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PubMed1983

A calcium/calmodulin-dependent protein kinase from mammalian brain that phosphorylates Synapsin I: partial purification and characterization.

A calcium/calmodulin-dependent protein kinase, which phosphorylates a synaptic vesicle-associated protein designated Synapsin I, has been shown to be present in both soluble and particulate fractions of rat brain homogenates. In the present study, the particulate activity was solubilized by washing with a low ionic strength solution, and the enzymes from the two fractions were partially purified by ion exchange chromatography and calmodulin-Sepharose affinity chromatography. By each of several criteria, the partially purified enzymes from the two sources were indistinguishable. These criteria included specificity for various substrate proteins, concentration dependence of activation by calcium and calmodulin, pH dependence, and apparent affinities for the substrates Synapsin I and ATP. The mild conditions that released the particulate enzyme indicated that it was not tightly bound to the membrane and suggested that it may exist in a dynamic equilibrium between soluble and particulate-bound states. The partially purified enzyme preparations from both the soluble and particulate fractions contained three proteins that were phosphorylated in the presence of calcium and calmodulin, a 50-kilodalton (Kd) protein and two proteins in the 60-Kd region. When compared by phosphopeptide mapping and two-dimensional gel electrophoresis, the proteins were indistinguishable from three proteins of corresponding molecular weights that were shown by Schulman and Greengard (Schulman, H., and P. Greengard (1978) Nature 271: 478-479) to be prominent substrates for calcium/calmodulin-dependent protein kinase in a crude particulate preparation from rat brain. The 50-Kd substrate was the major Coomassie blue staining protein in both partially purified enzyme preparations. The peak of this protein coincided with that of enzyme activity during DEAE-cellulose and calmodulin-Sepharose chromatography. These results suggest that the 50-Kd phosphoprotein may be an autophosphorylatable subunit of the Synapsin I Kinase or may exist in a complex with it.

Animals↗
PubMed1997

Immunocytochemical detection of acetylated alpha-tubulin and Drosophila synapsin in the embryonic crustacean nervous system.

The caridean shrimp Palaemonetes argentinus Nobili is well suited for studying developmental aspects of the crustacean nervous system due to its rapid embryonic development and short reproductive cycle. In the present paper, we demonstrate the pattern of central axonal pathways in embryos of this species by immunohistochemical detection of acetylated alpha-tubulin. Development of the neuropil was elucidated by using an antibody to a Drosophila synapsin. In the ventral nerve cord, the segmental axonal scaffold consists of the paired lateral connectives, a median connective, and the anterior and posterior commissures. Three nerve roots were found to branch off each ganglion anlage, i.e. the main segmental nerve root, a smaller posterior nerve and the intersegmental nerve. However, this pattern is different in the mandibular segment where no intersegmental nerve and only one commissure was encountered. The anterior part of the brain consists of a tritocerebral and a deutocerebral anlage as well asthe anlage of the medial protocerebrum. The latter is connected to the eyestalk via the protocerebral tract. The sequence of development of the eyestalk ganglia was demonstrated in specimens which were stained with the anti-synapsin antibody. The medulla terminalis and medulla interna are the first neuropils to appear and are still fused in early stages. Later, the medulla interna splits off the medulla terminalis. The lamina ganglionaris is the last of the eyestalk neuropils to develop. These findings prove that immunocytochemistry against acetylated alpha-tubulin and synapsin are valuable tools for studying the development of the crustacean nervous system.

Acetylation↗
PubMed1985

Ankyrin and synapsin: spectrin-binding proteins associated with brain membranes.

Brain membranes contain an actin-binding protein closely related in structure and function to erythrocyte spectrin. The proteins that attach brain spectrin to membranes are not established, but, by analogy with the erythrocyte membrane, may include ankyrin and protein 4.1. In support of this idea, proteins closely related to ankyrin and 4.1 have been purified from brain and have been demonstrated to associate with brain spectrin. Brain ankyrin binds with high affinity to the spectrin beta subunit at the midregion of spectrin tetramers. Brain ankyrin also has binding sites for the cytoplasmic domain of the erythrocyte anion channel (band 3), as well as for tubulin. Ankyrins from brain and erythrocytes have a similar domain structure with protease-resistant domains of Mr = 72,000 that contain spectrin-binding activity, and domains of Mr = 95,000 (brain ankyrin) or 90,000 (erythrocyte ankyrin) that contain binding sites for both tubulin and the anion channel. Brain ankyrin is present at about 100 pmol/mg membrane protein, or about twice the number of copies of spectrum beta chains. Brain ankyrin thus is present in sufficient amounts to attach spectrin to membranes, and it has the potential to attach microtubules to membranes as well as to interconnect microtubules with spectrin-associated actin filaments. Another spectrin-binding protein has been purified from brain membranes, and this protein cross-reacts with erythrocyte 4.1. Brain 4.1 is identical to the membrane protein synapsin, which is one of the brain's major substrates for cAMP-dependent and Ca/calmodulin-dependent protein kinases with equivalent physical properties, immunological cross-reaction, and peptide maps. Synapsin (4.1) is present at about 60 pmol/mg membrane protein, and thus is a logical candidate to regulate certain protein linkages involving spectrin.

Animals↗
PubMed1993

Comparison of immunolocalization patterns for the synaptic vesicle proteins p65 and synapsin I in macaque monkey retina.

The distributions of the two synaptic vesicle proteins p65 [Matthew et al. (1981) J. Cell Biol., 91:257-269] and synapsin I [De Camilli et al. (1983) J. Cell Biol., 96:1337-1354] were compared in macaque monkey retina using pre-embedding immunocytochemistry for both light and electron microscopy. The monoclonal antibody AB-48 against p65 labeled ribbon-containing synaptic terminals of cone, rod, and bipolar cells as well as many conventional synapses of amacrine cells. In contrast, a polyclonal antiserum against synapsin I (SYN I) labeled many amacrine conventional synapses but no photoreceptor or bipolar ribbon synaptic terminals. Horizontal cell pre- and post-synaptic profiles in the outer plexiform layer were not labeled by either antibody. At the light microscopic level, the banding patterns in the inner plexiform layer also differed for the two antibodies, with four bands of AB-48 immunoreactivity in sublayers S1, S2, S4, and S5 but only three bands of SYN I immunoreactivity in S1, S3, and S5. SYN I also labeled varicose fibers in both the inner nuclear layer and the outer plexiform layer that are probably processes of dopaminergic and GABAergic interplexiform cells. Varicose fibers in the ganglion cell layer were labeled by both antibodies. These results provide the first electron microscopic immunocytochemical labeling for AB-48 and SYN I in intact retina and confirm that AB-48 labels both ribbon and conventional synaptic terminals, whereas SYN I labels only conventional synapses.

Animals↗
PubMed1997

WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons.

WNT factors play a key role in early patterning of the embryo. However, expression of Wnt genes after cell commitment suggests additional roles in later developmental processes. We report here that Wnt-7a is expressed in cerebellar granule cell neurons as they begin to extend processes and form synapses. WNT-7a increases axonal spreading and branching in cultured granule cells. Moreover, WNT-7a increases the levels of synapsin I, a presynaptic protein involved in synapse formation and function. Lithium mimics WNT-7a in granule cells by inhibiting GSK-3beta, a component of the WNT signaling pathway. These results suggest a direct effect of WNT-7a in the regulation of neuronal cytoskeleton and synapsin I in granule cell neurons. We propose that WNT proteins have a novel function in the formation of neuronal connections.

Animals↗
PubMed2002

Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons.

Valproate (VPA) and lithium have been used for many years in the treatment of manic depression. However, their mechanisms of action remain poorly understood. Recent studies suggest that lithium and VPA inhibit GSK-3beta, a serine/threonine kinase involved in the insulin and WNT signaling pathways. Inhibition of GSK-3beta by high concentrations of lithium has been shown to mimic WNT-7a signaling by inducing axonal remodeling and clustering of synapsin I in developing neurons. Here we have compared the effect of therapeutic concentrations of lithium and VPA during neuronal maturation. VPA and, to a lesser extent, lithium induce clustering of synapsin I. In addition, lithium and VPA induce similar changes in the morphology of axons by increasing growth cone size, spreading, and branching. More importantly, both mood stabilizers decrease the level of MAP-1B-P, a GSK-3beta-phosphorylated form of MAP-1B in developing neurons, suggesting that therapeutic concentrations of these mood stabilizers inhibit GSK-3beta. In vitro kinase assays show that therapeutic concentrations of VPA do not inhibit GSK-3beta but that therapeutic concentrations of lithium partially inhibit GSK-3beta activity. Our results support the idea that both mood stabilizers inhibit GSK-3beta in developing neurons through different pathways. Lithium directly inhibits GSK-3beta in contrast to VPA, which inhibits GSK-3beta indirectly by an as-yet-unknown pathway. These findings may have important implications for the development of new strategies to treat bipolar disorders.

Animals↗
PubMed2002

Adenovirus-mediated Bcl-X(L) expression using a neuron-specific synapsin-1 promoter protects against disseminated neuronal injury and brain infarction following focal cerebral ischemia in mice.

The effects of an adenovirus-mediated Bcl-X(L) expression, driven by a neuron-specific human synapsin-1 promoter, on the degree of injury, were examined after transient focal ischemia in mice. Therefore, injections of vehicle, of an adenoviral E1-deleted control vector (Ad-dE1), or a Bcl-X(L) vector (Ad-Syn-Bcl-X(L)) were stereotactically made in the striatum. Seven days later, focal ischemia was induced either by 30 min or 2 h of intraluminal thread occlusion. In line with previous data, 30 min of middle cerebral artery (MCA) occlusion reproducibly resulted in disseminated neuronal injury of the striatum, as revealed by cresyl violet and TUNEL 3 days after ischemia. The degree of cell injury was significantly reduced in Ad-Syn-Bcl-X(L) treated as compared with Ad-dE1 and vehicle-treated animals. On the other hand, 2 h of MCA occlusion produced reproducible infarcts both in vehicle and Ad-dE1 treated animals 24 h after ischemia. The infarct area at the level of the striatum was significantly decreased by Ad-Syn-Bcl-X(L) treatment. The present data demonstrate that an adenoviral Bcl-X(L) expression with a neuron-specific synapsin-1 promoter provides a powerful tool, which not only diminishes disseminated neuronal injury, but also protects against tissue infarction.

Adenoviridae↗
PubMed1993

Cortical tubers demonstrate reduced immunoreactivity for synapsin I.

To evaluate the effects of tuberous sclerosis (TS) on cortical synaptic organization, we analyzed synaptic densities within cortical tubers from the brains of two TS patients using a polyclonal antibody directed against synapsin I, a synaptic terminal-specific protein. The synaptic densities of the tubers and adjacent histologically normal cortex were obtained by determining optical densities using an IBAS (Zeiss) image analysis system. The tubers showed abnormally low levels of synapsin I compared with the normal cortex. The data suggest that cortical tubers do not contain a normal complement of synapses. This may reflect focal underdevelopment of normal cortical-cortical connections. Altered afferent cortical projections may also contribute to synaptic loss in cortical tubers.

Cerebral Cortex↗
PubMed1991

Developmental changes in phosphorylation of MAP-2 and synapsin I in cytosol and taxol polymerised microtubules from chicken brain.

In cytosol, cyclic AMP stimulated phosphorylation of microtubule associated protein-2 (MAP-2) increased from 2 days to adult in proportion to the increase in the concentration of MAP-2. By contrast, the calmodulin stimulated phosphorylation of MAP-2 decreased in proportion to the decrease in the concentration of calmodulin stimulated protein kinase II (CMK II). Similarly, the cAMP stimulated phosphorylation of the site on synapsin I labeled by the cAMP stimulated protein kinase (PKA) changed little during development whereas the calcium/calmodulin stimulated phosphorylation of the CMK II site decreased dramatically in proportion to the decrease in the concentration of CMK II. The decrease in the concentration of CMK II which occurs in cytosol during synapse maturation was also observed in taxol polymerised microtubules and the effects of the change in the relative concentrations of CMK II and PKA on the phosphorylation of MAP-2 and synapsin I in this fraction were similar to that observed in the cytosol. These results are consistent with the hypothesis that the developmental changes in phosphorylation of endogenous substrates by PKA is controlled largely by changes in the concentration of those substrates, whereas the concentration of CMK II is limiting so that the developmental changes in the phosphorylation of endogenous substrates by CMK II are a function of the concentration of CMK II itself as well as the concentration of endogenous substrates. Some possible functional consequences of this during synapse maturation are discussed.

Alkaloids↗
PubMed1989

Synapsin I from human brain. Phosphorylation by Ca2+, phospholipid-dependent protein kinase.

Synapsin I has been isolated from human brain by a rapid and efficient purification technique, and its phosphorylation by human brain Ca2+, phospholipid-dependent protein kinase (protein kinase C) has been studied. The inhibitory effect of calmodulin on this process has been demonstrated. It is also found that non-esterified fatty acids and acidic phospholipids are inhibitory for synapsin I phosphorylation by Ca2+, calmodulin-dependent protein kinase II.

Brain↗
PubMed1993

Ganglioside GD3 enhances adherence of botulinum and tetanus neurotoxins to bovine brain synapsin I.

Tetanus toxin (TTx) and botulinum toxin serotype A (BTxA), preincubated with trisialoganglioside GT1b, adhere to proteins present on blots of bovine synaptosomal proteins. Differential solubilization and ammonium sulfate fractionation provided material enriched in two proteins that appeared to be adhered to most strongly by the labeled neurotoxins. After excision of the appropriate bands from blots of electrophoretically separated proteins, N-terminal amino acid sequence analysis permitted identification of the proteins as synapsins Ia and Ib. Comparison of the effectiveness of different gangliosides at enhancing adherence of the neurotoxins to blots of synapsins Ia and Ib indicated that GD3 was most effective.

Amino Acid Sequence↗
PubMed1995

Phosphorylation of synapsin I and dynamin in rat forebrain synaptosomes: modulation by sigma (sigma) ligands.

The effects of sigma (sigma) ligands on protein phosphorylation were examined in crude, rat forebrain synaptosomes. Synaptosomes were prelabelled with 32P(i) and incubated with the sigma ligands 1,3-di-o-tolylguanidine (DTG), (+)pentazocine and (-)pentazocine (3, 10, 30, 100, 300 microM), or haloperidol, reduced haloperidol, and (+)SKF 10,047 (100 microM). Aliquots were then incubated for 10 s in control (5 mM K+) or depolarising buffer (41 mM K+). All the sigma ligands increased basal phosphorylation of synapsin Ib and other proteins including dynamin, and inhibited the depolarisation-dependent increase in phosphorylation of synapsin Ib in synaptosomes. The effects of these ligands are not directly on protein kinases or protein phosphatases. This indicates that the sigma ligands are mediating their effects via interaction with sigma binding sites, and suggest, for the first time, that protein phosphorylation may be one mechanism through which sigma ligands produce their biological effects.

Animals↗
PubMed1992

Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes.

Genes encoding the neuron-specific phosphoprotein synapsin I (SYN1), the glycoprotein tissue inhibitor of metalloproteinases (TIMP), the proto-oncogene A-raf-1 (ARAF1), and properdin (PFC), a positive regulator of the alternative pathway of human complement, lie within a conserved synteny encompassing the proximal short arm of the human X chromosome (Xp21.1-p11) and the centromeric end of the mouse X chromosome (A1-A5). We have used a mouse interspecific cross to demonstrate genetic linkage of Syn-1, Timp, and Araf and also show physical linkage, with Timp lying only 10 kb from Araf, within an intron of the Syn-1 gene. Detailed restriction mapping shows that Timp is transcribed in the same direction as Araf but in the opposite direction to the Syn-1 gene. Analysis of the corresponding region of the human X chromosome indicates a similar arrangement and in addition shows that the properdin gene lies within 5 kb of the 5' end of the synapsin I gene.

Animals↗
PubMed2004

Synapsin IIb interacts with the C-terminal SH2 and SH3 domains of PLCgamma1 and inhibits its enzymatic activity.

To elucidate the function of PLCgamma1, we have investigated the proteins that bind to its SH (Src homology) domain. Immunoscreening was performed with purified antisera specific for SH223 (two SH2 and one SH3)-binding proteins. Several immunoreactive clones were identified as putative binding proteins and one of them was identified as synapsin IIb. We demonstrate a stable association between PLCgamma1 and synapsin IIb, which binds the carboxyl terminal SH2 and SH3 domains of the enzyme and inhibits it.

Animals↗
PubMed2005

Pregnenolone and dehydroepiandrosterone administration in neonatal rats alters the immunoreactivity of hippocampal synapsin I, neuropeptide Y and glial fibrillary acidic protein at post-puberty.

It is well documented that neurosteroids administered during the neonatal period influence the development of several brain systems. In our previous study, pregnenolone administered to rats during the neonatal period altered adenosinergic and dopaminergic functions in the striatum and cerebral cortex. The present study examined the effects of the treatment with pregnenolone and dehydroepiandrosterone (DHEA) from the postnatal day (P) 3-P7 on synapsin I (a marker for presynaptic terminals) and glial fibrillary acidic protein (GFAP: a marker for astroglia) levels in the hippocampus of Sprague-Dawley rats at 3 and 7 weeks of age. In addition, neuropeptide Y and dynorphin A immunoreactivity was measured. The administration of pregnenolone and DHEA to neonatal rats significantly altered the expression of synapsin I in the dentate gyrus and CA3 region at post-puberty but not at pre-puberty. A significantly greater expression of GFAP-immunoreactive astrocytes or processes was demonstrated in the pregnenolone- and DHEA-treated groups at both pre-puberty and post-puberty. A significant increase in the number and size of GFAP-immunoreactive astrocytes and in the extension of arborization was seen in the overall hippocampus. The number of neuropeptide Y-positive cells in the hilus region was also significantly increased in the neurosteroid-treated group at post-puberty. No differences were detected in dynorphin A immunoreactivity among the experimental groups. These results of this study suggest that pregnenolone and DHEA play an important role in the development of hippocampus.

Animals↗
PubMed2000

Increased synapsin I immunoreactivity during long-term potentiation in rat hippocampus.

The level of synapsin I, a synaptic vesicle protein and marker for synaptic activation, was studied 8 h after long-term potentiation (LTP) induction in rat hippocampus in vivo. Quantitative immunohistochemical analysis revealed that synapsin I increased significantly in the molecular layer of the dentate gyrus and the stratum lucidum of CA3, suggesting activation of the granule cells by synaptic input to the dentate gyrus, and persistent enhancement of glutamate release from the axon terminals of the dentate granule cells.

Animals↗
PubMed2001

A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients.

The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels.

Adult↗