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PubMed2004

The synaptic vesicle cycle.

Neurotransmitter release is mediated by exocytosis of synaptic vesicles at the presynaptic active zone of nerve terminals. To support rapid and repeated rounds of release, synaptic vesicles undergo a trafficking cycle. The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is followed by different routes of endocytosis and recycling. Recycling then leads to the docking and priming of the vesicles for another round of exo- and endocytosis. Recent studies have led to a better definition than previously available of how Ca2+ triggers exocytosis and how vesicles recycle. In particular, insight into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular Ca2+ sensor synaptotagmin 1 triggers fast release, and how the vesicular Rab3 protein regulates release by binding to the active zone proteins RIM1 alpha and RIM2 alpha has advanced our understanding of neurotransmitter release. The present review attempts to relate these molecular data with physiological results in an emerging view of nerve terminals as macromolecular machines.

Animals↗

PubMed1995

Redistribution of synaptic vesicles and their proteins in temperature-sensitive shibire(ts1) mutant Drosophila.

From an extract of Drosophila melanogaster head homogenates, a membrane fraction can be isolated that has the same sedimentation properties as vertebrate synaptic vesicles and contains Drosophila synaptotagmin. The fraction disappears from homogenates of temperature-sensitive (ts) mutant shibire(ts1) (shi(ts1)) flies paralyzed by exposure to non-permissive temperatures, and reappears on return to permissive temperatures. Since reversible, temperature-dependent depletion of synaptic vesicles is known to occur in shibire(ts1) flies, we conclude that the fraction we have identified contains synaptic vesicles. We have examined the fate of synaptic vesicle membrane proteins in shibire flies at nonpermissive temperatures and found that all of these vesicle antigens are transferred to rapidly sedimenting membranes and codistribute with a plasma membrane marker by both glycerol velocity and metrizamide density sedimentation and by confocal microscopy. Three criteria were used to establish that other neuron-specific antigens--neuronal synaptobrevin and cysteine-string proteins--are legitimate components of synaptic vesicles: cosedimentation with Drosophila synaptotagmin, immunoadsorption, and disappearance of these antigens from the vesicle fractions in paralyzed shibire flies.

Amino Acid Sequence↗

PubMed1991

Endocytosis of the synaptic vesicle protein, synaptophysin, requires the COOH-terminal tail.

Synaptic vesicles participate in a cycle of fusion with the plasma membrane and reformation by endocytosis. Endocytosis of membrane proteins by the well studied clathrin-coated vesicle pathway has been shown to involve specific sequences within the cytoplasmic tail domain. Proteins taken up by clathrin-coated vesicles are directed to early endosomes from which they may return to plasma membrane. Recent evidence suggests that the synaptic vesicle protein synaptophysin is targeted to early endosomes in transfected fibroblasts and in neuroendocrine cells. To begin to test whether sequences within the COOH-cytoplasmic domain are required for internalization we have expressed a synaptophysin molecule lacking this domain in 3T3 cells and measured its rate of internalization. While a full length synaptophysin was internalized efficiently, we could not detect internalization of the mutant construct. These data are consistent with a model in which the COOH-terminal tail is required for coated-pit localization and hence targeting of synaptophysin to early endosomes.

Animals↗

PubMed2000

Assessing accurate sizes of synaptic vesicles in nerve terminals.

Chemical synaptic transmission occurs when vesicles within a presynaptic neuron fuse to the membrane and release their neurotransmitter content into the synaptic cleft, eliciting a response in the postsynaptic cell. If concentration of neurotransmitter is the same in all synaptic vesicles, the volume of the vesicle determines how much transmitter is released. Thus, variation in vesicular volume may contribute to observed variance of synaptic quantal unit size. The present study provides an approach to more fully and accurately characterize the dimensions of synaptic vesicles within a population containing varied sizes of vesicles. The methodology can be applied in a wide range of stereological problems. The approach characterizes the distribution of vesicle sizes within a population and provides a means to assess effects of experimental manipulations on vesicle dimensions. The mathematical treatments to obtain the true distribution of vesicle sizes involve extraction of the observed distribution from an enlarged population containing smaller vesicle diameters produced by sectioning of the specimens. A FORTRAN program is provided.

Algorithms↗

PubMed1992

Purification of squid synaptic vesicles and characterization of the vesicle-associated proteins synaptobrevin and Rab3A.

Two proteins associated with mammalian synaptic vesicles, the integral membrane protein synaptobrevin and the GTP-binding protein rab3A, are identified in squid nervous tissue using Western blotting and subcellular fractionation of synaptosomes. They both copurify with synaptic vesicles prepared from squid optic lobe. Synaptobrevin (18.1 kDa) is present at high levels in synaptic terminals but at very low levels in axon. Rab3A (27.5 kDa) is a member of the rab family of low-molecular weight GTP-binding proteins which regulates vesicle traffic in secretory and endocytic processes. As resolved with 2-dimensional gels, squid neurons contain at least 16 GTP-binding species (19-29 kDa), and most of these are present in both soluble and particulate fractions. The 24 kDa class of GTP-binding proteins is highly enriched in axonal transport organelles. The characterization of synaptobrevin and rab3A in squid synaptic vesicles extends their known distributions to invertebrates and points to a fundamental importance of these proteins in neurotransmitter release.

Animals↗

PubMed2004

The synaptic vesicle protein CSP alpha prevents presynaptic degeneration.

Cysteine string protein alpha (CSPalpha)--an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40 chaperones--is thought to regulate Ca2+ channels and/or synaptic vesicle exocytosis. We now show that, in young mice, deletion of CSPalpha does not impair survival and causes no significant changes in presynaptic Ca2+ currents or synaptic vesicle exocytosis as measured in the Calyx of Held synapse. At 2-4 weeks of age, however, CSPalpha-deficient mice develop a progressive, fatal sensorimotor disorder. The neuromuscular junctions and Calyx synapses of CSPalpha-deficient mice exhibit increasing neurodegenerative changes, synaptic transmission becomes severely impaired, and the mutant mice die at approximately 2 months of age. Our data suggest that CSPalpha is not essential for the normal operation of Ca2+ channels or exocytosis but acts as a presynaptic chaperone that maintains continued synaptic function, raising the possibility that enhanced CSPalpha function could attenuate neurodegenerative diseases.

Animals↗

PubMed1993

Analysis of the structure and expression of the VAMP family of synaptic vesicle proteins.

VAMP/synaptobrevin proteins were first discovered as small integral membrane proteins in synaptic vesicles of vertebrates and invertebrates. At least two isoforms are expressed in the central nervous system of mammals in non-overlapping patterns. Biochemical studies have revealed that the VAMP synaptic vesicle proteins are the specific target in the presynaptic nerve terminal of botulinum B neurotoxin and tetanus toxin metalloendoprotease activities. The fact that these toxins rapidly and completely abrogate neurotransmission suggests that VAMP proteins play an essential role in this process. More recently, immunologically related proteins have been identified in non-neuronal cells such as adipocytes. In addition, molecular genetic studies of yeast secretion have identified VAMP-related proteins as playing important roles in vesicular transport between the endoreticulum and Golgi. Taken together, these results suggest that the VAMP proteins found on synaptic vesicles might represent specialized forms of proteins which participate in general aspects of cell membrane trafficking.

Amino Acid Sequence↗

PubMed1991

rab3A attachment to the synaptic vesicle membrane mediated by a conserved polyisoprenylated carboxy-terminal sequence.

rab3A is a small neuronal GTP-binding protein specifically localized to synaptic vesicles. Membrane-bound rab3A behaves like an intrinsic membrane protein in vitro, but reversibly dissociates from synaptic vesicles after exocytosis in vivo. Here we demonstrate that rab3A is attached to synaptic vesicle membranes by a carboxy-terminal Cys-X-Cys sequence that is posttranslationally modified. This modification is inhibited by compactin in a mevalonate-dependent manner, suggesting that the Cys-X-Cys sequence represents a novel polyisoprenylation sequence. Isolation of a rab3 homolog from D. melanogaster reveals high evolutionary conservation of rab3A, including its carboxy-terminal Cys-X-Cys sequence. The posttranslational modifications of soluble and membrane-bound rab3A are biochemically different, but both require the carboxy-terminal Cys-X-Cys sequence and are faithfully reproduced in nonneuronal cells. Our results suggest that the carboxy-terminal Cys-X-Cys sequence of rab3A is polyisoprenylated and is used as its regulatable membrane anchor. Furthermore, the hydrophobic modification of rab3A and its correct intracellular targeting to synaptic vesicles are independent, presumably consecutive events.

Amino Acid Sequence↗

PubMed1993

Association of three small GTP-binding proteins with cholinergic synaptic vesicles.

Several small (low molecular weight) GTP-binding proteins are associated with cholinergic synaptic vesicles derived from the electric organ of electric ray. Using GTP overlay techniques and direct micro sequencing we analyzed the association of small GTP-binding proteins with synaptic vesicles. Both experimental procedures revealed the specific occurrence of multiple small GTP-binding proteins with this organelle. Moreover, direct amino acid sequence analysis assigned at least three different small GTP-binding proteins, ora3, o-ral and o-rab3, to the vesicular compartment. Furthermore, the data reflect the relative abundance of these three proteins on the vesicle membrane, thereby demonstrating the predominant occurrence of o-rab3, the only exclusively synaptic vesicle specific small GTP-binding protein.

Amino Acid Sequence↗

PubMed1983

Reserpine labels the catecholamine transporter in synaptic vesicles from bovine caudate nucleus.

Tritiated reserpine binds to synaptic vesicles from bovine caudate with high affinity (Kappd = 1.25 nM, Bmax = 3.3 pmol/mg protein). This interaction is both ATP-dependent and sensitive to the protonophores CCCP and nigericin, suggesting that a proton electrochemical gradient is required for binding. Dopamine, epinephrine, norepinephrine and serotonin all inhibit reserpine binding at concentrations similar to those required for inhibition of dopamine uptake. Treatment with saponin to release vesicle contents results in complete loss of accumulated dopamine but retention of bound reserpine. These results indicate that reserpine binds to the catecholamine transport system of synaptic vesicles with high affinity and specificity.

Adenosine Triphosphate↗

PubMed2006

The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles.

In searching for binding partners of the intracellular domain of the immunoglobulin superfamily adhesion molecule CHL1, we identified the clathrin-uncoating ATPase Hsc70. CHL1 gene ablation resulted in reduced targeting of Hsc70 to the synaptic plasma membrane and synaptic vesicles, suggesting CHL1 as a synapse-targeting cue for Hsc70. CHL1 accumulates in presynaptic membranes and, in response to synapse activation, is targeted to synaptic vesicles by endocytosis. CHL1 deficiency or disruption of the CHL1/Hsc70 complex results in accumulation of abnormally high levels of clathrin-coated synaptic vesicles with a reduced ability to release clathrin. Generation of new clathrin-coated synaptic vesicles in an activity-dependent manner is inhibited when the CHL1/Hsc70 complex is disrupted, resulting in impaired uptake and release of FM dyes in synaptic boutons. Abnormalities in clathrin-dependent synaptic vesicle recycling may thus underlie brain malfunctions in humans and mice that carry mutations in the CHL1 gene.

Animals↗

PubMed2003

Retrograde regulation of synaptic vesicle endocytosis and recycling.

Sustained release of neurotransmitter depends upon the recycling of synaptic vesicles. Until now, it has been assumed that vesicle recycling is regulated by signals from the presynaptic bouton alone, but results from rat hippocampal neurons reported here indicate that this need not be the case. Fluorescence imaging and pharmacological analysis show that a nitric oxide (NO) signal generated postsynaptically can regulate endocytosis and at least one later step in synaptic vesicle recycling. The proposed retrograde pathway involves an NMDA receptor (NMDAR)-dependent postsynaptic production of NO, diffusion of NO to a presynaptic site, and a cGMP-dependent increase in presynaptic phosphatidylinositol 4,5-biphosphate (PIP2). These results indicate that the regulation of synaptic vesicle recycling may integrate a much broader range of neural activity signals than previously recognized, including postsynaptic depolarization and the activation of NMDARs at both immediate and nearby postsynaptic active zones.

Animals↗

PubMed1977

Synaptic vesicle fraction devoid of adenosine triphosphatase activity from bovine caudatolenticular nuclei and thalamus.

1. As a part of studies on the mechanism by which catecholamines are released from the nerve terminals, the synaptic vesicle fraction was isolated from bovine caudatolenticular nuclei and thalamus by differential centrifugation essentially according to the method of Kadota and Kadota (17). 2. Further centrifugation on a sucrose density gradient of the synaptic vesicle fraction by the method of Whittaker et al. (1) yielded white materials on the upper portion of 0.4 M sucrose, which consisted of vesicles averaging 600-800 A in diameter, and did not show Mg2+-dependent ATpase activity. On the other hand, the denser materials centering on 0.6 M sucrose, consisting of a mixture of microsomes and synaptic vesicles of 400-500 A diameter, showed an ATpase activity activated by either Mg2+ or Ca2+ but not inhibited by ouabain. 3. The white materials on 0.4 M sucrose were almost free of mitochondria, but they contained a large amount of non-heme iron, as reported elsewhere (2). Furthermore, the protein components analyzed on SDS-polyacrylamide gels were similar to those already reported for purified synaptic vesicles (3). 4. Based on these results, the white materials were assumed to be synaptic vesicles devoid of Mg2+-dependent ATPase activity.

Adenosine Triphosphatases↗

PubMed2003

Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release.

In Huntington disease (HD), polyglutamine expansion causes the disease protein huntingtin to aggregate and accumulate in the nucleus and cytoplasm. The cytoplasmic huntingtin aggregates are found in axonal terminals and electrophysiological studies show that mutant huntingtin affects synaptic neurotransmission. However, the biochemical basis for huntingtin-mediated synaptic dysfunction is unclear. Using electron microscopy on sections of HD mouse brains, we found that axonal terminals containing huntingtin aggregates often had fewer synaptic vesicles than did normal axonal terminals. Subcellular fractionation and electron microscopy revealed that mutant huntingtin is co-localized with huntingtin-associated protein-1 (HAP1) in axonal terminals in the brains of HD transgenic mice. Mutant huntingtin binds more tightly to synaptic vesicles than does normal huntingtin, and it decreases the association of HAP1 with synaptic vesicles in HD mouse brains. Brain slices from HD transgenic mice that had axonal aggregates showed a significant decrease in [(3)H]glutamate release, suggesting that neurotransmitter release from synaptic vesicles was impaired. Taken together, these findings suggest that mutant huntingtin has an abnormal association with synaptic vesicles and this association impairs synaptic function.

Animals↗

PubMed1982

Synaptic vesicle activity in stimulated and unstimulated photoreceptor axons in the housefly. A freeze-fracture study.

Light-stimulated and unstimulated photoreceptor (retinular) axon terminals in the lamina ganglionaris (first optic neuropil) of the housefly are examined using freeze-fracture replication. The presence of numerous, cross-fractured capitate projections permits unmistakable identification of the retinular axon terminal membrane. Regardless of the conditions of illumination, the protoplasmic face (P-face) of the terminal membrane contains numerous bowtie-shaped particle clusters (active zones) which resemble the en face form and disposition of the presynaptic ribbon found in thin sections. Estimates from freeze-fractured material indicate that each retinular axon possesses at least 175 such active zones. In eyes fixed during illumination, active zones are surrounded by many membrane dimples indicative of vesicle fusion sites. Such synaptic vesicle sites are seldom encountered in terminals which are dark-adapted and fixed in the dark. Results from light-adapted eyes placed in the dark following the onset of fixation suggest that endocytosis may occur in the extrasynaptic regions of this inhibitory synapse. P-face particles are uniformly distributed throughout the extrasynaptic regions of unstimulated terminals. Particle density increases in areas peripheral to the active zones in stimulated eyes, particularly within the regions presumed to be undergoing active endocytosis. These structural findings are discussed in the context of the Heuser-Reese model of vesicle exocytosis and recycling.

Animals↗

PubMed1994

Calmodulin and cAMP dependent synaptic vesicle protein phosphorylation in rat cortex following lead exposure.

The effect of in vivo and in vitro lead exposure on calmodulin and cAMP dependent synaptic vesicle protein phosphorylation has been investigated. Lead could enhance calmodulin activity following in vitro and in vivo lead exposure. The calmodulin dependent synaptic vesicle protein phosphorylation was enhanced following in vivo and in vitro lead exposure resulting in the depletion of the neurotransmitters norepinephrine and acetylcholine. The cAMP dependent synaptic vesicle protein phosphorylation was inhibited by both in vitro and in vivo lead treatment. The results suggest that lead adversely affects synaptic vesicle protein phosphorylation and this may ultimately effect synaptic functions.

Animals↗

PubMed1992

SV2, a brain synaptic vesicle protein homologous to bacterial transporters.

Synaptic vesicle protein 2 (SV2) is a membrane glycoprotein specifically localized to secretory vesicles in neurons and endocrine cells. As a first step toward understanding the function of SV2 in neural secretion, a rat brain complementary DNA (cDNA) that encodes SV2 was isolated and characterized. Analyses of this cDNA predict that SV2 contains 12 transmembrane domains. The NH2-terminal half of the protein shows significant amino acid sequence identity to a family of bacterial proteins that transport sugars, citrate, and drugs. Expression of the SV2 cDNA in COS cells yielded a high level of SV2-like immunoreactivity distributed in a reticular and punctate pattern, which suggests localization to intracellular membranes. Its localization to vesicles, predicted membrane topology, and sequence identity to known transporters suggest that SV2 is a synaptic vesicle-specific transporter.

Amino Acid Sequence↗

PubMed1990

Cholinergic synaptic vesicles are metabolically and biophysically heterogeneous even in resting terminals.

The metabolic heterogeneity of synaptic vesicles in the cholinergic nerve terminals of the electromotor neurons of Torpedo marmorata has been studied in resting tissue by evaluating the molecular acetylcholine content (MAC) of synaptic vesicles after extraction from frozen and crushed tissue and high-resolution centrifugal density gradient separation in a zonal rotor. Although vesicular acetylcholine was distributed in the gradient as a single, more or less symmetrical peak, 3 subpopulations of synaptic vesicles could be identified: a small, relatively light subpopulation of low MAC on the ascending limb of the acetylcholine peak, designated V0, a main population of fully charged vesicles designated V1, and a small, denser subpopulation also of low MAC on the descending limb of the acetylcholine peak, designated V2. The mean proportions and MACs of the 3 pools were: V0, 13%, 58,000; V1, 53%, 246,000; V2, 34%, 79,000. When tritiated acetate was perfused through excised blocks of electric organ for 1-2 h before vesicle isolation, the specific radioactivity of the acetylcholine in the V0 and V2 pools was 10-30 times higher than in the V1 pool. This suggests that both the V0 and V2 pools are not generated by the isolation procedure but are present in the intact endings and are functionally active. On the basis of their density and uptake of newly synthesized acetylcholine, the V0 and V2 pools were identified with the previously described VP0 pool of axonal vesicles and the VP2 pool of recycling vesicles in stimulated nerve terminals respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗