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At least 667 records · Page 37Linked to original sources
PubMed1986

Calspectin (fodrin or nonerythroid spectrin)-actin interaction: a possible involvement of 4.1-related protein.

The calspectin/actin complex extracted from the bovine brain membrane crosslinks F-actin, resulting in the increasing viscosity of F-actin determined by low-shear viscometry. We demonstrated the presence of a protein factor in this complex, which regulated the calspectin-F-actin interaction in a Ca2+- and calmodulin-dependent manner. Erythrocyte protein 4.1, but not synapsin I, mimics the function of this brain factor using a reconstitution system including purified calspectin, calmodulin and F-actin. In the brain complex, the Mr 120,000 and the Mr 80,000/77,000 polypeptides were detected to crossreact with anti-protein 4.1 antibody.

Actins↗
PubMed1994

Activation of calcium and calmodulin dependent protein kinase II during stimulation of insulin secretion.

Pancreatic islets contain an alloxan sensitive, calcium and calmodulin dependent protein kinase (CaM-PK) which may play an important part in the cellular control of insulin secretion. We have studied this activity in islets and the insulin secreting tumor cell line RINm5f with particular interest in the changes in kinase activity that accompany stimulation of secretion. Initial experiments showed that the CaM-PK activity enriched in microsomal preparations from RIN cells was similar to the islet cell kinase in terms of apparent endogenous substrates, Ca2+ and calmodulin dependence, and inactivation by alloxan. For studies of protein substrate specificity, tumor cell CaM-PK was isolated from other kinase activities and substantially purified by affinity chromatography with calmodulin-agarose. The major protein substrates of CaM-PK (54 kD and 57 kD) co-purified with the kinase activity, representing autophosphorylation of subunits of the enzyme. Exogenous substrates phosphorylated by these preparations included microtubule-associated protein 2, synapsin, and glycogen synthase; this pattern of substrate utilization identified the kinase as the Type II multifunctional kinase which has been extensively characterized in brain. A polyclonal antibody to rat brain CaM-PK II was employed to immunoprecipitate the kinase from RINm5f cells incubated with secretagogues to measure the effect of stimulation of secretion on autophosphorylation of CaM-PK (which reflects kinase activation). D-Glyceraldehyde (22 mM) and depolarizing concentrations of potassium increased autophosphorylation and insulin secretion in a parallel fashion. Potassium stimulated autophosphorylation was dose dependent and saturable, and was increased to near maximal levels at times as short as 1 min. These studies demonstrate that pancreatic islets and RINm5f cells contain a Type II CaM-PK which is activated during the secretion process.

Animals↗
PubMed1993

Distribution of GAP-43 in relation to CGRP and synaptic vesicle markers in rat skeletal muscles during development.

GAP 43 in nerve terminal structures of rat skeletal muscles, was investigated during postnatal development using immunofluorescence and confocal laser scanning microscopy. Comparison with synaptophysin, synapsin, SV2, CGRP, SP and NF was done in double immunoincubation studies. GAP 43-like immunoreactivity (LI) was demonstrated in preterminal axons and motor endplates in all age groups (from E18 to adult), although the intensity of immunofluorescence was considerably higher in the younger rats. The outgrowing nerve sprouts in E18 muscles were strongly GAP 43-positive. The intensity decreased with increasing age, but even in adult animals GAP 43-LI was present in some p38- or SV2-positive endplates. GAP 43-LI was also present in muscle spindles and preterminal nerve branches, and likewise decreased with age. Perivascular nerve terminals (around arteries mainly) were, however, strong in GAP 43-LI during both development and adulthood. GAP 43-LI was strong, and present in both small and large granules. SP-LI was observed in a few thin, presumably sensory, axons around vessels, which also contained a few GAP 43-positive large granules. Most of the strongly GAP 43-positive terminals around vessels were probably autonomic postganglionic terminals. The results suggest that GAP 43, in addition to development and regeneration, may play a significant role also in normal adult rats, especially in perivascular nerve terminals, possibly connected with a high potential for plasticity in this kind of nerve terminals.

Aging↗
PubMed1988

Reorganization of cerebellar cell suspension transplanted into the weaver mutant cerebellum and immunohistochemical detection of synaptic formation.

Dissociated cells prepared from the cerebellar primordia of normal 15-day mouse embryos were grafted into the cerebellum of 1-month-old weaver mutant mice which are characterized by degeneration of cerebellar granule cells during the early postnatal period. The growth of the grafted cells was investigated at 1 month after the operation. Implanted cells were highly developed to form a large mass of tissue in the host cerebellar folia. Histological examination revealed that a trilaminar cortical structure was partially developed in certain areas of the grafted tissue. The implanted granule-like cells were labeled with [3H]thymidine which was injected into the host, suggesting that the granule-like cells actively proliferate in the host cerebellum after the transplantation. In this area, strong immunoreactivity with synapsin I was detected indicating that the dissociated granule cells of the cerebellar primordia are able to develop a synaptic organization in the weaver mouse cerebellum.

Animals↗
PubMed1987

Effects of triethyltin bromide on protein phosphorylation in subcellular fractions from rat and rabbit brain.

Phosphorylation of specific proteins in subcellular fractions of rat brain is affected by the presence of low concentrations (1-50 microM) of triethyltin bromide (Et3SnBr), in vitro. SDS-PAGE and autoradiography showed that Et3SnBr increased phosphorylation of an Mr = 42,000 phosphorylation of an Mr = 52,000 component. The Mr = 42,000 and 76,000-80,000 phosphoproteins have been identified as the alpha-subunit of pyruvate dehydrogenase (PDH) and synapsin, respectively. Et3SnBr-induced phosphorylation of rabbit brain PDH results in partial inactivation of the PDH complex.

Animals↗
PubMed1996

Biochemical and functional characterization of the synaptic vesicle-associated form of CA2+/calmodulin-dependent protein kinase II.

Ca+/calmodulin-dependent protein kinase II (CaMPKII) is a brain-enriched protein kinase that plays important roles in synaptic transmission and plasticity. In nerve terminals, a form of CaMPKII is associated with synaptic vesicles and binds the COOH-terminal region of synapsin I (SYNI). The biochemical properties of the vesicle-associated form of CAMPKII have been investigated and compared with those of the soluble forebrain enzyme. Both the alpha- and beta-subunits of CaMPKII copurifying with synaptic vesicles were tightly associated with the vesicle membrane. The vesicle-associated form of CaMPKII was indistinguishable from the soluble form with respect to sites of autophosphorylation, kinetics of both autophosphorylation and SYNI phosphorylation, and induction of autonomous activity upon autophosphorylation. Although both subunits of the soluble CaMPKII interacted with a photoactivatable SYNI derivative, only the alpha-subunit of the synaptic vesicle-associated CaMPKII bound to the COOH-terminal region of SYNI. The latter interaction was strongly dependent on the phosphorylation state of SYNI and on divalent cations, but appeared to be independent of autophosphorylation. These results demonstrate that, although the vesicle-associated form of CaMPKII is catalytically indistinguishable from the soluble form, it exhibits distinct characteristics concerning its association with the vesicle membrane and with SYNI.

Animals↗
PubMed1993

Myelin basic protein domains involved in the interaction with actin.

A fluorescence assay was used to measure the interaction of myelin basic protein (MBP) with monomeric actin labeled with a fluorescent compound (IAEDANS). The complex actin-IAEDANS increase the fluorescence in presence of MBP. The enhancement of the fluorescence has a sigmoidal dependence on the concentration of MBP and the fluorescence maximum is reached at a MBP:actin molar ratio of 1:20. The fluorescence maximum in absence of Ca2+ and ATP is 4 times lower than that in their presence although it is reached at the same MBP:actin molar ratio. Similar behavior is observed when synapsin replaces MBP, while acetylated MBP and bovine serum albumin fail to induce any fluorescence change. To define possible interacting domains on MBP involved in the actin-MBP interaction, experiments were performed using MBP-derived peptides obtained under controlled proteolysis of the whole molecule. The fluorescence changes induced by the different peptides depend on their location in the native protein and can not be explained simply by a difference in the net charge of the peptides. The results suggest that two sites are involved in the interaction. A Ca2+/ATP-dependent site located in the amino-terminal region (peptide 1-44) and a Ca2+/ATP-independent one near the carboxyl terminus of the MBP molecule. The actin-MBP interaction was also observed using immunoblot and ELISA techniques.

Actins↗
PubMedDate not supplied

The concentration of glial fibrillary acidic protein increases with age in the mouse and rat brain.

The role of aging in the expression of the astrocyte protein, glial fibrillary acidic protein (GFAP), was examined. In both mice and rats the concentration of GFAP increased throughout the brain as a function of aging. The largest increase (2-fold) was observed in striatum for both species. The neuron-specific proteins, synapsin I and neurofilament-200 (Mr 200 kilodaltons), were not altered by aging in any region of the mouse or rat brain. Brains of aged rats, but not mice, showed a decrease in beta-tubulin. The data suggest that astrocytic hypertrophy observed with aging involves an accumulation of glial filaments.

Aging↗
PubMedDate not supplied

Mutant and native human beta-amyloid precursor proteins in transgenic mouse brain.

Human beta-amyloid precursor protein (beta APP) has been targeted to transgenic neurons using synapsin I promoter-based chimeric transgenes. Native human beta APP was introduced as well as beta APP containing mutations genetically linked to familial Alzheimer's disease (AD) and to hereditary cerebral hemorrhage with amyloidosis-Dutch type. In mouse brain, human beta APP RNA was up to 60% as abundant as total endogenous beta APP RNA. Human beta APP gene expression was most abundant in the CA subfields of the hippocampus and in the piriform cortex. Correct processing of human beta APP at the beta-secretase cleavage site was demonstrated in transgenic mouse brains. Despite a 40% increase in total beta APP immunoreactivity in lines expressing mutant human beta APP, no evidence of amyloid deposition was found in brains of mice up to 14 months in age. Higher levels of mutant human beta APP, increased age, or other factors may be necessary to elicit beta-amyloid-related neuropathologies in the rodent brain.

Amyloid beta-Protein Precursor↗
PubMed1994

Increase in synaptic vesicle proteins accompanies long-term potentiation in the dentate gyrus.

Maintenance of long-term potentiation in synapses formed by the perforant path on to granule cells of the dentate gyrus is accompanied by a sustained increase in the extracellular concentration of glutamate, the presumed transmitter at this excitatory hippocampal pathway. Quantal analysis indicates that, at least in the first hour of induction, this reflects an increase in transmitter release rather than a decrease in glutamate uptake, while biochemical studies have suggested that the increase in release persists for several hours. Morphological studies have described early but persistent increases in the spine number and area. Increases in the number of segmented/perforated synapses persisting for at least 1 h after induction of long-term potentiation, have also been reported. These morphological changes suggest both presynaptic and postsynaptic modifications. Increases in synaptic vesicle number and distribution lasting for at least 1 h specifically indicate presynaptic changes. To explore further the role of the presynaptic terminal in long-term potentiation, we have investigated changes in three synaptic vesicle proteins, synapsin, synaptotagmin and synaptophysin, in control tissue and in tissue prepared from potentiated dentate gyrus 45 min and 3 h after induction of long-term potentiation. We found that there was an increase in the concentration of the three proteins 3 h after induction of long-term potentiation. No such increase was observed 45 min after induction or in tissue prepared from animals in which an intraventricular injection of the N-methyl-D-aspartate receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid, blocked induction of long-term potentiation.

2-Amino-5-phosphonovalerate↗
PubMed1990

Efficient linkage of 10 loci in the proximal region of the mouse X chromosome.

Interspecific Mus species crosses were used to construct a multilocus genetic map of the mouse X chromosome that extends for more than 50 cM. In these studies, we established the segregation of eight loci in more than 200 backcross progeny from crosses of M. musculus and M. spretus with a common inbred strain (C57BL/6JRos). Genetic divergence at the level of the nucleotide sequences makes these crosses a useful cumulative genetic resource for mapping additional genes defined by genomic or cDNA probes in a highly efficient manner. We have therefore devised a mapping strategy that uses a subset of these backcrosses that are recombinant between successive anchor loci to both localize and order an additional set of six genes without necessarily resorting to an analysis of the entire backcross series. Using this approach, we have defined the linkage of cytochrome b245 beta-chain (Cybb), synapsin (Syn-1), and two members of the X-linked lymphocyte-regulated gene family (Xlr-1, Xlr-2), as well as DXSmh141 and DXSmh172, two loci defined by random genomic probes. All six loci have been localized to the proximal portion of the mouse X chromosome and their order has been defined as Cybb, Otc, Syn-1/Timp, DXSmh141/Xlr-1, DXSmh172, Hprt, Xlr-2, Cf-9. Gene order was established by minimizing multiple recombination events across the region spanning an estimated 20 cM of the proximal X chromosome. The possible significance of the Xlr loci is discussed with respect to other X-chromosome loci that regulate the immune response.

Animals↗
PubMed1988

Redistribution of synaptic vesicle antigens is correlated with the disappearance of a transient synaptic zone in the developing cerebral cortex.

To examine the distribution of synaptic vesicle antigens during development of the cerebral cortex, antibodies against synapsin I and p65 were used on sections of cat cerebral cortex between E40 and adulthood. In the adult, the layers of the cerebral cortex are immunoreactive for each of these antigens, while the white matter is free of staining. In contrast, the fetal and neonatal pattern of immunostaining is reversed: the cortical plate (future cortical layers) is devoid of immunoreactivity, while the marginal (future layer 1) and the intermediate zones (future white matter) are stained. Electron microscopic immunohistochemistry shows that immunolabeling is associated with presynaptic nerve terminals in the adult and during development. These observations suggest that during development the white matter is a transient synaptic neuropil and that a global redistribution of synapses takes place as the mature pattern of connections within the cerebral cortex emerges.

Aging↗
PubMed1994

Genetic analysis of neurotransmitter release at the synapse.

The recent application of genetics to the study of synaptic mechanisms has examined the in vivo significance of individual synaptic proteins and has tested hypotheses that were derived from biochemical observations on these proteins. In the case of synapsin I and Rab3A, the phenotypes of mice lacking these proteins was startlingly mild; only subtle alterations in transmission were observed. Whereas in synaptotagmin mutants of flies and nematodes, transmission was severely curtailed, though not abolished. A detailed analysis of the phenotype has led to a hypothesis that this protein stabilizes the docking of vesicles at release sites. The analysis of additional synaptic proteins, Unc-18/Rop and the cysteine string protein, has indicated that these are important players in synaptic mechanisms and may soon illuminate their function at the synapse.

Animals↗
PubMed2004

Cellular and subcellular localization of the inhibitory glycine receptor in hippocampal neurons.

Inhibitory glycine receptors are most abundant in spinal cord and brainstem, and glycinergic synapses have a well-established role in the regulation of locomotor behavior. Little is known about the function of glycine receptors in cortex and hippocampus, where GABA plays a dominant role in synaptic inhibition. Therefore, we have investigated tissue and cellular expression of glycine receptor alpha-subunits. Western blot and immunohistochemical analyses reveal the presence of glycine receptors in hippocampal tissue. Immunocytochemical experiments in hippocampal cultures show prominent cellular expression of glycine receptors in pyramidal neurons and GAD-positive interneurons similar to the calcium-binding protein VILIP-1 with widespread hippocampal distribution. On the subcellular level we found co-staining of GlyR and the presynaptic marker synapsin I. Furthermore, co-staining with GAD at synaptic terminals indicated partial co-localization of GABA- and glycine receptors.

Animals↗
PubMed2006

Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally.

The synthesis of brain phosphatidylcholine may utilize three circulating precursors: choline; a pyrimidine (e.g., uridine, converted via UTP to brain CTP); and a PUFA (e.g., docosahexaenoic acid); phosphatidylethanolamine may utilize two of these, a pyrimidine and a PUFA. We observe that consuming these precursors can substantially increase membrane phosphatide and synaptic protein levels in gerbil brains. (Pyrimidine metabolism in gerbils, but not rats, resembles that in humans.) Animals received, daily for 4 weeks, a diet containing choline chloride and UMP (a uridine source) and/or DHA by gavage. Brain phosphatidylcholine rose by 13-22% with uridine and choline alone, or DHA alone, or by 45% with the combination, phosphatidylethanolamine and the other phosphatides increasing by 39-74%. Smaller elevations occurred after 1-3 weeks. The combination also increased the vesicular protein Synapsin-1 by 41%, the postsynaptic protein PSD-95 by 38% and the neurite neurofibrillar proteins NF-70 and NF-M by up to 102% and 48%, respectively. However, it had no effect on the cytoskeletal protein beta-tubulin. Hence, the quantity of synaptic membrane probably increased. The precursors act by enhancing the substrate saturation of enzymes that initiate their incorporation into phosphatidylcholine and phosphatidylethanolamine and by UTP-mediated activation of P2Y receptors. Alzheimer's disease brains contain fewer and smaller synapses and reduced levels of synaptic proteins, membrane phosphatides, choline and DHA. The three phosphatide precursors might thus be useful in treating this disease.

Administration, Oral↗
PubMed2006

Assessment of CMV, RSV and SYN1 promoters and the woodchuck post-transcriptional regulatory element in adenovirus vectors for transgene expression in cortical neuronal cultures.

In order to investigate protein function in rat primary cortical neuronal cultures, we modified an adenoviral vector expression system and assessed the strength and specificity of the cytomegalovirus (CMV), rous sarcoma virus (RSV), and rat and human synapsin 1 (SYN1) promoters to drive DsRed-X expression. We also incorporated the woodchuck post-transcriptional regulatory element (WPRE) and a CMV promoter-enhanced green fluorescent protein (EGFP) reporter cassette. We observed that the RSV promoter activity was strong in neurons and moderate in astrocytes, while the CMV promoter activity was weak-to-moderate in neurons and very strong in astrocytes. The rat and human SYN1 promoters exhibited similar but weak activity in neurons, despite inclusion of the WPRE. We confirmed that the WPRE enhanced RSV promoter-mediated DsRed-X expression in a time-dependent fashion. Interestingly, we observed very weak SYN1-mediated DsRed-X expression in astrocytes and HEK293 cells suggesting incomplete neuronal-restrictive behavior for this promoter. Finally, using our adenoviral expression system, we demonstrated that RSV promoter-mediated Bcl-X(L) overexpression attenuated neuronal death caused by in vitro ischemia and oxidative stress.

Animals↗
PubMed2006

A regulatory role for actin in dendritic spine proliferation.

Dendritic spines are small protrusions that receive 90% of excitatory cortical synapses and are critically important to neural function. Each dendritic spine is supported by a dynamic actin cytoskeleton that responds to internal and external cues to allow spine development, elongation, retraction and movement. Multiple proteins have roles in spinogenesis, but until now, a regulatory role for actin itself has not been established. Here, we show that, in the acute slice preparation, actin expression increases during a period of rapid spinogenesis. Furthermore, actin overexpression in organotypic hippocampal cultures leads to a significant increase in spine density on CA1 pyramidal cells. Specifically, the number of filopodia (long, thin protrusions without heads) increases by 38% on secondary apical dendrites and 88% on basal dendrites and the number of elongated spines with heads increases by 162% on secondary apical dendrites and 113% on basal dendrites. Synapsin-I immunostaining demonstrated that the majority of filopodia and elongated spines are apposed by axon terminals. Additionally, we show that overexpressed actin enters both new and established spines within 24 h. These data demonstrate that neurons undertaking spinogenesis upregulate actin expression, that actin overexpression per se increases spine density, and that both new and established spines incorporate exogenous actin.

Actins↗
PubMed2006

Stargazin mutation impairs cerebellar synaptogenesis, synaptic maturation and synaptic protein distribution.

Stargazin mutation results in absence epilepsy and cerebellar ataxia in stargazer (stg) mice. We have previously discovered defects of AMPA receptor function, failure of BDNF expression and immature morphology specifically in the cerebellar cortex of stg mice. To further characterize the nature of synaptic abnormalities, we examined the ultrastructure of cerebellar granule cell output synapses and measured the expression levels of several synaptic proteins in different brain regions of stg mutant. Electron microscopic examination revealed a number of immature features in the molecular layer of the mutant cerebellar cortex, including the presence of desmosoid plaques, concentric profiles of parallel fibers, smaller presynaptic terminal and fewer synaptic vesicles. Quantitative measurement showed a significantly lower number of synapses and smaller area of presynaptic terminals in adult stg cerebellum when compared with age-matched wildtype. Immunoblotting analysis of the SNARE proteins revealed selective reduction of the levels of synaptobrevin and synaptophysin in synaptosomes from stg cerebellum. The expression levels of synapsins were not altered in stg cerebellum, but showed a significant upregulation in stg cerebral cortex and hippocampus. Our results suggest that, despite the relatively normal gross morphology of cerebellum, stargazin mutation results in abnormal ultrastructure of cerebellar synapses, and stargazin-induced regional failure of BDNF expression may be responsible for abnormal SNARE protein distribution and partially attributes to the defects in the synaptic ultrastructure.

Animals↗