron microscopy was employed to study the content of neurotransmitters in the synaptic vesicles of adrenergic nerve fibers of Vas deferens of the rat following depletion of the meadiator's reserves by tyramine and subsequent accumulation of exogenous norepinephrine. Subject to investigation was also the effect of antidepressants (phthoracizine and imipramine) on the accumulation of exogenous norepinephrine in the synaptic vesicles. Phthoracizine and imipramine (1 and 10 gamma/ml) are shown to block the acculation of norepinephrine in the vesicles, when the mediator is introduced in a concentration of 0,5 gamma/ml, and not to impede this process, if the mediator's concentration is increased to 30 gamma/ml.

Animals↗
PubMed2000

The synaptic vesicle protein SV2 is complexed with an alpha5-containing laminin on the nerve terminal surface.

Interactions between growing axons and synaptic basal lamina components direct the formation of neuromuscular junctions during nerve regeneration. Isoforms of laminin containing alpha5 or beta2 chains are potential basal lamina ligands for these interactions. The nerve terminal receptors are unknown. Here we show that SV2, a synaptic vesicle transmembrane proteoglycan, is complexed with a 900-kDa laminin on synaptosomes from the electric organ synapse that is similar to the neuromuscular junctions. Although two laminins are present on synaptosomes, only the 900-kDa laminin is associated with SV2. Other nerve terminal components are absent from this complex. The 900-kDa laminin contains an alpha5, a beta1, and a novel gamma chain. To test whether SV2 directly binds the 900-kDa laminin, we looked for interaction between purified SV2 and laminin-1, a laminin isoform with a similar structure. We find SV2 binds with high affinity to purified laminin-1. Our results suggest that a synaptic vesicle component may act as a laminin receptor on the presynaptic plasma membrane; they also suggest a mechanism for activity-dependent adhesion at the synapse.

Animals↗
PubMed1986

Plasticity of expression of a synaptic vesicle antigen in adult rat superior cervical ganglion.

The effects of deafferentation and alterations of synaptic activity on levels of a synaptic vesicle-specific membrane protein (SV) were studied in the adult rat superior cervical ganglion (SCG) in vivo, using a monoclonal antibody directed against the protein. Levels of SV were quantified by radioimmunoassay. Deafferentation of the SCG results in a transient increase in SV levels in the SCG on days 7 and 10 after surgery, with levels then dropping below control levels on days 14, 21, and 30 after surgery. Immunohistochemical labeling of deafferented ganglia indicates that the increase is confined to the perikarya of principal ganglionic neurons. Levels of SV in an SCG target tissue, the iris, do not differ from control levels on day 7 after deafferentation, but are elevated at days 10, 14, and 30 after surgery. After reinnervation of the SCG, levels of SV in the SCG are elevated above control values, but do not differ from control values in the iris. Treatment with chlorisondamine, which blocks synaptic transmission in sympathetic ganglia, produces a significant increase in SV levels in the SCG after 7 d of treatment. Long-term chlorisondamine treatment results in reductions in SV in the SCG after 14 and 28 d. Treatment with phenoxybenzamine for 6 d, which reflexly increases synaptic activity, produces a marked decrease in SV in the SCG. These results suggest that activity, mediated by transsynaptic factors, contributes to the regulation of synthesis of a synaptic vesicle protein in the SCG. The results further suggest that accumulation of synaptic vesicles in terminals of the principal ganglion neurons may help regulate the maintenance of normal synaptic vesicle pools within sympathetic neurons.

Animals↗
PubMed1984

Free amino acids in synaptic vesicles isolated from the cerebellum and cerebral hemispheres of control and neonatally X-irradiated rats.

X-irradiation of the rat brain (1000R, at two days of age), suppresses the normal age-related increase in the weight of the cerebellum and cerebral hemispheres and influences amino acid levels. The decrease in glutamic acid concentration, particularly in the cerebellum, supports the previously advanced proposition that this amino acid may be associated with or may be the transmitter of, the rat cerebellar granule cells. Subfractionation of the cerebellar tissue reveals that the decrease in the glutamic acid level consequent to the loss of granule cells, is reflected in the cytoplasmic fraction but not in the synaptic vesicle subfraction, where glutamic acid was increased. The reduced weight gain in the cerebral hemispheres after irradiation, is accompanied by a significant decrease of aspartate in the cytoplasmic fraction, changes which suggest that a specific cell type, with aspartic acid as its neurotransmitter (possibly in the hippocampus), may also be radiosensitive in the early postnatal period. In contrast, in the synaptic vesicle fraction from cerebral hemispheres, all free amino acids, with the exception of glutamine, increased significantly. Overall, the changes in free amino acid concentration induced by X-irradiation in the cytoplasmic fraction in both brain regions studied are opposite to those found in the synaptic vesicle fraction and although they may indicate changes in specific cell populations, as proposed above, they could also reflect changes in cellular compartmentalization and metabolism or changes in the relative axonal arborization of the affected regions.

Amino Acids↗