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  • 1
    Electronic Resource
    Electronic Resource
    A non-amyloidogenic function of BACE-2 in the secretory pathway (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: β-Site amyloid precursor protein cleavage enzyme (BACE)-1 and BACE-2 are members of a novel family of membrane-bound aspartyl proteases. While BACE-1 is known to cleave β-amyloid precursor protein (βAPP) at the β-secretase site and to be required for the generation of amyloid β-peptide (Aβ), the role of its homologue BACE-2 in amyloidogenesis is less clear. We now demonstrate that BACE-1 and BACE-2 have distinct specificities in cleavage of βAPP in cultured cells. Radiosequencing of the membrane-bound C-terminal cleavage product revealed that BACE-2 cleaves βAPP in the middle of the Aβ domain between phenylalanines 19 and 20, resulting in increased secretion of APPs-α- and p3-like products and reduced production of Aβ species. This cleavage can occur in the Golgi and later secretory compartments. We also demonstrate that BACE-1-mediated cleavage of βAPP at Asp1 of the Aβ domain can occur as early as in the endoplasmic reticulum, while cleavage at Glu11 occurs in later compartments. These data indicate that the distinct specificities of BACE-1 and BACE-2 in their cleavage of βAPP differentially affect the generation of Aβ.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00908.x
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  • 2
    Electronic Resource
    Electronic Resource
    Attenuation of Cyclic AMP Production by Carbamazepine (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The anticonvulsant carbamazepine is an effective treatment both for epilepsy and for bipolar affective disorder, but the molecular mechanism(s) underlying its therapeutic effects have not been identified. We have found that carbamazepine exerts significant inhibitory effects on the cyclic AMP (cAMP) generating system. Within the clinical therapeutic range (∼50 µM), carbamazepine inhibited both basal and forskolin-stimulated cAMP production, without having any significant effects on phosphodiesterase activity. Carbamazepine also exerted its inhibitory effects on the cAMP generating system in pertussis toxin-treated cells, suggesting that the action of carbamazepine was likely mediated through an inhibitory guanine nucleotide binding protein-independent mechanism. A forskolin affinity purification column was used to purify adenylyl cyclases from rat cerebral cortex, and we found that carbamazepine inhibited both basal and forskolin-stimulated activity of purified adenylyl cyclase. We also investigated the effects of carbamazepine on the levels of the transcription factor, cAMP response element binding protein in the phosphorylated (active) state, and found that carbamazepine significantly inhibited forskolin-induced phosphorylation of the cAMP response element binding protein. The data indicate that carbamazepine inhibits adenylyl cyclase activity as well as the downstream effects of activation of adenylyl cyclase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67052079.x
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  • 3
    Electronic Resource
    Electronic Resource
    Chronic Sodium Valproate Selectively Decreases Protein Kinase C α and ε In Vitro (1994)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 63 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Valproic acid (VPA) is a fatty acid antiepileptic with demonstrated antimanic properties, but the molecular mechanism or mechanisms underlying its therapeutic efficacy remain to be elucidated. In view of the increasing evidence demonstrating effects of the first-line antimanic drug, lithium, on protein kinase C (PKC), we investigated the effects of VPA on various aspects of this enzyme. Chronic exposure (6–7 days) of rat C6 glioma cells to “therapeutic” concentrations (0.6 mM) of VPA resulted in decreased PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane ratio of PKC activity. Western blot analysis revealed isozyme-selective decreases in the levels of PKC α and ε (but not δ or ζ) in both the membrane and cytosolic fractions after chronic VPA exposure; VPA added to reaction mixtures did not alter PKC activity or 3H-phorbol ester binding. Together, these data suggest that chronic VPA indirectly lowers the levels of specific isozymes of PKC in C6 cells. Given the pivotal role of PKC in regulating neuronal signal transduction and modulating intracellular cross-talk between neurotransmitter systems, the specific decreases in PKC α and ε may play a role in the antimanic effects of VPA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.63062361.x
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  • 4
    Electronic Resource
    Electronic Resource
    Ethanol-Induced Inhibition of [3H]Thienylcyclohexylpiperidine (TCP) Binding to NMDA Receptors in Brain Synaptic Membranes and to a Purified Protein Complex (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: N-Methyl-d-asparate receptors (NMDARs) are a major target of ethanol effects in the nervous system. Haloperidol-insensitive, but dizocilpine (MK-801)-sensitive, binding of N-[1-(2-[3H]thienyl)cyclohexyl]piperidine ([3H]TCP) to synaptic membranes has the characteristics of ligand interaction with the ion channel of NMDARs. In the present studies, ethanol produced a concentration-dependent decrease in the maximal activation of [3H]TCP binding to synaptic membranes by NMDA and Gly, but a moderate change in the activation by l-Glu when l-Glu was present at concentrations 〈 100 µM. However, ethanol (100 mM) inhibited completely the activation of [3H]TCP binding produced by high concentrations of l-Glu (200–400 µM). It also inhibited strongly the activation of [3H]TCP binding by spermidine or spermidine plus Gly. In a purified complex of proteins that has l-Glu-, Gly-, and [3H]TCP-binding sites, ethanol (100 mM) decreased significantly the maximal activation of [3H]TCP binding produced by either l-Glu or Gly. Activation constants (Kact) for l-Glu and Gly acting on the purified complex were 12 and 28 µM, respectively. Ethanol had no significant effect on the Kact of l-Glu but caused an increase in the Kact of Gly. These studies have identified at least one protein complex in neuronal membranes whose response to both l-Glu and Gly is inhibited by ethanol. These findings may explain some of the effects of acute and chronic ethanol treatment on the function and expression of the subunits of this complex in brain neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67010201.x
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  • 5
    Electronic Resource
    Electronic Resource
    Nicotinic-acetylcholine receptors are functionally coupled to the nitric oxide/cGMP-pathway in insect neurons (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In addition to their ionotropic role, neuronal nicotinic acetylcholine receptors (nAChRs) can influence second messenger levels, transmitter release and gene transcription. In this study, we show that nAChRs in an insect CNS control cGMP levels by coupling to NO production. In conditions that inhibit spiking, nicotine induced cGMP synthesis. This increase in cGMP was blocked by nicotinic antagonists, and by inhibitors of both nitric oxide synthase and soluble guanylyl cyclase. The nicotinic-evoked increase in cGMP was localized to specific NO-sensitive neurons in the CNS, several of which are identified motoneurons. Because NO production requires Ca2+, we investigated the effect of nicotinic stimulation on [Ca2+]i in cultured neurons. We found that activation of nAChRs increased [Ca2+]i, which was blocked by nAChR antagonists. Nicotinic stimulation of neurons in the isolated CNS in low-Na+, also evoked increases in [Ca2+]i independent of fast changes in voltage. In addition, approximately 10% of the nicotinic-evoked [Ca2+]i increase in cultured neurons persisted when voltage-gated Ca2+ channels were blocked by Ni2+. Under the same conditions, nicotinic stimulation of cGMP in the CNS was unaffected. These combined results suggest that nicotinic stimulation is coupled to NOS potentially by directly gating Ca2+.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01147.x
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  • 6
    Electronic Resource
    Electronic Resource
    Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 76 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies, and tau protein kinase II is reported to play a role in the pathogenesis of Alzheimer's disease. Recently, we reported that tau protein kinase II (cdk5/p20)-phosphorylated human tau inhibits microtubule assembly, and tau protein kinase II (cdk5/p20) phosphorylation of microtubule-associated tau results in dissociation of phosphorylated tau from the microtubules and tubulin depolymerization. In the studies reported here, a combination of mass spectrometric techniques was used to study the phosphorylation of human recombinant tau by recombinant tau protein kinase II (cdk5/p20) in vitro. The extent of phosphorylation was determined by measuring the molecular mass of phosphorylated tau using mass spectrometry. Reaction of human recombinant tau with tau protein kinase II (cdk5/p20) resulted in the formation of two major species containing either five or six phosphate groups. The specific amino acid residues phosphorylated were determined by analyzing tryptic peptides by tandem mass spectrometry via either MALDI/TOF post-source decay or by electrospray tandem mass spectrometry. Based on these experiments, we conclude that tau protein kinase II (cdk5/p20) can phosphorylate human tau at Thr181, Thr205, Thr212, Thr217, Ser396 and Ser404.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00130.x
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  • 7
    Electronic Resource
    Electronic Resource
    Temperature-Sensitive Expression of Drosophila Neuronal Nicotinic Acetylcholine Receptors (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Heterologous expression of cloned Drosophila nicotinic acetylcholine receptor (nAChR) subunits indicates that these proteins misfold when expressed in mammalian cell lines at 37°C. This misfolding can, however, be overcome either by growing transfected mammalian cells at lower temperatures or by the expression of Drosophila nAChR subunits in a Drosophila cell line. Whereas the Drosophila nAChR β subunit (SBD) cDNA, reported previously, lacked part of the SBD coding sequence, here we report the construction and expression of a full-length SBD cDNA. We have examined whether problems in expressing functional Drosophila nAChRs in either Xenopus oocytes or mammalian cell lines can be attributed to an inability of these expression systems to assemble correctly Drosophila nAChRs. Despite expression in what might be considered a more native cellular environment, we have been unable to detect functional nAChRs in a Drosophila cell line unless Drosophila nAChR subunit cDNAs are coexpressed with vertebrate nAChR subunits. Our results indicate that the folding of Drosophila nAChR subunits is temperature-sensitive and strongly suggest that the inability of these Drosophila nAChR subunits to generate functional channels in the absence of vertebrate subunits is due to a requirement for coassembly with as yet unidentified Drosophila nAChR subunits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68051812.x
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  • 8
    Electronic Resource
    Electronic Resource
    Norepinephrine Increases Cyclic GMP Levels in Cerebellar Cells from Neuronal Nitric Oxide Synthase Knockout Mice (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cyclic GMP is an important intracellular messenger in the nervous system that may mediate cellular forms of neuronal plasticity. Previous studies show that most neurotransmitters stimulate cyclic GMP levels by the activation of nitric oxide synthase (NOS). In this study, we report that in primary cell cultures from the cerebellum of neuronal NOS knockout mice, norepinephrine stimulates an increase in cyclic GMP content. This increase is seen in both granule cell and astrocyte cultures and is not blocked by inhibitors of NOS or by inhibition of soluble guanylyl cyclase. These results suggest a novel pathway by which norepinephrine enhances cyclic GMP levels in the nervous system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71010440.x
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  • 9
    Electronic Resource
    Electronic Resource
    Fast modelling of marine surface multiples (2002)
    Oxford, UK : Blackwell Science Ltd
    Geophysical prospecting 50 (2002), S. 0 
    Details
    ISSN: 1365-2478
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Geosciences , Physics
    Notes: In the development and testing of water-surface multiple-removal algorithms, it is valuable to have accurate synthetic seismograms which exhibit multiples, for which the multiple-free solution is known. A method is presented for constructing 2D and 3D solutions of the acoustic wave equation in water, by combining the solution from a primary source with other scaled solutions of secondary sources, which simulate diffractors. The computation involves function evaluation rather than numerical solution of differential equations and is consequently accurate and comparatively fast. The analytic formulae on which the method is based give insights into methods for multiple removal. Generalized reflection coefficients, defined on a horizontal plane above the diffractors, are derived and used to construct the integral equations which are the basis for many multiple-removal schemes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-2478.2002.00321.x
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  • 10
    Electronic Resource
    Electronic Resource
    The Caenorhabditis elegans lev-8 gene encodes a novel type of nicotinic acetylcholine receptor α subunit (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 93 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We have cloned Caenorhabditis elegans lev-8 and demonstrated that it encodes a novel nicotinic acetylcholine receptor (nAChR) subunit (previously designated ACR-13), which has functional roles in body wall and uterine muscles as part of a levamisole-sensitive receptor. LEV-8 is an α subunit and is the first to be described from the ACR-8-like group, a new class of nAChR with atypical acetylcholine-binding site (loop C) and channel-lining motifs. A single base pair change in the first intron of lev-8 in lev-8(x15) mutants leads to alternative splicing and the introduction of a premature stop codon. lev-8(x15) worms are partially resistant to levamisole-induced egg laying and paralysis, phenotypes rescued by expression of the wild-type gene. lev-8(x15) worms also show reduced rates of pharyngeal pumping. Electrophysiological recordings from body wall muscle show that currents recorded in response to levamisole have reduced amplitude in lev-8(x15) compared with wild-type animals. Consistent with these phenotypic observations, green fluorescent protein fused to LEV-8 is expressed in body wall and uterine muscle, motor neurons and epithelial-derived socket cells. Thus, LEV-8 is a levamisole receptor subunit and exhibits the most diverse expression pattern of any invertebrate nAChR subunit studied to date.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02951.x
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