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PubMedDate not supplied

Synapsin I in intraocular hippocampal transplants during maturation and aging: effects of brainstem cografts.

The role of target innervation for maintenance of synaptic proteins in the hippocampal formation during aging was investigated. Fetal CA1 tissue and brainstem tissue containing the nucleus locus coeruleus was dissected from albino rats and grafted sequentially into the anterior chamber of the eye of adult rat recipients. Synapsin protein distribution and levels were evaluated by immunohistochemistry and quantitative immunolabeling in single hippocampal grafts or brainstem-hippocampal double grafts at 6, 12, or 24 mo postgrafting. The synapsin levels in 6-mo-old single hippocampal transplants were significantly lower than those in situ, and remained at these lower levels at 12 and 24 mo. On the contrary, synapsin levels were close to normal in the hippocampal portion of double grafts in the 6- and the 12-mo-group. However, in the 24-mo-old double transplants the levels had declined significantly, approaching levels seen in single hippocampal grafts. The immunoblot results were supported by morphological observations with synapsin antibodies and immunohistochemistry. The present data demonstrate that hippocampal tissue maintained near normal synapsin levels when grafted together with brainstem tissue, as compared to the lower levels seen in single hippocampal grafts. This normalization of synapsin levels was, however, not seen in the aged hippocampal-brainstem double grafts.

Aging↗
PubMed1995

Ca2+/calmodulin-dependent protein kinase II and synapsin I-like protein in mouse insulinoma MIN6 cells.

Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) may play a key role in the regulation of insulin secretion. We obtained evidence for the presence of CaM kinase II and its substrate, a 84-kilodalton (kDa) protein, in mouse insulinoma MIN6 cells. CaM kinase II from MIN6 cells has one subunit of 55 kDa, determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, is autophosphorylated in a Ca2+/CaM-dependent manner, and phosphorylates several substrates that serve for rat brain CaM kinase II. In the membrane fraction of MIN6 cells, we identified a 84-kDa protein that was immunoreactive with the antirat brain synapsin I antibody. One-dimensional phosphopeptide mapping by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed the sites of the phosphorylation by cAMP-dependent protein kinase (cAMP kinase) and that by CaM kinase II to be site 1 (10 kDa) and site 2 (30 kDa), respectively, therefore, the same as for rat brain synapsin I. In this context, we tentatively termed it synapsin I-like protein. In 32P-labeled cells, nonfuel insulin secretagogues, such as ionomycin, KCl, and tolbutamide, and a fuel secretagogue, glucose, stimulated autophosphorylation of CaM kinase II and the phosphorylation of synapsin I-like protein. These secretagogues potentiated the Ca(2+)-independent activity of CaM kinase II and secretion of insulin from MIN6 cells. The 84-kDa protein is apparently a newly identified member of the synapsin family. We suggest that CaM kinase II regulates insulin secretion via phosphorylation of synapsin I-like protein.

Animals↗
PubMed1990

Developmental changes of synapsin I subcellular localization in rat cerebellar neurons.

Synapsin I, one of the major synaptic proteins, is thought to associate with synaptic vesicles and to play a regulatory role in neurotransmitter release. In mature neurons, it is concentrated almost exclusively in presynaptic nerve endings. Here, we studied the subcellular localization of synapsin I during the development of rat cerebellar cortices by immunocytochemistry, using anti-synapsin I antibodies and found that during the development of rat cerebellar cortices it tentatively exists in the dendritic growth cones of immature internal granule cells and in the axonal growth cones of mossy fibers as well as mature presynaptic endings. Also, we found that synapsin I, in the axonal and dendritic growth cones does not necessarily associate with vesicles, but rather with fuzzy filamentous structures in the cytoplasm. In search of the structure of synapsin I in vivo, we employed the quick-freeze, deep-etch technique after immunogold labeling. Synapsin I seems to thereby connect synaptic vesicles or anchor them to cytoskeletons in presynaptic endings.

Animals↗
PubMed2006

Protein kinase A-mediated synapsin I phosphorylation is a central modulator of Ca2+-dependent synaptic activity.

Protein kinase A (PKA) modulates several steps of synaptic transmission. However, the identification of the mediators of these effects is as yet incomplete. Synapsins are synaptic vesicle (SV)-associated phosphoproteins that represent the major presynaptic targets of PKA. We show that, in hippocampal neurons, cAMP-dependent pathways affect SV exocytosis and that this effect is primarily brought about through synapsin I phosphorylation. Phosphorylation by PKA, by promoting dissociation of synapsin I from SVs, enhances the rate of SV exocytosis on stimulation. This effect becomes relevant when neurons are challenged with sustained stimulation, because it appears to counteract synaptic depression and accelerate recovery from depression by fostering the supply of SVs from the reserve pool to the readily releasable pool. In contrast, synapsin phosphorylation appears to be dispensable for the effects of cAMP on the frequency and amplitude of spontaneous synaptic currents and on the amplitude of evoked synaptic currents. The modulation of depolarization-evoked SV exocytosis by PKA phosphorylation of synapsin I is primarily caused by calmodulin (CaM)-dependent activation of cAMP pathways rather than by direct activation of CaM kinases. These data define a hierarchical crosstalk between cAMP- and CaM-dependent cascades and point to synapsin as a major effector of PKA in the modulation of activity-dependent SV exocytosis.

Analysis of Variance↗
PubMed1999

Quantification of neuromodulin (GAP-43, B-50) and synapsin I in rat striata.

We reported previously that phosphorylated neuromodulin and phosphorylated synapsin I content increased in the striata of amphetamine-sensitized rats; however, the neuronal pathways responsible for the increase were unclear. In the present study, changes in neuromodulin and synapsin I content resulting from the manipulation of lesions were quantified to elucidate the responsible pathways. Nerve terminals originating in the corticostriatal pathway, those from the nigrostriatal pathway and those from interneurons in the striatum, were impaired by unilateral cortical ablation, 6-hydroxydopamine (6-OHDA) treatment and kainic acid injection into the striatum, respectively. Neuromodulin and synapsin I content in the ipsilateral striatum after unilateral ablation of the frontal cortex decreased by 51 and 31%, respectively. The impairment of dopaminergic terminals by 6-OHDA reduced the neuromodulin content by 22%; however, no significant alteration was observed in the synapsin I content as the result of 6-OHDA treatment. The injection of kainic acid did not cause the content of either protein to decrease. These results suggest that corticostriatal nerve terminals possess a large part of the total neuromodulin and almost all the synapsin I in the striatum. Therefore, the increase in phosphorylated neuromodulin induced by repeated treatment with amphetamine may occur in corticostriatal glutamatergic terminas and/or nigrostriatal dopaminergic terminals. On the other hand, the increase in phosphorylated synapsin I may preferentially occur in the corticostriatal glutamatergic terminals.

Animals↗
PubMed2001

Opposing changes in phosphorylation of specific sites in synapsin I during Ca2+-dependent glutamate release in isolated nerve terminals.

Synapsins are major neuronal phosphoproteins involved in regulation of neurotransmitter release. Synapsins are well established targets for multiple protein kinases within the nerve terminal, yet little is known about dephosphorylation processes involved in regulation of synapsin function. Here, we observed a reciprocal relationship in the phosphorylation-dephosphorylation of the established phosphorylation sites on synapsin I. We demonstrate that, in vitro, phosphorylation sites 1, 2, and 3 of synapsin I (P-site 1 phosphorylated by cAMP-dependent protein kinase; P-sites 2 and 3 phosphorylated by Ca(2+)-calmodulin-dependent protein kinase II) were excellent substrates for protein phosphatase 2A, whereas P-sites 4, 5, and 6 (phosphorylated by mitogen-activated protein kinase) were efficiently dephosphorylated only by Ca(2+)-calmodulin-dependent protein phosphatase 2B-calcineurin. In isolated nerve terminals, rapid changes in synapsin I phosphorylation were observed after Ca(2+) entry, namely, a Ca(2+)-dependent phosphorylation of P-sites 1, 2, and 3 and a Ca(2+)-dependent dephosphorylation of P-sites 4, 5, and 6. Inhibition of calcineurin activity by cyclosporin A resulted in a complete block of Ca(2+)-dependent dephosphorylation of P-sites 4, 5, and 6 and correlated with a prominent increase in ionomycin-evoked glutamate release. These two opposing, rapid, Ca(2+)-dependent processes may play a crucial role in the modulation of synaptic vesicle trafficking within the presynaptic terminal.

4-Aminopyridine↗
PubMed1990

Synapsin II. Mapping of a domain in the NH2-terminal region which binds to small synaptic vesicles.

The synapsins are a family of neuron-specific phosphoproteins that selectively bind to small synaptic vesicles in the presynaptic nerve terminal. Using the cDNA encoding rat synapsin IIb, we employed an Escherichia coli expression system to synthesize a variety of fusion proteins containing a truncated protein A linked to different portions of the NH2-terminal region of synapsin II. The recombinant proteins were purified by IgG-Sepharose chromatography and tested in vitro for their ability to bind to purified synaptic vesicles. These experiments identified a region between amino acids 43 and 121 of the amino-terminal portion of synapsin II which binds to synaptic vesicles. Mild trypsinization of synaptic vesicles reduces binding of recombinant proteins to synaptic vesicles, suggesting that the interaction between synapsin II and the vesicles is in part mediated by a synaptic vesicle protein. The 42 NH2-terminal amino acids of synapsin II are not necessary for binding to synaptic vesicles, although this domain contains the phosphorylation site for cAMP-dependent protein kinase.

Animals↗
PubMed1990

Do synapsin I and microtubule-associated proteins bind to a common site on polymerized tubulin?

Synapsin I plays an important role in the regulation of neurotransmitter release, since it binds to synaptic vesicles and to the cytoskeleton, and it bundles F-actin and microtubules. We have previously shown by tryptic digestion of synapsin I that a 44 kDa fragment contains a binding site for polymerized tubulin. In the present experiments, we test whether synapsin I and microtubule-associated proteins (MAPs) have the same or a different binding site on tubulin molecules. Our results show that heat stable MAPs do not compete with synapsin I for binding to taxol tubulin. In addition, subtilisin digestion of tubulin, which suppresses MAPs binding, does not abolish synapsin I cosedimentation with taxol tubulin. Thus, our results strongly suggest that synapsin I (as reported for kinesin) does not bind to the 4 kDa subtilisin digested C-terminal part of the tubulin molecule.

Animals↗
PubMed1996

Invertebrate synapsins: a single gene codes for several isoforms in Drosophila.

Vertebrate synapsins constitute a family of synaptic proteins that participate in the regulation of neurotransmitter release. Information on the presence of synapsin homologs in invertebrates has been inconclusive. We have now cloned a Drosophila gene coding for at least two inferred proteins that both contain a region with 50% amino acid identity to the highly conserved vesicle- and actin-binding "C" domain of vertebrate synapsins. Within the C domain coding sequence, the positions of two introns have been conserved exactly from fly to human. The positions of three additional introns within this domain are similar. The Drosophila synapsin gene (Syn) is widely expressed in the nervous system of the fly. The gene products are detected in all or nearly all conventional synaptic terminals. A single amber (UAG) stop codon terminates the open reading frame (ORF1) of the most abundant transcript of the Syn gene 140 amino acid codons downstream of the homology domain. Unexpectedly, the stop codon is followed by another 443 in-frame amino acid codons (ORF2). Using different antibodies directed against ORF1 or ORF2, we demonstrate that in the adult fly small and large synapsin isoforms are generated. The small isoforms are only recognized by antibodies against ORF1; the large isoforms bind both kinds of antibodies. We suggest that the large synapsin isoform in Drosophila may be generated by UAG read-through. Implications of such an unconventional mechanism for the generation of protein diversity from a single gene are discussed.

Amino Acid Sequence↗
PubMed2002

Mutation analysis of synapsin III gene in schizophrenia.

Synapsin III is a new synapsin family gene with the putative function of synaptogenesis regulation and neurotransmitter release in the brain. The gene was mapped to 22q12-q13, a schizophrenia susceptible region gene as suggested by several linkage studies. Hence, the synapsin III gene is considered a candidate gene of schizophrenia. We systematically sequenced the protein coding and 5'-promoter regions of the synapsin III gene to look for mutations in 62 Han Chinese schizophrenic patients from Taiwan with positive family history. Further case-control association study was performed among 163 patients and 151 controls using the genetic polymorphic markers identified from these 62 patients. Three single nucleotide polymorphisms (SNPs) were identified: g.-631C > G and g.-196G>A at 5'-promoter region, and g.69G>A at exon 1. Besides, no other mutations were identified in these patients. The g.69G>A polymorphism does not alter the amino acid threonine at codon 23 (ACG>ACA). Further case-control association studies also did not find significant differences of genotype or allele frequency distributions of these three polymorphisms between 163 patients and 151 non-psychotic comparison individuals. Hence, our data are not in favor of a large effect of synapsin III gene in the pathogenesis of schizophrenia.

Asian People↗
PubMed2004

Differential expression of synapsin in visual neurons of the locust Schistocerca gregaria.

In many taxa, photoreceptors and their second-order neurons operate with graded changes in membrane potential and can release neurotransmitter tonically. A common feature of such neurons in vertebrates is that they have not been found to contain synapsins, a family of proteins that indicate the presence of a reserve pool of synaptic vesicles at synaptic sites. Here, we provide a detailed analysis of synapsin-like immunoreactivity in the compound eye and ocellar photoreceptor cells of the locust Schistocerca gregaria and in some of the second-order neurons. By combining confocal laser scanning microscopy with electron microscopy, we found that photoreceptor cells of both the compound eye and the ocellus lacked synapsin-like immunostaining. In contrast, lamina monopolar cells and large ocellar L interneurons of the lateral ocellus were immunopositive to synapsin. We also identified the output synapses of the photoreceptors and of the L interneurons, and, whereas the photoreceptor synapses lacked immunolabeling, the outputs of the L interneurons were clearly labeled for synapsin. These findings suggest that the photoreceptors and the large second-order neurons of the locust differ in the chemical architecture of their synapses, and we propose that differences in the time course of neurotransmission are the reason for this.

Animals↗
PubMed1999

Invertebrate tissue inhibitor of metalloproteinase: structure and nested gene organization within the synapsin locus is conserved from Drosophila to human.

Vertebrate tissue inhibitors of metalloproteinases (TIMPs) regulate extracellular matrix metalloproteinases and are thus involved in a wide variety of developmental and physiological processes. By identifying cDNAs of a transcript detected within an intron of the Drosophila synapsin gene we have cloned the Drosophila TIMP gene (Timp), which represents the first invertebrate member of the TIMP gene family. Sequence analysis revealed an open reading frame of 210 amino acids with 35% identity to human TIMPs and a conserved exon-intron structure. Analysis of sequence data from the Sanger Centre demonstrated that the human TIMP3 gene is encoded within intron V of the human synapsin-III gene, indicating that the nested organization of TIMP and synapsin genes may be a general feature conserved in evolution. We therefore speculate that the human TIMP4 gene will be located in intron V of the human synapsin-II gene on chromosome 3p25, and we present preliminary evidence that a human synapsin-IV gene is located near the TIMP2 gene on chromosome 17q23-q25.

Amino Acid Sequence↗
PubMed1987

Synapsin I, a phosphoprotein associated with synaptic vesicles: possible role in regulation of neurotransmitter release.

The data presented here provide evidence that the study of neuronal phosphoproteins can lead to the identification of previously unknown proteins and that these proteins may play important roles in neuronal communication. Specifically, in the case of synapsin I, direct evidence has been obtained that this phosphoprotein is involved in regulating neurotransmitter release. A tentative explanation of the results obtained in the micro-injection studies is as follows: synapsin I, in the dephosphostate, is bound to the cytoplasmic surface of synaptic vesicles and inhibits the ability of the vesicle to interact with the plasma membrane; increases in intracellular calcium activate calmodulin kinase II which in turn phosphorylates synapsin I and the phosphorylated synapsin I dissociates from the synaptic vesicle thus removing a constraint on the release of neurotransmitter. Clearly, more studies need to be done to rigorously test this hypothesis. Nevertheless these studies of synapsin I suggest that the study of previously unknown phosphoproteins will lead to the elucidation of previously unknown regulatory processes in neurons.

Animals↗
PubMed1991

Immunocytochemical localization of synapsin I in the adrenal medulla of rats.

The localization of synapsin I in the rat adrenal medulla was studied using the light- and electronmicroscopic immunohistochemistry. By light microscopy, many dot-like reaction products for synapsin I were recognized to be distributed throughout the medullary tissue. The immunoelectron microscopy clearly revealed that gold particles for synapsin I accumulated in abundance in the nerve terminals forming synapses with the chromaffin cell, while the particles were not localized in the chromaffin cells at all. In the nerve terminal, the gold particles were localized exclusively in the region occupied by synaptic vesicles except for the region just beneath the presynaptic plasma membrane. The synaptic vesicles were frequently linked with the adjacent ones by filamentous structures implicated in synapsin I. It is concluded morphologically that synapsin I is a highly-specific protein for the genuine neuron, and is not detected even in the chromaffin cell which originates from the neural crest.

Adrenal Medulla↗
PubMed1984

On the disposition of a phosphorylated protein ("synapsin I") and its associated kinases in synaptosomes from rat brain.

Endogenous phosphorylation of synapsin I (protein I), a phosphoprotein located on the surface of synaptic vesicles, was studied in vesicles prepared from synaptosomes lysed in the absence (control) or presence of 50 microM-cyclic AMP ("cAMP-treated"). Compared to synaptic plasma membrane (SPM) fractions prepared in parallel, and confirming previous work, the vesicle fractions were highly enriched on a unit protein basis in Ca2+-calmodulin-dependent kinase activity towards synapsin I. In contrast, with control vesicles the magnitude of the total phosphorylation of synapsin I in the presence of cyclic AMP was similar to that observed in SPM, but regulation by cyclic AMP was only partial. In "cAMP-treated" vesicles, however, synapsin I phosphorylation was highly enriched compared to SPM and the activity was virtually independent of cyclic AMP. The results show that while the free catalytic subunit of the cyclic AMP-dependent kinase remains associated with synapsin I during vesicle isolation the holoenzyme remains bound to membrane fragments, probably through its regulatory subunit.

Animals↗
PubMed2002

The synapsins: beyond the regulation of neurotransmitter release.

The synapsins are a family of five closely related neuron-specific phosphoproteins associated with the membranes of synaptic vesicles. The synapsins have been implicated in the regulation of neurotransmitter release. They tether synaptic vesicles to actin filaments in a phosphorylation-dependent manner, controlling the number of vesicles available for release at the nerve terminus. A growing body of evidence suggests that the synapsins play a broad role during neuronal development. They participate in the formation and maintenance of synaptic contacts among central neurons. In addition, each synapsin has a specific role during the elongation of undifferentiated processes and their posterior differentiation into axons and dendrites. In this review, we focus on these novel roles of synapsins during the early stages of development.

Animals↗
PubMed1987

Involvement of pentylenetetrazole in synapsin I phosphorylation associated with calcium influx in synaptosomes from rat cerebral cortex.

To determine precisely how pentylenetetrazole (PTZ) is involved in the biochemical processes at the presynaptic nerve terminal, the effect of PTZ, under various conditions, on the phosphorylation of synapsin I (previously called protein I) was investigated, using 32Pi in synaptosomes from rat cerebral cortex. PTZ markedly stimulated the incorporation of 32P into this protein as determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and autoradiography, but it failed to stimulate protein phosphorylation in Ca2+-free medium containing ethylene glycol bis-(beta-aminoethylether)-N',N'-tetraacetic acid (EGTA). Moreover, the PTZ-stimulated synapsin I phosphorylation was reversed by addition of EGTA sufficient to chelate all external free Ca2+. PTZ also stimulated synaptosomal accumulation of Ca2+. The PTZ-stimulatory effects of both synapsin I phosphorylation and synaptosomal accumulation of Ca2+ were inhibited markedly by tetrodotoxin as well as by cobalt chloride and lanthanum chloride. The calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7, strongly) and N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5, weakly) reduced the PTZ-stimulatory effect on synapsin I phosphorylation by about 75 and 15%, respectively, whereas these antagonists had essentially no effect on PTZ-stimulated synaptosomal accumulation of Ca2+. These results suggest that PTZ causes the influx of Ca2+ into the presynaptic nerve terminal secondary to the elevated Na+ and is consequently involved in the synapsin I phosphorylation step, facilitating the Ca2+/calmodulin-mediated presynaptic event leading to seizure discharge.

Animals↗
PubMed1985

The use of Synapsin I as a biochemical marker for neuronal damage by trimethyltin.

The content of Synapsin I (Protein I) was examined in brain regions of adult rats exposed to trimethyltin (TMT), and in control animals. Long Evans hooded rats were intragastrically dosed with 4 mg TMT hydroxide/kg body weight for 4 days. No perturbations in Synapsin I levels were evident by 24 h following the fourth dose; however, by 36 h, a significant decrease of 28% in Synapsin I level was present in the hippocampus of TMT treated animals. This decrease was selective, no other brain region examined was affected. As determined by regional analysis of inorganic tin, this specificity was not due to a profound preferential accumulation of tin in the hippocampus. Despite the absence of an alteration in Synapsin I levels at 24 h, morphological examination revealed perturbation in the normal uniform arrangement of granule cell neurons, with dead neurons diffusely distributed throughout the facia dentata. At 36 h, these changes were only slightly more extensive. In contrast, examination of the terminal projection area of these cells, the mossy boutons, showed to be unaffected at 24 h after the 4th dose of TMT. However, by 36 h, many of the mossy boutons contained dense bodies and showed signs of degeneration. This result suggested that the loss of Synapsin I coincides with degeneration of the nerve terminal region. In order to better establish the temporal correlation, a less severe dosing regimen (only 3 days of exposure to 4 mg TMT/kg body wt) was utilized to attenuate the time course of necrosis. Again, necrotic changes were visible in the perikaryon by 1 day after termination of toxicant dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗