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PubMed2001

Abnormalities in the synaptic vesicle fusion machinery in Huntington's disease.

We have recently described the progressive and selective loss of the presynaptic protein complexin II in brains of mice (R6/2) transgenic for the Huntington's disease (HD) mutation. Here we have determined the expression of components of the synaptic vesicle fusion machinery in the striatum and hippocampus from post-mortem brains of HD cases and neurologically normal controls. As in the brains of R6/2 mice, complexin II was markedly depleted in the HD striatum; the depletion was compartmentally organized, with complexin II-poor regions corresponding with areas of low immunoreactivity toward the matrix marker calbindin D(28K). Decreases in the levels of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) protein synaptobrevin 2 and of rab3A were also seen, but none of the other proteins tested was significantly affected. In the hippocampus, levels of complexin II, synaptobrevin 2, rab3A, and also of alpha-SNAP, were markedly elevated in HD brains. We suggest that the observed abnormalities in the expression of proteins known to be involved in the control of neurotransmitter release, including both modulators and core components of the vesicle fusion machinery, might account for at least some of the functional abnormalities seen in HD.

Adaptor Proteins, Vesicular Transport↗

PubMed2005

Breakdown of axonal synaptic vesicle precursor transport by microglial nitric oxide.

The mechanism of axonal injury in inflammatory brain diseases is still unclear. Increased microglial production of nitric oxide (NO) is a common early sign in neuroinflammatory diseases. We found by fluorescence correlation spectroscopy that synaptophysin tagged with enhanced green fluorescence protein (synaptophysin-EGFP) moves anterogradely in axons of cultured neurons. Activated microglia focally inhibited the axonal movement of synaptophysin-EGFP in a NO synthase-dependent manner. Direct application of a NO donor to neurons resulted in inhibition of axonal transport of synaptophysin-EGFP and synaptotagmin I tagged with EGFP, mediated via phosphorylation of c-jun NH2-terminal kinase (JNK). Thus, overt production of reactive NO by activated microglia blocks the axonal transport of synaptic vesicle precursors via phosphorylation of JNK and could cause axonal and synaptic dysfunction.

Animals↗

PubMed2005

Expression of amino acid sequences of the chromogranin A molecule and synaptic vesicle protein 2 in neuroendocrine tumors of the lung.

Chromogranin A (CgA) and its valuable complement synaptic vesicle protein 2 (SV2) are neuroendocrine (NE) markers. Post-translational processing of CgA has been reported to vary in different NE cell types and tumors, but little is known regarding the expression of various CgA epitopes and SV2 in NE pulmonary tumors. We studied the immunoreactivity to six CgA epitopes and SV2 in ten typical (TC) and ten atypical (ACT) carcinoids, five large-cell NE carcinomas (LCNEC) and five small-cell carcinomas (SCLC), also comparing the results with clinicopathological characteristics of tumors. The sequences CgA 17--38 (vasostatin), 176--195 (chromacin), 375--384 (parastatin) and 411--424 (C-terminal parastatin) and SV2 were relevant markers for the CT/ATC group, whereas the antibody to CgA 176--195 was a better marker for the LCNEC/SCLC group. An inverse correlation was found between proliferative activity and granule-related markers in the CT/ACT group, and a direct correlation in poorly differentiated tumors. The expression of granule-related markers did not correlate with hormone content or clinical characteristics of NE tumors. The expression of CgA epitopes and SV2 occurs in all NE tumors, differing between better differentiated and poorly differentiated tumors but not within the respective groups.

Adult↗

PubMed2006

SAD: a presynaptic kinase associated with synaptic vesicles and the active zone cytomatrix that regulates neurotransmitter release.

A serine/threonine kinase SAD-1 in C. elegans regulates synapse development. We report here the isolation and characterization of mammalian orthologs of SAD-1, named SAD-A and SAD-B, which are specifically expressed in the brain. SAD-B is associated with synaptic vesicles and, like the active zone proteins CAST and Bassoon, is tightly associated with the presynaptic cytomatrix in nerve terminals. A short conserved region (SCR) in the COOH-terminus is required for the synaptic localization of SAD-B. Overexpression of SAD-B in cultured rat hippocampal neurons significantly increases the frequency of miniature excitatory postsynaptic current but not its amplitude. Introduction of SCR into presynaptic superior cervical ganglion neurons in culture significantly inhibits evoked synaptic transmission. Moreover, SCR decreases the size of the readily releasable pool measured by applying hypertonic sucrose. Furthermore, SAD-B phosphorylates the active zone protein RIM1 but not Munc13-1. These results suggest that mammalian SAD kinase presynaptically regulates neurotransmitter release.

Animals↗

PubMed1979

Stereospecific (--)-[3H]norepinephrine binding to bovine hypothalamus. Possible identification of the catecholamine uptake site in synaptic vesicles.

A (--)-[3H]norepinephrine binding site was identified in a crude synaptosomal fraction isolated from bovine hypothalamus which bound norepinephrine rapidly, reversibly, and stereospecificially. The results were most consistent with binding of (-)-[H]norepinephrine to the carrier molecule used to translocate biogenic amines into synaptic vesicles. The binding studies indicated that specific binding of (--)-[3H]norepinephrine to the crude synaptosomal fraction was greatly enhanced by 4 mM MgCl2 pand 1 mM ATP. The increased binding of (--)-[3H5norepinephrine also occurred in the presence of MgCl2 and GTP, but AMP, adenosine and adenyl-5'-yl imidodiphosphate would not substitute for ATP. Neither CaCl2 nor ZnSO4 could be substituted for the MgCl2. In the presence of MgCl2 and ATP, the dissociation constant for (--)-[3H]norepinephrine was 280 nM with a specific binding site density of 4.8 pmol/mg protein. Binding was stereospecific with ratios of 15, 4, and 6.5 for the affinities of (--)-isomers to (+)-isomers for norepinephrine, epinephrine and isoproterenol, respectively. Drug competition studies, conducted in the presence of Mg2+ and ATP, indicated that (--)-epinephrine, (--)-norepinephrine, dopamine and serotonin had inhibitory constants ranging from 0.25 to 0.8 micron with (--)-isoproterenol and tyramine having inhibitory constants around 2 micron. Reserpine was the most potent inhibitor having an inhibition constant of 8.6 +/- 0.3 nM. The binding data were not consistent with the specific site being the alpha- or beta-receptors for norepinephrine, the Uptake1 Site for norepinephrine into synaptosomes or the metabolizing enzymes for norepinephrine.

Adenine Nucleotides↗

PubMed1981

Occurrence of uranaffin-positive synaptic vesicles in both adrenergic and non-adrenergic nerves of the rat anococcygeus muscle.

The uranaffin reaction in rat anococcygeus muscle, which receives a dual innervation of both adrenergic and non-cholinergic, non-adrenergic nerves was examined. Dense reaction product was observed in the vesicular membranes and/or the cores of some synaptic vesicles in the adrenergic nerve terminals. Occasional vesicles were filled up with dense reaction product. In the prominent population of small clear vesicles, however, no dense reaction product was observed. The number of small granular vesicles in the adrenergic nerve terminals was markedly increased after the administration of 5-hydroxydopamine (5-OHDA). These granular vesicles were moderately stained with uranaffin deposit on the cores but their limiting membranes possessed no uranaffin deposit at all. In the non-adrenergic nerve terminals, on the other hand, uranaffin deposit of variable density was observed on the cores of large granular vesicles but never on their limiting membranes or on the small clear vesicles. There was no change in the axon profiles after the administration of 5-OHDA. The possible occurrence of purines in the cores of large granular vesicles in the non-adrenergic nerves is discussed.

Adrenergic Fibers↗

PubMed1992

Development of calcitonin-gene-related peptide, chromogranin A, and synaptic vesicle markers in rat motor endplates, studied using immunofluorescence and confocal laser scanning.

The presence of calcitonin-gene-related peptide (CGRP) and chromogranin A was investigated in the developing rat (E18-adult) motor system, using immunofluorescence and confocal laser scanning, and compared with synaptic vesicle markers, synaptophysin and synapsin I. In lumbar motor perikarya CGRP-LI and Chr A-LI were present in high intensities in E18 and P1 perikarya in the anterior horn. With increasing age immunoreactivity decreased. Chr A-LI was sparse in the adult. In peroneal endplates, p38-LI and SYN I-LI were present in all stages, including E18. Peptide-LI was very weak or absent in early stages (E18 and P1), but abundant in P8 and P18, especially CGRP-LI, and decreased again in P32 and adult animals. These observations indicate that the peptides have precise functions during certain developmental stages, possibly related to synapse maturation, receptor concentration, and reduction of supernumerary endplates. Both peptides are rapidly transported anterogradely in adult motor axons, and may serve physiological functions also in the adult.

Animals↗

PubMed1982

A search in rat brain cortex synaptic vesicles for endogenous ligands for kainic acid receptors.

Conditions were found for stabilizing rat brain cortex kainic acid (KA) receptors. Such receptors had the same Hill number (about 0.6) for KA and for glutamate. The receptors were then used as detectors for endogenous ligands present in brain cortex synaptic vesicle (SV) soluble extracts. When these SV extracts were fractionated by gel filtration on Sephadex G-10, by thin-layer chromatography, or by high voltage electrophoresis, a single endogenous component, that in all cases comigrated with glutamic acid, was found.

Animals↗

PubMed1983

Cholinergic synaptic vesicles from Torpedo marmorata contain an atractyloside-binding protein related to the mitochondrial ADP/ATP carrier.

Atractyloside is known to bind to the ADP/ATP translocase of the inner mitochondrial membrane, a complex formed by two basic protein subunits of relative molecular mass around 30 000. We found that synaptic vesicles from the electric organ of Torpedo marmorata, which store acetylcholine and ATP, bind atractyloside as well. Similarly to mitochondria, a protein-atractyloside complex could be solubilized from vesicle membranes with Triton X-100. Characterization of the complex by gel filtration, isoelectric focusing and gel electrophoresis revealed that atractyloside was bound to protein V11, earlier described as a major vesicle membrane component with a relative molecular mass around 34 000 and a basic isoelectric point. Since earlier experiments have already shown that uptake of ATP into isolated vesicles in vitro is inhibited by atractyloside, we can conclude now that V11 constitutes the nucleotide carrier of this secretory organelle. The structural and functional relationship of the mitochondrial and vesicular nucleotide translocases suggest a common evolutionary origin.

Animals↗

PubMed1993

Chromogranin A, a soluble synaptic vesicle protein, is found in cortical neurons other than previously defined peptidergic neurons in the human neocortex.

Neuropeptides in the cerebral cortex have previously been identified in non-pyramidal neurons only. By comparing the location of chromogranin A (CgA), a soluble protein of large dense-core synaptic vesicles, with that of SMI-32, neuropeptide Y (NPY), parvalbumin (PV) and calbindin (CaBP) using double label immunohistochemistry, we demonstrate that CgA is present in pyramidal neurons as well as in several subtypes of non-pyramidal neurons.

Adult↗

PubMed2004

The effects of ebselen on [3H]glutamate uptake by synaptic vesicles from rat brain.

Ebselen is a selenium organic compound, which has been shown to be a neuroprotective agent in brain disorders involving glutamate receptors. However, the effects of ebselen on the functionality of the glutamatergic system are still poorly investigated. In this study, by using synaptic vesicle preparation, we investigated the effects of ebselen (0.3 to 10 microM) on (i) vesicular glutamate uptake, (ii) bafilomycin-sensitive H+ -ATPase activity, and (iii) proton gradient formation (DeltapH). Ebselen presented a dual effect on glutamate uptake: the 1 microM concentration resulted in a 60% increase of the uptake, while the 10 microM concentration resulted in 60% inhibition. We also observed that ebselen (10 microM) inhibited the H+ -ATPase activity and dissipated the DeltapH. The inhibitory effects of ebselen were prevented by dithiothreitol (DTT). These findings suggest that high concentrations of ebselen may oxidize the essential thiol groups of the H+ -ATPase, which in turn affect its activity and compromise the vesicular glutamate uptake, and consequently lead to an impairment of the neural homeostasis.

Animals↗

PubMed1999

Synaptic vesicle dynamics in rat fast and slow motor nerve terminals.

We have investigated whether rat motor nerve terminals with different in vivo activity patterns also have different vesicle trafficking characteristics. To do this, we monitored, using combined optical and electrical techniques, the rate of exocytosis (during different frequencies and patterns of activity), the releasable pool size, and the recycle time of synaptic vesicles in terminals on soleus (slow-twitch) and extensor digitorum longus [(EDL); fast-twitch] muscle fibers. EDL terminals had a higher initial quantal content (QC) than soleus, but during tonic or phasic stimulation at 20-80 Hz, EDL QC ran down to a greater extent than soleus QC. By recording loss of fluorescence from exocytosing vesicles labeled with the dye FM1-43, EDL terminals were found to destain faster than those in soleus. Simultaneous intracellular recording of end plate potentials, to count the number of vesicles released, permitted estimation of the total vesicle pool (VP) size and the recycle time by combining the optical and electrophysiological data. Soleus vesicle pool was larger than EDL, but recycle time was not significantly different. These terminals, therefore, are adapted to their in vivo activity patterns by alterations in QC and VP size but not recycle time.

Adaptation, Physiological↗

PubMed1976

[Changes in the distribution of synaptic vesicles in cone endings following electrical stimulation of the retina].

The conditions were found (hypoxic state of the retina) under which exhausture of the transmitter in presynaptic endings of photoreceptors may be supposed from a decrease in responses of horizontal cells to electric stimulation of the retina. Under these conditions the electric stimulation is accompanied by a decrease in the number of small synaptic vesicles near the presynaptic membranes in cones. However, there are no reliable changes in the total number of vesicles in cone endings.

Animals↗

PubMed2001

The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis.

When nerve terminals in the brain are stimulated, a group of phosphoproteins called the dephosphins are coordinately dephosphorylated by calcineurin, the Ca(2+)-dependent protein phosphatase. Amazingly, the seven presently known dephosphins are not structurally related, yet each has been independently shown to be essential for synaptic vesicle endocytosis (SVE). Nowhere else in biology is there a similar example of the coordinated dephosphorylation of such a large group of proteins each sharing roles in the same biological response. This suggests that dephosphorylation and phosphorylation of the dephosphins is essential for SVE. Recent studies in synaptosomes have confirmed this view, with calcineurin-mediated dephosphorylation of the dephosphins essential for triggering SVE. The phosphorylation cycle of the dephosphins might regulate SVE by targeting the proteins to sites of action and by stimulating the assembly of several large essential endocytic protein complexes.

Animals↗

PubMed2003

Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles.

l-Glutamic acid decarboxylase (GAD) exists as both membrane-associated and soluble forms in the mammalian brain. Here, we propose that there is a functional and structural coupling between the synthesis of gamma-aminobutyric acid (GABA) by membrane-associated GAD and its packaging into synaptic vesicles (SVs) by vesicular GABA transporter (VGAT). This notion is supported by the following observations. First, newly synthesized [(3)H]GABA from [(3)H]l-glutamate by membrane-associated GAD is taken up preferentially over preexisting GABA by using immunoaffinity-purified GABAergic SVs. Second, the activity of SV-associated GAD and VGAT seems to be coupled because inhibition of GAD also decreases VGAT activity. Third, VGAT and SV-associated Ca(2+)calmodulin-dependent kinase II have been found to form a protein complex with GAD. A model is also proposed to link the neuronal stimulation to enhanced synthesis and packaging of GABA into SVs.

Animals↗

PubMed1979

Aggregations of synaptic vesicles on the exposed inner membrane of presynaptic mitochondria in brain.

Fragments of rat cerebral cortex have been incubated under various conditions. When divalent cations are present, patches of the external membrane of some mitochondria are disassembled leaving the inner mitochondrial membrane exposed to the cytoplasm. Sometimes the entire external membrane is missing. In presynaptic bulbs the synaptic vesicles are attracted and adhere to the exposed outer face of the inner mitochondrial membrane. The mode of attraction and adhesion of the vesicles is discussed. Possibly this could serve as a model for further investigation of the attraction of vesicles to the active zone of the presynaptic membrane.

Animals↗

PubMed1990

Depolarization regulates expression of a synaptic vesicle protein in rat superior cervical ganglia in vitro.

The role of membrane depolarization in the regulation of expression of a neuron specific protein was evaluated by culturing superior cervical ganglia from neonatal rats in defined medium and manipulating neuronal activity by depolarizing agents. P65 is an integral membrane protein of synaptic vesicles and can be used as a marker for general neuronal maturation. P65 antigen levels were quantified by indirect radioimmunoassay, using monoclonal antibodies. The expression of p65 in ganglion explants increased by 40-100% when the cultures were treated with the depolarizing agents, veratridine or high potassium. The veratridine effect could be blocked by simultaneous treatment with the sodium channel blocker, tetrodotoxin (TTX). The rise in p65 was not evident until 36 h after depolarizing treatment had begun and reached peak levels after 48 h, with no further increases observed with sustained treatment. After removal of the depolarizing treatment, p65 levels returned to control values after 24 h. P65 joins a growing number of molecules whose expression is regulated by membrane depolarization.

Animals↗

PubMed2003

Glomerular podocytes possess the synaptic vesicle molecule Rab3A and its specific effector rabphilin-3a.

Several recent studies have focused on similarities between glomerular podocytes and neurons because the two cells share a specialized cytoskeletal organization and several expression-restricted proteins, such as nephrin and synaptopodin. In neurons, the small guanosine triphosphatase Rab3A and its effector rabphilin-3A form a complex required for the correct docking of synaptic vesicles to their target membrane. Because rabphilin-3A binds in neurons to cytoskeletal proteins also important for podocyte homeostasis, and the complex rabphilin-3A-Rab3A has been demonstrated in neurons and neuroendocrine cells, the aim of our work was to investigate their possible expression and regulation in podocytes. Normal kidneys from mouse, rat, and human were studied by immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction to evaluate the expression of Rab3A and rabphilin-3A. Double-staining immunohistochemistry and immunogold electron microscopy were then used to precisely localize the two proteins at the cellular and subcellular levels. Rab-3A and rabphilin-3A regulations in disease were then analyzed in growth hormone-transgenic mice, a well established model of focal and segmental glomerulosclerosis, and in human biopsies from proteinuric patients. Our results demonstrated that rabphilin-3A and Rab3A are present in normal mouse, rat, and human kidneys, with an exclusively glomerular expression and a comma-like pattern of positivity along the glomerular capillary wall, suggestive for podocyte staining. Co-localization of both molecules with synaptopodin confirmed their presence in podocytes. By immunogold electron microscopy both proteins were found around vesicles contained in podocyte foot processes. Their expression was increased in growth hormone-transgenic mice compared to their wild-type counterpart, and in a subset of biopsies from proteinuric patients. Our data, demonstrating the presence of two synaptic proteins in podocytes, further supports similarities between cytoskeletal and vesicular organization of podocytes and neurons. The altered expression observed in mouse and human proteinuric diseases suggests a possible role for these molecules in glomerulopathies.

Adaptor Proteins, Signal Transducing↗