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PubMed1999

Synapsins as regulators of neurotransmitter release.

One of the crucial issues in understanding neuronal transmission is to define the role(s) of the numerous proteins that are localized within presynaptic terminals and are thought to participate in the regulation of the synaptic vesicle life cycle. Synapsins are a multigene family of neuron-specific phosphoproteins and are the most abundant proteins on synaptic vesicles. Synapsins are able to interact in vitro with lipid and protein components of synaptic vesicles and with various cytoskeletal proteins, including actin. These and other studies have led to a model in which synapsins, by tethering synaptic vesicles to each other and to an actin-based cytoskeletal meshwork, maintain a reserve pool of vesicles in the vicinity of the active zone. Perturbation of synapsin function in a variety of preparations led to a selective disruption of this reserve pool and to an increase in synaptic depression, suggesting that the synapsin-dependent cluster of vesicles is required to sustain release of neurotransmitter in response to high levels of neuronal activity. In a recent study performed at the squid giant synapse, perturbation of synapsin function resulted in a selective disruption of the reserve pool of vesicles and in addition, led to an inhibition and slowing of the kinetics of neurotransmitter release, indicating a second role for synapsins downstream from vesicle docking. These data suggest that synapsins are involved in two distinct reactions which are crucial for exocytosis in presynaptic nerve terminals. This review describes our current understanding of the molecular mechanisms by which synapsins modulate synaptic transmission, while the increasingly well-documented role of the synapsins in synapse formation and stabilization lies beyond the scope of this review.

Animals↗
PubMed1991

Regulation by synapsin I and Ca(2+)-calmodulin-dependent protein kinase II of the transmitter release in squid giant synapse.

1. Presynaptic or simultaneous pre- and postsynaptic voltage-clamp protocols were implemented in the squid giant synapse in order to determine the magnitude and time course of the presynaptic calcium current (ICa) and its relation to transmitter release before and after presynaptic injection of proteins. These included several forms of synapsin I, calcium-calmodulin-dependent protein kinase II (CaM kinase II) and avidin. 2. The quantities and location of these proteins were monitored by fluorescence video-enhanced microscopy during the electrophysiological measurements. 3. Presynaptic injection of dephosphorylated synapsin I inhibited synaptic transmission with a time course consistent with diffusion of the protein through the terminal and action at the active release zone. A mathematical model relating the diffusion of synapsin I into the terminal with transmitter release was developed to aid in the interpretation of these results. 4. Synapsin I inhibition of transmitter release was reversible. 5. The action of synapsin I was highly specific, as phosphorylation of the tail region only or head and tail regions prevented synapsin I from inhibiting release. 6. Injections of heat-treated synapsin I or of avidin, a protein with a size and isoelectric point similar to those of synapsin I, had no effect on transmitter release. 7. CaM kinase II injected presynaptically was found to facilitate transmitter release. This facilitation, which could be as large as 700% of the control response, was related to the level of penetration of the enzyme along the length of the preterminal A mathematical model of this facilitation indicates a reasonable fit between the distribution of CaM kinase II within the terminal and the degree of facilitation. 8. The overall shape of the postsynaptic response was not modified by either synapsin I or CaM kinase II injection. 9. The data suggest that, in addition to releasing transmitter, calcium also penetrates the presynaptic cytosol and activates CaM kinase II. When activated, CaM kinase II phosphorylates synapsin I, which reduces its binding to vesicles and/or cytoskeletal structures, enabling more vesicles to be released during a presynaptic depolarization. The amplitude of the postsynaptic response will then be both directly and indirectly regulated by depolarization induced Ca2+ influx. This model provides a molecular mechanism for synaptic potentiation.

Action Potentials↗
PubMed2006

The conserved protein kinase-A target motif in synapsin of Drosophila is effectively modified by pre-mRNA editing.

BACKGROUND: Synapsins are abundant synaptic vesicle associated phosphoproteins that are involved in the fine regulation of neurotransmitter release. The Drosophila member of this protein family contains three conserved domains (A, C, and E) and is expressed in most or all synaptic terminals. Similar to mouse mutants, synapsin knock-out flies show no obvious structural defects but are disturbed in complex behaviour, notably learning and memory. RESULTS: We demonstrate that the N-terminal phosphorylation consensus motif RRxS that is conserved in all synapsins investigated so far, is modified in Drosophila by pre-mRNA editing. In mammals this motif represents the target site P1 of protein kinase A (PKA) and calcium/calmodulin dependent protein kinase I/IV. The result of this editing, by which RRFS is modified to RGFS, can be observed in cDNAs of larvae and adults and in both isolated heads and bodies. It is also seen in several newly collected wild-type strains and thus does not represent an adaptation to laboratory culture conditions. A likely editing site complementary sequence is found in a downstream intron indicating that the synapsin pre-mRNA can form a double-stranded RNA structure that is required for editing by the adenosine deaminase acting on RNA (ADAR) enzyme. A deletion in the Drosophila Adar gene generated by transposon remobilization prevents this modification, proving that the ADAR enzyme is responsible for the pre-mRNA editing described here. We also provide evidence for a likely function of synapsin editing in Drosophila. The N-terminal synapsin undeca-peptide containing the genomic motif (RRFS) represents an excellent substrate for in-vitro phosphorylation by bovine PKA while the edited peptide (RGFS) is not significantly phosphorylated. Thus pre-mRNA editing by ADAR could modulate the function of ubiquitously expressed synapsin in a cell-specific manner during development and adulthood. CONCLUSION: Similar to several other neuronal proteins of Drosophila, synapsin is modified by ADAR-mediated recoding at the pre-mRNA level. This editing likely reduces or abolishes synapsin phosphorylation by PKA. Since synapsin in Drosophila is required for various forms of behavioural plasticity, it will be fascinating to investigate the effect of this recoding on learning and memory.

Adenosine Deaminase↗
PubMed2001

Synapsin I is expressed in epithelial cells: localization to a unique trans-Golgi compartment.

Synapsin I is abundant in neural tissues. Its phosphorylation is thought to regulate synaptic vesicle exocytosis in the pre-synaptic terminal by mediating vesicle tethering to the cytoskeleton. Using anti-synapsin antibodies, we detected an 85 kDa protein in liver cells and identified it as synapsin I. Like brain synapsin I, non-neuronal synapsin I is phosphorylated in vitro by protein kinase A and yields identical (32)P-peptide maps after limited proteolysis. We also detected synapsin I mRNA in liver by northern blot analysis. These results indicate that the expression of synapsin I is more widespread than previously thought. Immunofluorescence analysis of several non-neuronal cell lines localizes synapsin I to a vesicular compartment adjacent to trans-elements of the Golgi complex, which is also labeled with antibodies against myosin II; no sub-plasma membrane synapsin I is evident. We conclude that synapsin I is present in epithelial cells and is associated with a trans-Golgi network-derived compartment; this localization suggests that it plays a role in modulating post-TGN trafficking pathways.

Animals↗
PubMed1994

Redistribution of synapsin I and synaptophysin in response to electrical stimulation in the rat neurohypophysial nerve endings.

To understand the dynamics of synaptic vesicles and synapsin I, we have studied the localization of synapsin I and synaptophysin in resting and stimulated nerve endings by ultracryomicrotomy and colloidal gold-immunocytochemistry. First, we characterized microvesicles in resting nerve endings of the rat neurohypophysis, which was chosen as the model of nerve ending in this study. Synaptophysin was localized in microvesicles that were clustered beneath the plasma membrane. Quick-freeze deep-etching electron microscopy showed that short strands cross-linked microvesicles to each other, which highly resemble the structures observed in our studies of the presynaptic nerve terminals of central and peripheral nervous system and in vitro reconstitution of synapsin I and synaptic vesicles. Immunocytochemistry showed that synapsin I was localized to the region of cluster of microvesicles. Second, using this system, we examined localization of synapsin I and synaptophysin in nerve endings after electrical stimulation. Besides release of neurosecretory granules, clusters of microvesicles dissappeared and both microvesicles and synaptophysin were scattered over nerve endings. These changes were also confirmed by quick-freeze, freeze-substitution. Immunocytochemistry of the stimulated sample revealed that synapsin I was also scattered. The results show that microvesicles in neurohypophysis have similar characteristics of typical synaptic vesicles and synapsin I has a role as a scaffold to cross-link microvesicles to be clustered in resting nerve endings. This scaffold of synapsin I was disengaged after stimulation to redistribute microvesicles and synapsin I itself, which may be the mechanism of synapsin I to regulate the availability of synaptic vesicles for release.

Animals↗
PubMed2003

New aspects of neurotransmitter release and exocytosis: involvement of Ca2+/calmodulin-dependent phosphorylation of synapsin I in insulin exocytosis.

The exocytosis of insulin from pancreatic beta-cells is closely related to intracellular elevation of Ca(2+). The effects of Ca(2+) may be mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Four subunits of CaMKII, termed alpha, beta, gamma, and delta, are encoded by distinct genes, and various isoforms of these subunits exist as different splicing variants. In the brain, phosphorylation of synapsin I by the alpha isoform induces neurotransmitter release. In order to clarify whether phosphorylation of synapsin I by CaMKII was involved in insulin exocytosis, we cloned the isoforms of CaMKII and synapsin I from mouse insulinoma MIN6 cells. We found that beta'e and delta2 are the major isoforms of CaMKII and that synapsin Ib is a major isoform of synapsin I in MIN6 cells. It was interesting that delta2 and synapsin Ib were co-localized with insulin secretory granules in the cells. Treatment of MIN6 cells with glucose and tolbutamide rapidly activated CaMKII. Immunoblot analysis with two antibodies against synapsin I phosphorylated by CaMKII demonstrated the increase in phosphorylation of synapsin I by the secretagogues. Furthermore, the secretagogue-induced phosphorylation of synapsin I and insulin secretion were potentiated by transient overexpression of the beta'e or delta2 isoform. These results suggest that activation of CaMKII and the concomitant phosphorylation of synapsin I induce insulin exocytosis from pancreatic beta-cells.

Animals↗
PubMed1999

Cloning of cDNAs encoding human synapsins IIa and IIb.

The synapsins are a family of neuronal phosphoproteins that are specifically associated with the cytoplasmic surface of synaptic vesicles. In mammals, distinct genes for synapsins I, II, and III give rise to members of the synapsin family. The synapsins are implicated in neurotransmitter release and synaptogenesis, processes believed to be aberrant in several neuropsychiatric diseases. The characterization of human synapsins is therefore important for evaluating the possible role of synapsins in human neuropathology. In this report, we describe the cloning and sequence of human synapsins IIa and IIb, products of the synapsin II gene. Human synapsins IIa and IIb conform to the previously described domain model of the synapsins, and the most conserved protein domains are A, C, and E.

Amino Acid Sequence↗
PubMed2000

Synapsin III: developmental expression, subcellular localization, and role in axon formation.

We have investigated the developmental expression and subcellular localization of synapsin III, the newest member of the synapsin family, in cultured mouse hippocampal neurons. Our results indicate that synapsin III is expressed early during development, with levels peaking 7 d after plating and declining thereafter. Synapsin III is highly concentrated in growth cones. Using specific antisense oligonucleotides, we have also examined the effect of depleting synapsin III on neurite elongation and synaptogenesis. When synapsin III was suppressed immediately after plating, hippocampal neurons extended minor processes but failed to differentiate one of them as the axon. The suppression of synapsin III after axonal elongation did not affect the time course of synapse formation. The results indicate that synapsin III has a developmental time course, a subcellular localization, and a developmental function very different from those of synapsin I and synapsin II.

Animals↗
PubMed1996

Increased in vivo phosphorylation state of neuromodulin and synapsin I in striatum from rats treated with repeated amphetamine.

Repeated, intermittent treatment of rats with amphetamine results in a sensitization of locomotor and stereotyped behaviors that is accompanied by an enhancement in stimulus-induced dopamine release. The effects of repeated treatment with amphetamine on the phosphorylation state of neuromodulin and synapsin I, proteins involved in neurotransmitter release, were investigated. Rats were injected with 2.5 mg/kg AMPH, twice a week for 5 weeks (intermittent treatment). One week after the last injection, a challenge dose of 2.5 mg/kg AMPH was given 30 min before sacrifice. We previously reported an increase in neuromodulin phosphorylation with this sensitization paradigm. Site 3-phospho-synapsin I, site 1-phospho-synapsin I and phosphoser41-neuromodulin were detected with phosphorylation state-specific antibodies. Acute treatment with amphetamine did not increase the state of synapsin phosphorylation at either site 1 or site 3, but both site 1-phospho-synapsin I and site 3-phospho-synapsin I were increased (38% and 34%, respectively) after repeated, intermittent amphetamine. Immunoreactivity for phosphoser41-neuromodulin was increased by acute amphetamine. Site 3-phospho-synapsin I, site 1-phospho-synapsin I and phosphoser41-neuromodulin were also measured in striatum from rats receiving a different regimen in which amphetamine is given in escalating doses for 4 weeks. With this regimen, behavioral sensitization and enhanced dopamine release are exhibited in rats withdrawn 4 weeks, but not 3 days, after pretreatment. Small but significant increases in site 3-phospho-synapsin I and phosphoser41-neuromodulin were found in rats withdrawn 4 weeks from the escalating dose regimen, but not in those withdrawn 3 days. The increase in the phosphorylation state of synapsin I and neuromodulin reflect changes in the presynaptic signal transduction pathways which could play a role in the behavioral sensitization and contribute to the enhanced dopamine release reported in amphetamine-sensitized rats.

Animals↗
PubMed1985

Molecular cloning of cDNAs for the nerve-cell specific phosphoprotein, synapsin I.

To provide access to synapsin I-specific DNA sequences, we have constructed cDNA clones complementary to synapsin I mRNA isolated from rat brain. Synapsin I mRNA was specifically enriched by immunoadsorption of polysomes prepared from the brains of 10-14 day old rats. Employing this enriched mRNA, a cDNA library was constructed in pBR322 and screened by differential colony hybridization with single-stranded cDNA probes made from synapsin I mRNA and total polysomal poly(A)+ RNA. This screening procedure proved to be highly selective. Five independent recombinant plasmids which exhibited distinctly stronger hybridization with the synapsin I probe were characterized further by restriction mapping. All of the cDNA inserts gave restriction enzyme digestion patterns which could be aligned. In addition, some of the cDNA inserts were shown to contain poly(dA) sequences. Final identification of synapsin I cDNA clones relied on the ability of the cDNA inserts to hybridize specifically to synapsin I mRNA. Several plasmids were tested by positive hybridization selection. They specifically selected synapsin I mRNA which was identified by in vitro translation and immunoprecipitation of the translation products. The established cDNA clones were used for a blot-hybridization analysis of synapsin I mRNA. A fragment (1600 bases) from the longest cDNA clone hybridized with two discrete RNA species 5800 and 4500 bases long, in polyadenylated RNA from rat brain and PC12 cells. No hybridization was detected to RNA from rat liver, skeletal muscle or cardiac muscle.

Animals↗
PubMed1994

Synapsin I expression in spinal cord neurons during chick embryo development.

The cellular distribution of synapsin I in chick spinal cord has been examined during embryo development and in cultured neurons from different developmental stages. Using immunocytochemical methods we have observed that synapsin I appears lightly detectable in spinal cord of embryonic day (E)5-E8 embryos when the motor neurons have already established functional contacts with muscle fibers, and increases at E9. Until E8 synapsin I immunoreactivity appeared mainly localized in the gray matter of spinal cord; immunostaining of white matter becomes clearly evident only at E9. These observations indicate that synapsin I expression and possibly its transport to the nerve terminals may be stimulated by sequential signals. The cellular distribution of synapsin I observed in vivo is maintained in E8 and E9 spinal cord neuron cell cultures. In fact, in E8 cultured neurons, synapsin I immunostaining is observed only in the cell body, while in E9 cultured neurons both cell body and fibers are stained. The addition of muscle extracts to E8 cultures induces synapsin I decoration of fibers similar to that observed in E9 cultured neurons. Indeed Western and Northern blot analysis and in situ hybridization demonstrate an increase of synapsin I and its mRNA in spinal cord neurons kept in the presence of muscle extracts. These data suggest that synapsin I expression, as previously reported for other neuronal markers, can be modulated by soluble factors present in target cells.

Animals↗
PubMed1996

Changes in the expression of synapsin I and II messenger RNA during postnatal rat brain development.

Synapsin Ia, Ib, IIa, and IIb are neuronal phosphoproteins, which are supposed to play a role in the short-term regulation of neurotransmitter release. Besides a high degree of homology among the four synapsin subtypes, there are structural differences in the 3'end of their coding region. Here we present the first extensive study of the expression of their gene transcripts by using in situ hybridization and northern blot analysis. Our results show regionally and temporally distinct expression patterns of synapsin Ia, Ib, IIa, and IIb, which suggests different functional properties of the four synapsin subtypes. There was no specific messenger RNA (mRNA) expression of synapsin IIb in most brain regions apart from the cerebellum, suggesting a minor functional role of this synapsin subtype. Synapsin Ia, Ib, and IIa mRNA were expressed earlier in ontogenetically older brain regions such as the piriform cortex, the thalamus, and the hippocampus and later in ontogenetically younger areas such as the neocortex and the cerebellum. Owing to the distinct expression pattern of the synapsin subtypes, we suppose that the synapsins might be essential for the underlying molecular mechanism of pattern formation and plasticity in distinct brain regions during different states of rat brain development.

Animals↗
PubMed1990

Synapsin I expression in the rat retina during postnatal development.

The expression of the synapsin I gene was studied during postnatal development of the rat retina at the mRNA and protein levels. In situ hybridization histochemistry showed that synapsin I mRNA was expressed already in nerve cells in the ganglion cell layer of the neonatal retina, while it appeared in neurons of the inner nuclear layer from postnatal day 4 onward. Maximal expression of synapsin I mRNA was observed at P12 in ganglion cells and in neurons of the inner nuclear layer followed by moderate expression in the adult. At the protein level a shift of synapsin I appearance was observed from cytoplasmic to terminal localization during retinal development by immunohistochemistry. In early stages (P4 and P8), synapsin I was seen in neurons of the ganglion cell layer and in neurons of the developing inner nuclear layer as well as in the developing inner plexiform layer. In the developing outer plexiform layer synapsin I was localized only in horizontal cells and in their processes. Its early appearance at P4 indicated the early maturation of this cell type. A shift and strong increase of labelling to the plexiform layers at P12 indicated the localization of synapsin I in synaptic terminals. The inner plexiform layer exhibited a characteristic stratified pattern. Photoreceptor cells never exhibited synapsin I mRNA or synapsin I protein throughout development.

Animals↗
PubMed1992

Cyclic inhibition-potentiation of the crosslinking of synapsin I with brain microtubules by protein kinase FA (an activator of ATP.Mg-dependent protein phosphatase).

The ATP.Mg-dependent type-1 protein phosphatase activating factor (FA) was identified as a protein kinase that could phosphorylate synapsin I, a neuronal protein that coats synaptic vesicles, binds to cytoskeleton and is believed to be involved in the modulation of neurotransmission. More importantly, more than 90% of the phosphates in 32P-synapsin I phosphorylated by FA could be removed by the activated ATP.Mg-dependent type-1 protein phosphatase and the synapsin I phosphatase activity was found to be strictly FA-dependent. Functional study further revealed that as a synapsin I kinase, factor FA could phosphorylate synapsin I and thereby inhibits crosslinking of synapsin I with tubulin, while as a synapsin I phosphatase activator, FA could promote the crosslinking copolymerization of synapsin I with tubulin. Taken together, the results provide initial evidence that a cyclic modulation of the crosslinking copolymerization of synapsin I with brain microtubules can be controlled by factor FA, representing an efficient cyclic cascade control mechanism for the regulation of axonal transport process during neurotransmission.

Animals↗
PubMed1996

Expression of synapsin I correlates with maturation of the neuromuscular synapse.

Synapsins are a family of neuron-specific phosphoproteins that are localized within the presynaptic terminals in adult brain. Previous work has demonstrated that introduction of exogenous synapsins I(a + b) or IIa into Xenopus spinal neurons promoted maturation of the neuromuscular synapse in a nerve-muscle co-culture system. We have now studied the expression of endogenous Xenopus synapsin I during synaptic maturation in vivo and in culture, using a polyclonal antibody raised against Xenopus synapsin I. Immunoprecipitation experiments indicated that synapsin I was not detectable during the early phase of synaptogenesis in vivo, and exhibited a marked increase during the period of synaptic maturation. In contrast, the expression of synaptophysin, another synaptic vesicle protein, was detected at the start of nervous system formation, and remained at a high level thereafter. Similar expression profiles for the two proteins were also observed in immunocytochemical studies of Xenopus spinal neurons in culture: intense staining of synaptophysin was found on the first day, while synapsin I was not detected until after three days in culture. The expression of synapsin I correlated very well with the appearance of a bell-shaped amplitude distribution of spontaneous synaptic currents, a physiological parameter which reflects functional maturation of the neuromuscular synapse. In one-day-old cultures grown in the absence of laminin, an extracellular matrix protein known to be present at the neuromuscular junction, the amplitude distribution of virtually all synapses was skewed towards smaller values. In contrast, when laminin was used as a culture substrate, many synapses exhibited a bell-shaped amplitude distribution. Laminin treatment also induced synapsin I expression in one-day-old cultures. These results suggest that the expression of endogenous synapsin I may regulate maturation at neuromuscular synapses.

Animals↗
PubMed1993

Fluorescence approaches to the study of the actin-nucleating and bundling activities of synapsin I.

Synapsin I is a neuron-specific phosphoprotein which binds to small synaptic vesicles and actin in a phosphorylation-dependent fashion. We have analyzed the ability of synapsin I to interact with actin monomers and filaments using purified proteins derivatized with fluorescent probes. Synapsin I accelerates the initial rate of actin polymerization and increases the final steady-state levels of polymerized actin. The fraction of total actin polymerized by synapsin I strongly depends on the synapsin I-actin ratio. We have visualized the actin-bundling activity of synapsin I using a non-perturbing method, video-enhanced microscopy of fluoresceinated synapsin I and actin filaments. Our findings suggest that synapsin I exerts a control on the physical characteristics of the cytoskeletal network of the nerve terminal and are consistent with the proposed role of synapsin I in mediating the interaction of synaptic vesicles with actin.

Actins↗
PubMed2001

Spatial learning induces neurotrophin receptor and synapsin I in the hippocampus.

We report that rats learning a spatial memory task in the Morris water maze show elevated expression of the signal transduction receptor for BDNF and the synaptic associated protein synapsin I in the hippocampus. Nuclease protection assays showed maximal levels of TrkB and synapsin I mRNAs in the hippocampus by the time that asymptotic learning performance had been reached (Day 6). Increases in synapsin I mRNA were matched by changes in synapsin I protein as revealed by western blot analysis. Synapsin I is a downstream effector for the BDNF tyrosine kinase cascade pathway which has important roles in synaptic remodeling and function. Therefore, parallel changes in TrkB and synapsin I mRNAs suggest a role of the BDNF system in synaptic function or adaptation. Levels of TrkB mRNA in the hippocampus were attenuated after learning acquisition (Day 20), but synapsin I mRNA was still elevated, suggesting that the BDNF system may participate in events secondary to learning, such as strengthening of neural circuits. TrkB and synapsin I mRNAs showed an increasing trend in the cerebellum of learning rats and no changes were observed in the caudal cerebral cortex. The selectivity of the changes in trkB and synapsin I, affecting the hippocampus, is in agreement with the role of this structure in processing of spatial information. Behavioral regulation of neurotrophins may provide a molecular basis for the enhanced cognitive function associated with active lifestyles, and guide development of strategies to promote neural healing after CNS injury or disease.

Animals↗
PubMed2002

Neuronal differentiation of cultured human NTERA-2cl.D1 cells leads to increased expression of synapsins.

The synapsin family consists of three neuronal-specific phosphoproteins associated with dynamic reorganization of the neuronal cytoskeleton. Synapsin I and II are implicated in axonal and synaptic differentiation, formation and maintenance, whereas the function of synapsin III is not as well defined. We report a significant transcriptional upregulation of all three synapsins (synapsin I, 2.1-fold; synapsin II, 2.6-fold; and synapsin III, 5.5-fold) by retinoic acid-induced differentiation of NTera-2cl.D1 cells, a human paradigm for neuronal differentiation. The observed stronger regulation of synapsin III might be due to still active neurite elongation and a rather early state of presynaptic maturation at the time-point investigated, as synapsin III was previously found to be highly enriched in growth cones and during early synaptic development.

Cell Aggregation↗