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At least 1,117 records · Page 62Linked to original sources
PubMed1987

Purification and properties of a multifunctional calcium/calmodulin-dependent protein kinase from rat pancreas.

A calcium/calmodulin-dependent protein kinase (Ca/calmodulin protein kinase) was purified from rat pancreas using hydrophobic chromatography followed by gel filtration and affinity chromatography. Ca/calmodulin protein kinase from pancreas resembled previously described multifunctional Ca/calmodulin protein kinases from other tissues with respect to substrate specificity, autophosphorylation on serine and threonine residues, and catalytic and hydrodynamic properties. While Ca/calmodulin protein kinase from other tissues contains subunits of 53-60 kDa with variable proportions of a smaller 50-52 kDa subunit, pancreatic Ca/calmodulin protein kinase was found to contain a single component of 51 kDa. Experiments mixing brain Ca/calmodulin protein kinase with pancreatic homogenate suggest that the absence of a larger subunit in the pancreatic Ca/calmodulin protein kinase is not due to proteolytic degradation during enzyme preparation. Ca/calmodulin protein kinase binding to 125I-labeled calmodulin in solution was demonstrated using the photoaffinity cross-linker, N-hydroxysuccinimidyl-4-azidobenzoate. 125I-labeled calmodulin binding to Ca/calmodulin protein kinase was also demonstrated using filters containing Ca/calmodulin protein kinase transferred from polyacrylamide gels after two-dimensional gel electrophoresis. Finally, the ribosomal substrate for Ca/calmodulin protein kinase was identified as the ribosomal protein, S6. The purification procedure presented in this study promises to be useful in characterizing Ca/calmodulin protein kinase in other tissues and in clarifying the role of these enzymes in cellular function.

Animals↗
PubMed1994

Exploring the functional domain and the target of the tetanus toxin light chain in neurohypophysial terminals.

The tetanus toxin light chain blocks calcium induced vasopressin release from neurohypophysial nerve terminals. Here we show that histidine residue 233 within the putative zinc binding motif of the tetanus toxin light chain is essential for the inhibition of exocytosis, in the rat. The zinc chelating agent dipicolinic acid as well as captopril, an inhibitor of zinc-dependent peptidases, counteract the effect of the neurotoxin. Synthetic peptides, the sequences of which correspond to motifs present in the cytoplasmic domain of the synaptic vesicle membrane protein synaptobrevin 1 and 2, prevent the effect of the tetanus toxin light chain. Our results indicate that zinc bound to the zinc binding motif constitutes the active site of the tetanus toxin light chain. Moreover they suggest that cleavage of synaptobrevin by the neurotoxin causes the inhibition of exocytotic release of vasopressin from secretory granules.

Amino Acid Sequence↗
PubMed1981

Presynaptic localization of phosphoprotein B-50.

A major phosphoprotein of synaptic membranes, the phosphorylation of which is stimulated by Ca2+ and inhibited by ACTh, appears to be identical with protein B-50 described by Zwiers, Schotman and Gispen [40]. We have investigated its subsynaptic localization by means of a variety of subfractionation techniques and compared it with that of a number of other phosphoproteins found in synaptic membranes. It appears to be predominantly, if not exclusively, associated with presynaptic membranes of low bouyant density. This localization pattern is similar to, but somewhat more extreme than that exhibited by Protein I, as a brain specific phosphoprotein studied by Greengard and his collaborators [11].

Animals↗
PubMed1987

Stimulation-dependent phosphorylation of tyrosine hydroxylase in rat corpus striatum.

Incubation of rat corpus striatal synaptosomes with 32PO4 led to a time-dependent incorporation of 32P into tyrosine hydroxylase. Depolarization of the synaptosomes with elevated [K+]o increased 32P incorporation into tyrosine hydroxylase. The depolarization-dependent increase in 32P incorporation into tyrosine hydroxylase occurred rapidly (less than 15 sec), persisted in the presence of elevated [K+]o (up to 120 sec), required the presence of [Ca++]o, and was associated with serine (but not threonine or tyrosine) residues. After limit tryptic digestion of the 32P-tyrosine hydroxylase, several phosphopeptides were separated by HPLC, and elevated [K+]o increased 32P incorporation into two of these phosphopeptides. Thus, depolarization of dopaminergic terminals from the rat corpus striatum increased the phosphorylation of tyrosine hydroxylase, and the increase in phosphorylation appeared to occur at multiple sites. Multiple-site phosphorylation of tyrosine hydroxylase has been previously shown in peripheral catecholaminergic tissues. However, substantial differences in the elution profiles of tyrosine hydroxylase phosphopeptides from striatal synaptosomes and from bovine adrenal chromaffin cells were observed. Thus, qualitative differences in the regulation of tyrosine hydroxylase may exist among the many catecholaminergic systems.

Animals↗
PubMedDate not supplied

Hippocampal synaptogenesis in hydrocephalic HTX-rats using a monoclonal anti-synaptic vesicle protein antibody.

The fluorescence intensity (FI) on immunohistochemical staining with a monoclonal antibody (Mab 171 B5) against a synaptic vesicle-associated protein (SVP-38) was measured in the CA1 sector of the hippocampus of brains obtained from hydrocephalic and non-hydrocephalic HTX-rats aged 1, 7, 14, 21 and 28 days. FI was significantly increased on the 21st and 28th postnatal days in hydrocephalic rats as compared to in non-hydrocephalic rats, despite the presence of marked morphological stretching and rotation of the dendritic arborization of Golgi-impregnated neurons in the CA1 sector. The increase in FI appeared to indicate an increase in synaptic density. As previous reports have indicated a marked reduction in SVP-38 FI in the thin cerebral cortex of 28th postnatal day hydrocephalic brains, our findings may suggest that hippocampal synaptogenesis is more resilient than that of the cerebral cortex in hydrocephalic brains.

Animals↗
PubMed1996

Exposure to perinatal morphine promotes developmental changes in rat striatum.

This study shows that perinatal exposure to morphine promotes developmental changes (up to 8 months of life) in the striatum by up-regulating concentrations of substance P and met-enkephalin with changes of prometenkephalin A mRNA expression at the day of birth only. Dopamine metabolism (up to 60 days) is also increased as suggested by the reduced concentrations of dopamine and increased content of 3,4-dihydroxyphenylacetic acid. Tyrosine hydroxylase mRNA expression is selectively reduced only in the substantia nigra by perinatal morphine. Serotonin content is reduced only during the early postnatal days and is unaffected thereafter. Supplementation of naltrexone to morphine-exposed rats prevents monoaminergic and neuropeptidergic changes in the striatum, which directly implicates opioid receptors in the developmental changes caused by morphine. The data suggest that perinatal morphine may inhibit met-enkephalin release, causing accumulation of the peptide without corresponding changes in specific mRNA. Dopamine release may also be increased as indicated by a higher metabolism and consequent reduction of tyrosine hydroxylase mRNA expression in the substantia nigra.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

The kinetics of synaptic vesicle recycling measured at single presynaptic boutons.

We used the fluorescent membrane probe FM 1-43 to label recycling synaptic vesicles within the presynaptic boutons of dissociated hippocampal neurons in culture. Quantitative time-lapse fluorescence imaging was employed in combination with rapid superfusion techniques to study the dynamics of synaptic vesicles within single boutons. This approach enabled us to measure exocytosis and to analyze the kinetics of endocytosis and the preparation of endocytosed vesicles for re-release (repriming). Our measurements indicate that under sustained membrane depolarization, endocytosis persists much longer than exocytosis, with a t1/2 approximately 60 s (approximately 24 degrees C); once internalized, vesicles become reavailable for exocytosis in approximately 30 s. Furthermore, we have shown that endocytosis is not dependent on membrane potential and, unlike exocytosis, that it is independent of extracellular Ca2+.

Animals↗
PubMed1991

Synaptic transmission in the retina.

A recent highlight in the study of the retina has been the publication of evidence that the response of the ON bipolar cells is generated by a cGMP-mediated second messenger system. This GTP-binding protein mechanism is activated by the binding of glutamate, the photoreceptor neurotransmitter, to the 2-amino-4-phosphonobutyrate (APB) class of receptor.

Adaptation, Physiological↗
PubMed2004

Frequency dependence of synaptic vesicle exocytosis in aortic baroreceptor neurons and the role of group III mGluRs.

Synaptic transmission between baroreceptor afferents and the nucleus tractus solitarius (NTS) is essential for reflex regulation of blood pressure. High frequency stimulation of the afferents in vivo leads to a decrease in synaptic strength and is generally attributed to reduction in presynaptic neurotransmitter release. It has been hypothesized that during high frequency stimulation glutamate a major neurotransmitter at the baroreceptor afferent terminals inhibits its own release via presynaptic group III metabotropic glutamate receptors (mGluRs). A key player in modulation of presynaptic release is vesicle exocytosis. The present study utilized cultured aortic baroreceptor neurons and the styryl dye FM2-10 to characterize (1) the dependence of exocytosis at these afferent nerve terminals on the frequency of neuronal activation, (2) the effect of duration of stimulation on the rate of exocytosis and (3) the role of mGluRs in the frequency-dependent modulation of exocytosis. Destaining in the FM2-10 loaded boutons during 3 min of stimulation, a measure of exocytosis, progressively decreased with increasing frequency (0.5, 1.0 and 10 Hz). Blockade of group III mGluRs with 300 microM (RS)-cyclopropyl-4-phosphonophenylglycine (CPPG) facilitated exocytosis evoked by 10 Hz stimulation but not at 0.5 Hz. The data suggest that aortic baroreceptor terminals exhibit frequency-dependent depression of exocytosis and support a role for group III mGluRs in the frequency-dependent modulation of exocytosis.

Analysis of Variance↗
PubMed2006

Induction of neuronal differentiation of adult human olfactory neuroepithelial-derived progenitors.

Neurosphere forming cells (NSFCs) have been established from cultures of adult olfactory neuroepithelium obtained from patients and cadavers as described previously. They remained undifferentiated in serum or defined media with or without neurotrophic factors. Many factors affect the differentiation of stem cells along a neuronal pathway. Retinoic acid (RA), forskolin (FN), and sonic hedgehog (Shh) have been reported to act as growth promoters during neurogenesis of embryonic CNS in vivo. The effect of RA, FN, and Shh on NSFCs' neuronal lineage restriction has not been described. The application of RA, FN, and Shh to NSFCs induced the expression of motoneuronal transcription factors, tyrosine hydroxylase, an indicator of dopamine production, and neurite formation. These studies further heighten the potential for using olfactory neuroepithelial progenitors for future autologous cell replacement strategies in neurodegenerative conditions and trauma as well as for use in diagnostic evaluation.

Adult↗
PubMed2006

Immunohistochemical analysis of subcortical white matter astroglia of infant and adult primate brains, with a note on resident neurons.

An immunohistochemical analysis of brain subcortical white matter astroglia from human (infant, adult) and adult monkey (Cebus apella, Macaca nemestrina) cases without any known neurological disease, is described. Expression of synaptic vesicle-associated proteins, excitatory amino acid transporters (EAAT1 and EAAT2) and GABAA Ralpha2 receptor produced coarse punctate labeling in human adult white matter astrocytes. A finer, generalized, punctate labeling was observed in human infants and adult C. apella monkeys. Labeling of neuronal somata and processes with microtubule-associated proteins (MAP2a-c) and neuron nuclear (NeuN) antibodies, was also observed in subcortical white matter of humans and monkeys. Results suggest competence of subcortical white matter astroglia of the primate brain to participate in various transmitter regulatory pathways. It is also proposed that, collectively with resident neurons, they may exert some role in affecting the transfer of information that takes place through the various associational and projecting fiber systems coursing through this brain compartment.

Aged↗
PubMed2006

A component of BRAF-HDAC complex, BHC80, is required for neonatal survival in mice.

BHC80 is a component of BRAF-HDAC complex (BHC) involved in transcriptional repression of neuron-specific genes in non-neuronal cells. However, BHC80 is present in both neuronal and non-neuronal cells. To explore the physiological importance of BHC80 in vivo, and the precise mechanism underlying neuron-specific gene repression by BHC80, we have produced mutant mice lacking Bhc80. The loss of Bhc80 resulted in neonatal lethality without sucking mother's breast milk sufficiently. Although Bhc80-deficient mice showed no developmental defect in the neuronal and non-neuronal tissues, Bhc80 is indispensable for the survival of neonatal pups.

Animals↗
PubMed2004

A pre-embedding immunogold approach for detection of synaptic endocytic proteins in situ.

During the past decade, many molecular components of clathrin-mediated endocytosis have been identified and proposed to play various hypothetical roles in the process [Nat. Rev. Neurosci. 1 (2000) 161; Nature 422 (2003) 37]. One limitation to the evaluation of these hypotheses is the efficiency and resolution of immunolocalization protocols currently in use. In order to facilitate the evaluation of these hypotheses and to understand more fully the molecular mechanisms of clathrin-mediated endocytosis, we have developed a protocol allowing enhanced and reliable subcellular immunolocalization of proteins in synaptic endocytic zones in situ. Synapses established by giant reticulospinal axons in lamprey are used as a model system for these experiments. These axons are unbranched and reach up to 80-100 microm in diameter. Synaptic active zones and surrounding endocytic zones are established on the surface of the axonal cylinder. To provide access for antibodies to the sites of synaptic vesicle recycling, axons are lightly fixed and cut along their longitudinal axis. To preserve the ultrastructure of the synaptic endocytic zone, antibodies are applied without the addition of detergents. Opened axons are incubated with primary antibodies, which are detected with secondary antibodies conjugated to gold particles. Specimens are then post-fixed and processed for electron microscopy. This approach allows preservation of the ultrastructure of the endocytic sites during immunolabeling procedures, while simultaneously achieving reliable immunogold detection of proteins on endocytic intermediates. To explore the utility of this approach, we have investigated the localization of a GTPase, dynamin, on clathrin-coated intermediates in the endocytic zone of the lamprey giant synapse. Using the present immunogold protocol, we confirm the presence of dynamin on late stage coated pits [Nature 422 (2003) 37] and also demonstrate that dynamin is recruited to the coat of endocytic intermediates from the very early stages of the clathrin coat formation. Thus, our experiments show that the current pre-embedding immunogold method is a useful experimental tool to study the molecular mechanisms of synaptic vesicle recycling.

Animals↗
PubMed2005

Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron.

Neurons undergo a complex differentiation process that endows them with the ability to generate electrical signals and to transmit them via synaptic connections. There is increasing evidence that glial cells regulate specific aspects of neuronal differentiation including synapse formation, but the underlying mechanisms are not well understood. Here, we show how glia-derived cholesterol promotes the development of synapses in microcultures of highly purified retinal ganglion cells (RGCs) from postnatal rats. We identify dendrite differentiation as rate limiting step for glia-induced synaptogenesis and we show that this process requires cholesterol. Furthermore, we show that cholesterol enhances directly presynaptic differentiation and that it is essential for continuous synaptogenesis and for the stability of evoked transmitter release. These results reveal new roles of cholesterol in neuronal differentiation and underline the importance of neuron-glia interactions during brain development.

Animals↗
PubMed2006

Laminins containing the beta2 chain modulate the precise organization of CNS synapses.

Synapses are formed and stabilized by concerted interactions of pre-, intra-, and post-synaptic components; however, the precise nature of the intrasynaptic components in the CNS remains obscure. Potential intrasynaptic components include extracellular matrix molecules such as laminins; here, we isolate beta2-containing laminins, including perhaps laminins 13 (alpha3beta2gamma3) and 14 (alpha4beta2gamma3), from CNS synaptosomes suggesting a role for these molecules in synaptic organization. Indeed, hippocampal synapses that form in vivo in the absence of these laminins are malformed at the ultrastructural level and this malformation is replicated in synapses formed in vitro, where laminins are provided largely by the post-synaptic neuron. This recapitulation of the in vivo function of laminins in vitro suggests that the malformations are a direct consequence of the removal of laminins from the synapse. Together, these results support a role for neuronal laminins in the structural integrity of central synapses.

Animals↗
PubMed2005

Differential expression of NMDA receptor subunits and splice variants among the CA1, CA3 and dentate gyrus of the adult rat.

N-Methyl-d-aspartate (NMDA)-type glutamate receptors in the hippocampus are important mediators of both memory formation and excitotoxicity. It is thought that glutamatergic neurons of the CA1, CA3 and dentate gyrus regions of the hippocampus contribute differentially to memory formation and are differentially sensitive to excitotoxicity. The subunit and/or splice variant composition of the NMDA receptor controls many aspects of receptor function such as ligand affinity, calcium permeability and channel kinetics, as well as interactions with intracellular anchoring and regulatory proteins. Thus, one possible explanation of the differences in NMDA receptor-dependent processes, such as synaptic plasticity and excitotoxicity, among the hippocampal sub-regions is that they differ in subunit and/or splice variant expression. Here we report that the NMDA receptor subunits NR1 and NR2B, along with the four splice variant cassettes of the NR1 subunit are differentially expressed in the CA1, CA3 and dentate gyrus of the hippocampus. Expression of the AMPA receptor subunits GluR1 and GluR2 also differ. These differences may contribute to functional differences, such as with excitotoxicity and synaptic plasticity, that exist between the sub-regions of the hippocampus.

Actinin↗