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PubMed1990

Synaptoporin, a novel putative channel protein of synaptic vesicles.

By homology screening of a rat brain library, we have isolated cDNAs that encode a novel member of the synaptophysin/connexin channel protein superfamily. The deduced protein, named synaptoporin, displays 58% amino acid identity to synaptophysin, with highly conserved transmembrane segments, but a divergent cytoplasmic tail. Northern blot analysis and PCR amplification of RNA from different rat tissues indicate expression of synaptoporin transcripts in the CNS. Antibodies against a synthetic peptide or a fusion construct encompassing the cytoplasmic tail region of synaptoporin detect a polypeptide of 37 kd that copurifies with small synaptic vesicles. Our data suggest the existence of a family of vesicular channel proteins whose members may be differently distributed among synaptic vesicle subpopulations.

Amino Acid Sequence↗

PubMed1992

Carnosine-like immunoreactivity is associated with synaptic vesicles in photoreceptors of the frog retina.

The distribution of carnosine-like immunoreactivity in photoreceptors of the frog retina was studied by post-embedding electron microscope immunocytochemistry. Different fixation and embedding procedures were applied and the best results were achieved on sections from tissue embedded in the hydrophilic resin LR White. All photoreceptor types present in the frog retina (red and green rods, single and double cones) were intensely reactive for the carnosine antiserum. The immunoreactivity was particularly prominent in the synaptic terminal, nucleus and myoid, but decreased in the ellipsoid and in the outer segment. Müller glial cells and horizontal and bipolar cell processes in the outer plexiform layer were completely unstained. At the level of the photoreceptor terminals, the presence of gold particles within the synaptic vesicles could be demonstrated. This study is the first to provide the anatomical evidence for the presence of carnosine in the synaptic vesicles of a nervous cell. The present data may be relevant to the understanding of the biological functions of carnosine (and related dipeptides) and offer an exploitable system in which to verify its proposed role as a neurotransmitter or neuromodulator in sensory systems.

Animals↗

PubMed1990

Synaptophysin: a substrate for the protein tyrosine kinase pp60c-src in intact synaptic vesicles.

Expression of pp60c-src, the first well defined proto-oncogene product, is developmentally regulated and tissue-specific, with neuronal tissues displaying high amounts of the c-src encoded pp60c-src kinase activity. In the central nervous system pp60c-src is preferentially expressed in regions characterized by a high content of grey matter and elevated density of nerve terminals. In this study we show for the first time a direct interaction between pp60c-src and synaptophysin as a physiological target protein in neurons by demonstrating that endogenous pp60c-src is able to phosphorylate synaptophysin (p38). p38 is a major constituent of the synaptic vesicle membrane protein and is thought to play a key role in the exocytosis of small synaptic vesicles and possibly small clear vesicles in neuroendocrine cells.

Animals↗

PubMed1996

ZnT-3, a putative transporter of zinc into synaptic vesicles.

The murine ZnT3 gene was cloned by virtue of its homology to the ZnT2 gene, which encodes a membrane protein that facilitates sequestration of zinc in endosomal vesicles. ZnT-3 protein is predicted to have six transmembrane domains and shares 52% amino acid identity with ZnT-2, with the homology extending throughout the two sequences. Human ZnT-3 cDNAs were also cloned; the amino acid sequence is 86% identical to murine ZnT-3. The mouse ZnT3 gene has 8 exons and maps to chromosome 5. Northern blot and reverse transcriptase-PCR analyses demonstrate that murine ZnT-3 expression is restricted to the brain and testis. In situ hybridization reveals that within the brain, ZnT-3 mRNA is most abundant in the hippocampus and cerebral cortex. Antibodies raised against the C-terminal tail of mouse ZnT-3 react with the projections from these neurons and produce a pattern similar to that obtained with Timm's reaction, which reveals histochemically reactive zinc within synaptic vesicles. We propose that ZnT-3 facilitates the accumulation of zinc in synaptic vesicles.

Amino Acid Sequence↗

PubMed1997

Synaptic vesicle endocytosis impaired by disruption of dynamin-SH3 domain interactions.

The proline-rich COOH-terminal region of dynamin binds various Src homology 3 (SH3) domain-containing proteins, but the physiological role of these interactions is unknown. In living nerve terminals, the function of the interaction with SH3 domains was examined. Amphiphysin contains an SH3 domain and is a major dynamin binding partner at the synapse. Microinjection of amphiphysin's SH3 domain or of a dynamin peptide containing the SH3 binding site inhibited synaptic vesicle endocytosis at the stage of invaginated clathrin-coated pits, which resulted in an activity-dependent distortion of the synaptic architecture and a depression of transmitter release. These findings demonstrate that SH3-mediated interactions are required for dynamin function and support an essential role of clathrin-mediated endocytosis in synaptic vesicle recycling.

Amino Acid Sequence↗

PubMed1987

A phosphatase activity and a synaptic vesicle antigen in multivesicular bodies of frog retinal photoreceptor terminals.

Previous work has suggested that multivesicular bodies participate in endocytosis and membrane cycling at nerve terminals, including the presynaptic terminals of retinal photoreceptors. We now have found that multivesicular bodies located in the presynaptic terminals of photoreceptors in retinae of Rana pipiens show reaction product in preparations incubated to demonstrate phosphatase activity at pH 5, using cytidine monophosphate as the substrate. Evidently, multivesicular bodies in photoreceptors can possess at least some hydrolytic enzymes during their sojourn in the terminals. We have also found that the multivesicular bodies in frog retinal photoreceptor terminal stain, immunocytochemically, for the presence of SV2, an antigen of synaptic vesicles. This observation supports the suggestion that, along with the extensive, repeated reuse of membrane components for synaptic vesicle recycling, there is some incorporation of the components into structures that are potentially degradative.

Animals↗

PubMed2001

Inhibition of glutamate uptake into synaptic vesicles from rat brain by 3-nitropropionic acid in vitro.

The exact mechanisms by which 3-nitropropionic acid (3-NP), a naturally occurring plant and fungal neurotoxin, exerts its neurotoxic effects are not fully understood. However, blockage of ATP synthesis by the irreversible inhibition of succinate dehydrogenase activity, increased production of free radicals, and secondary excitotoxicity have been implicated in its actions. In the present study, synaptic vesicle preparations from brain of adult rats were incubated with 3-NP at final concentrations ranging from 0.01 to 10 mM for the determination of glutamate uptake. The effect of 3-NP on gamma-aminobutyric acid (GABA) and glycine uptake was also studied. Glutamate incorporation into vesicles was inhibited by 3-NP in a dose-dependent manner, whereas doses of up to 10 mM neurotoxin did not affect GABA or glycine uptake. Moreover, 3-NP did not inhibit the ATPase activity of synaptic vesicles. These findings indicate that low concentrations of 3-NP are able to selectively prevent vesicular glutamate storage, and this may represent at least one of the mechanisms responsible for the neurotoxic effects of 3-NP.

Adenosine Triphosphatases↗

PubMed1993

The chemical nature of the main central excitatory transmitter: a critical appraisal based upon release studies and synaptic vesicle localization.

The chemical nature of the central transmitter responsible for fast excitatory events and other related phenomena is analysed against the historical background that has progressively clarified the structure and function of central synapses. One of the problems posed by research in this field has been whether one or more of the numerous excitatory substances endogenous to the brain is responsible for fast excitatory synaptic transmission, or if such a substance is, or was, a previously unknown one. The second question is related to the presence in the CNS of three main receptor types related to fast excitatory transmission, the so-called alpha-amino-3-hydroxy-5-methylisoxazole propionic acid, kainate and N-methyl-D-aspartate receptors. This implies the possibility that each receptor type might have its own endogenous agonist, as has sometimes been suggested. To answer such questions, an analysis was done of how different endogenous substances, including L-glutamate, L-aspartate, L-cysteate, L-homocysteate, L-cysteine sulfinate, L-homocysteine sulfinate, N-acetyl-L-aspartyl glutamate, quinolinate, L-sulfoserine, S-sulfo-L-cysteine, as well as possible unknown compounds, were able to fulfil the more important criteria for transmitter identification, namely identity of action, induced release, and presence in synaptic vesicles. The conclusion of this analysis is that glutamate is clearly the main central excitatory transmitter, because it acts on all three of the excitatory receptors, it is released by exocytosis and, above all, it is present in synaptic vesicles in a very high concentration, comparable to the estimated number of acetylcholine molecules in a quantum, i.e. 6000 molecules. Regarding a possible transmitter role for aspartate, for which a large body of evidence has been presented, it seems, when this evidence is carefully scrutinized, that it is either inconclusive, or else negative. This suggests that aspartate is not a classical central excitatory transmitter. From this analysis, it is suggested that the terms alpha-amino-3-hydroxy-5-methylisoxazole propionic acid, kainate and N-methyl-D-aspartate receptors, should be changed to that of glutamate receptors, and, more specifically, to GLUA, GLUK and GLUN receptors, respectively. When subtypes are described, a Roman numeral may be added, as in GLUNI, GLUNII, and so on.

Animals↗

PubMed1989

Intraneuronal distribution of a synaptic vesicle membrane protein: antibody binding sites at axonal membrane compartments and trans-Golgi network and accumulation at nodes of Ranvier.

The distribution of a cholinergic synaptic vesicle-specific transmembrane glycoprotein (Buckley and Kelly, 1985, J. Cell Biol. 100, 1284-1294) was investigated in the entire electromotor neuron of Torpedo marmorata using a monoclonal antibody and immunocytochemistry at the light- and electron-microscopical level (immunoperoxidase, colloidal gold). In the nerve, terminal binding of immunogold particles is restricted to synaptic vesicles. In the axon a number of additional membrane compartments like multivesicular bodies, vesiculotubular structures, lamellar bodies and electron-dense granules share the surface located synaptic vesicle-specific transmembrane glycoprotein-epitope. Membranous structures likely to represent the axoplasmic reticulum inside axons and nerve terminals are not labelled. Antibody-binding membrane compartments are accumulated at nodes of Ranvier. In the perikaryon the tubules of the trans-Golgi network as well as multivesicular bodies, lamellar bodies, electron-lucent vesicles, granules with electron-dense core and peroxisomes are labelled. Immunotransfer blots of isolated synaptic vesicles and tissue extracts of electric organ display a 100,000 mol. wt band of broad electrophoretic mobility typical of the synaptic vesicle-specific transmembrane glycoprotein. Extracts of electromotor nerve and electric lobe contain in addition a strong band at 85,000 mol. wt and a few lower molecular weight bands. We suggest that the synaptic vesicle originates directly from the trans-Golgi network. The endoplasmic reticulum is not involved in vesicle formation or retrieval. On retrograde transport the vesicle membrane compartment is likely to fuse with other intra-axonal (endosomal?) organelles.

Animals↗

PubMed1995

Synaptic vesicle recycling intermediates revealed.

Neurotransmitter release takes place by the exocytosis of loaded synaptic vesicles. The vesicles then fuse to the presynaptic membrane and are recycled by an endocytotic mechanism. A quantitative optical assay that detects uptake and release of a fluorescent dye during presynaptic activity was recently developed and used on the frog neauromuscular junction. I discuss a report that demonstrates the effective application of this method to a Drosophila preparation. The authors use the shibire mutation and a spider venom to identify two intermediates in vesicle recycling. Their report, along with other recent studies, demonstrates the power and promise of the genetic approach for the understanding of mechanisms of synapse function and development.

Animals↗

PubMed1995

Increase in synaptic vesicle proteins in synapsin-transfected NG108-15 cells: a subcellular fractionation study.

We have examined the subcellular distribution of synapsins and synaptophysin in density gradients from synapsin- and vector-transfected NG108-15 cells, since we recently found that transfection of synapsin IIb cDNA into neuroblastoma x glioma hybrid cells (NG108-15) resulted in cell lines that had a more neuronal phenotype than controls. The increase in synapsins and synaptophysin in the transfected cells was maximal in the region of the gradient containing small synaptic vesicles. The transferrin receptor, a marker for early endosomes, did not increase in the synapsin-containing fractions in the transfected cells. Secretogranin I, a soluble protein stored in and secreted from large dense cored vesicles, showed a very pronounced increase in the dense regions of gradients from transfected cells. These subcellular fractionation data suggest a possible role for the synapsins in the regulation of synaptic vesicle function.

Animals↗

PubMed1990

Amino acid neurotransmission: spotlight on synaptic vesicles.

The vesicle hypothesis describing quantal release of neurotransmitter at the cholinergic neuromuscular junction was introduced in 1956. Since then, the concept of vesicular storage and release of acetylcholine has become firmly established and extended to include other synapses and neurotransmitters. However, for the amino acids, which are the major class of neurotransmitters in the mammalian CNS, there was no direct experimental evidence of the participation of synaptic vesicles in neurotransmission. This area of research has now moved out of the shadows and this article discusses recent findings which indicate that amino acid neurotransmitters are accumulated and stored by synaptic vesicles in presynaptic nerve endings.

Amino Acids↗

PubMed2004

Snake presynaptic neurotoxins with phospholipase A2 activity induce punctate swellings of neurites and exocytosis of synaptic vesicles.

The mechanisms of action of four snake presynaptic phospholipase A2 neurotoxins were investigated in cultured neurons isolated from various parts of the rat brain. Strikingly, physiological concentrations of notexin, beta-bungarotoxin, taipoxin or textilotoxin induced a dose-dependent formation of discrete bulges at various sites of neuronal projections. Neuronal bulging was paralleled by the redistribution of the two synaptic vesicle markers synaptophysin I (SypI) and vesicle-attached membrane protein 2 (VAMP2) to the bulges, and by the exposure of the luminal domain of synaptotagmin on the cell surface. These neurotoxins induced glutamate release from cultured neurons similarly to the known evoked release of acetylcholine from neuromuscular junctions. In addition, partial fragmentation of F-actin and neurofilaments was observed in neurons, but not in astrocytes. These findings indicate that these snake presynaptic neurotoxins act with by same mechanism and that the observed phenotype results from the fusion of synaptic vesicles with the plasma membrane not balanced by an adequate membrane retrieval. These changes closely resemble those occurring at neuromuscular junctions of intoxicated animals and fully qualify these primary neuronal cultures as pertinent models for studying the molecular mode of action of these neurotoxins.

Animals↗

PubMed1975

[Changes in the synaptic vesicles of cat motor cortex axon terminals upon stimulation].

The relation of the synaptic vesicle size to the distance between the vesicle and the synapse active zone was studied in the axon terminals at the motor cortex neuron spines and dendrites of resting cats (under moderate barbiturate anesthesia) and after prolonged repetitive stimulation of the somatosensory SII area. Thes sizes of the vesicles belonging to any of the three strata observed in the terminal section profile under the electron microscope were registered as a decrementing variation sequence. The predominance of small vesicles in stratum I adjoining to the synapse active zone was found by means of the statistical analysis (symbol criterion and criterion chi2), both in the control and experimental material. A significant gradient of the vesicle size diminution from peripheral stratum III to stratum I as well as vesicle size decrease both in stratum I and intermediate stratum II in comparison with the control developed after the cortico-cortical projection stimulation. The functional role of this phenomenon is discussed.

Animals↗

PubMed1991

A small GTP-binding protein dissociates from synaptic vesicles during exocytosis.

Low-molecular-weight GTP-binding proteins are strong candidates for regulators of membrane traffic. In yeast, mutations in the sec4 or ypt1 genes encoding small GTP-binding proteins inhibit constitutive membrane flow at the plasma membrane or Golgi complex, respectively. It has been suggested that membrane fusion-fission events are regulated by cycling of small GTP-binding proteins between a membrane-bound and free state, but although most of these small proteins are found in both soluble and tightly membrane-bound forms, there is no direct evidence to support such cycling. In rat brain a small GTP-binding protein, rab3A, is exclusively associated with synaptic vesicles, the secretory organelles of nerve terminals. Here we use isolated nerve terminals to study the fate of rab3A during synaptic vesicle exocytosis. We find that rab3A dissociates quantitatively from the vesicle membrane after Ca2(+)-dependent exocytosis and that this dissociation is partially reversible during recovery after stimulation. These results are direct evidence for an association-dissociation cycle of a small GTP-binding protein during traffic of its host membrane.

Animals↗

PubMed1997

On the dynamics of synaptic vesicles: effects on the rate of neurotransmitter release.

Release of transmitter substances during synaptic communication in a biological process of great importance, and it is worthwhile to ascertain the basic molecular events underlying this process. We present a minimal model of synaptic vesicle (SV) dynamics, with which most of the major experimentally observed features of evoked neurotransmitter release can be reproduced. The effect of different parameters on the time course of evoked release as well as the effect of repetitive stimulation on this model system has been examined.

Animals↗

PubMed1986

Immunocytochemical characterization of neuron-rich primary cultures of embryonic rat brain cells by established neuronal and glial markers and by monospecific antisera against cyclic nucleotide-dependent protein kinases and the synaptic vesicle protein synapsin I.

Primary cell cultures derived from embryonic rat brain were characterized by immunocytochemical methods using established cell markers and monospecific antisera against cyclic nucleotide-dependent protein kinases and the synaptic vesicle protein, synapsin I. The cultures contained predominantly neurons, few astroglial cells and no oligodendroglial cells, based on immunocytochemical studies of the distribution of neuron-specific enolase, glial fibrillary acidic protein, myelin basic protein and galactocerebroside. Subsequently, the immunocytochemical localization of synapsin I, the cyclic GMP-dependent protein kinase and the various subunits of cyclic AMP-dependent protein kinase was determined. Synapsin I, a substrate for both the cyclic AMP- and Ca2+/calmodulin-dependent protein kinases, appeared particularly useful as a specific neuronal marker in primary cultures. Both immunocytochemical and immunoblotting techniques readily detected synapsin I in neuron-rich embryonic brain cultures, but indicated that synapsin I was absent from glia-rich primary cultures of newborn rat brain cells which lacked neurons. The intracellular localization of synapsin I in neurons changed markedly during the time of cell culture. In the first 10 days of cell culture, synapsin I appeared to be confined to neuronal cell bodies, whereas later it shifted to a patchy distribution in neuronal processes, perhaps indicating the transport of synapsin I in synaptic vesicles from the compartment of protein synthesis to its final synaptic location. Within neuron-rich embryonic cultures, the regulatory subunit (R-II) and the catalytic subunit (C) of cyclic AMP-dependent protein kinase appeared to be highly concentrated in neurons examined immunocytochemically. However, biochemical experiments demonstrated that R-II and C were also present in non-neuronal cell types of brain cell primary cultures. Cyclic GMP-dependent protein kinase, a marker protein for cerebellar Purkinje cells and for smooth muscle cells, was not detected immunocytochemically in neuron-rich cultures of embryonic brain cells, suggesting that Purkinje cells and smooth muscle cells were either absent from or not sufficiently developed in these cultures.

Animals↗

PubMed1992

Widespread Distribution of Synaptophysin, a Synaptic Vesicle Glycoprotein, in Growing Neurites and Growth Cones.

Synaptophysin, a 38-kD glycoprotein, is one of the most abundant of the integral membrane proteins of small synaptic vesicles. The protein is widely distributed at synapses throughout the nervous system, where it is believed to be involved in the exocytosis of stored neurotransmitter. We show here that synaptophysin is also widely expressed in growing neurites and growth cones both in vitro and in vivo. In dissociated rat cerebral cortical cultures anti-synaptophysin antiserum (G-95) stains growth cones punctately as soon as they emerge from the cell body. In early cultures all neurites are immunoreactive. Later, synaptophysin is redistributed to become concentrated in axonal varicosities. In developing rat embryos, synaptophysin is expressed in the growing axons of, for instance, the spinal commissural interneurons and the parallel fibres of the cerebellar granule cells long before these neurons have established synaptic connections. These observations suggest that synaptic vesicle proteins like synaptophysin are functionally important in neuronal development.

Journal Article↗