DOCSLIB.ORG

The Effect of N-Acetyl-Aspartyl-Glutamate and N-Acetyl-Aspartate on White Matter Oligodendrocytes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Effect of N-Acetyl-Aspartyl-Glutamate and N-Acetyl-Aspartate on White Matter Oligodendrocytes doi:10.1093/brain/awp087 Brain 2009: 132; 1496–1508 | 1496 BRAIN A JOURNAL OF NEUROLOGY The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes Karolina Kolodziejczyk,1 Nicola B. Hamilton,1 Anna Wade,1 Ragnhildur Ka´rado´ ttir2 and David Attwell1 1 Department of Physiology, University College London, London, UK 2 Department of Veterinary Medicine, University of Cambridge, Cambridge, UK Correspondence to: David Attwell, Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK E-mail: [email protected] Elevations of the levels of N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) are associated with myelin loss in the leucodystrophies Canavan’s disease and Pelizaeus-Merzbacher-like disease. NAAG and NAA can activate and antagonize neuronal N-methyl-D-aspartate (NMDA) receptors, and also act on group II metabotropic glutamate receptors. Oligodendrocytes and their precursors have recently been shown to express NMDA receptors, and activation of these receptors in ischaemia leads to the death of oligodendrocyte precursors and the loss of myelin. This raises the possibility that the failure to develop myelin, or demyelination, occurring in the leucodystrophies could reflect an action of NAAG or NAA on oligodendrocyte NMDA receptors. However, since the putative subunit composition of NMDA receptors on oligodendrocytes differs from that of neuronal NMDA receptors, the effects of NAAG and NAA on them are unknown. We show that NAAG, but not NAA, evokes an inward membrane current in cerebellar white matter oligodendrocytes, which is reduced by NMDA receptor block (but not by block of metabotropic glutamate receptors). The size of the current evoked by NAAG, relative to that evoked by NMDA, was 2+ much smaller in oligodendrocytes than in neurons, and NAAG induced a rise in [Ca ]i in neurons but not in oligodendrocytes. These differences in the effect of NAAG on oligodendrocytes and neurons may reflect the aforementioned difference in receptor subunit composition. In addition, as a major part of the response in oligodendrocytes was blocked by tetrodotoxin (TTX), much of the NAAG-evoked current in oligodendrocytes is a secondary consequence of activating neuronal NMDA receptors. Six hours exposure to 1 mM NAAG did not lead to the death of cells in the white matter. We conclude that an action of NAAG on oligodendrocyte NMDA receptors is unlikely to be a major contributor to white matter damage in the leucodystrophies. Keywords: leucodystrophy; Pelizaeus-Merzbacher-like disease; Canavan’s disease; glutamate; NMDA Abbreviations: mGluR3 = metabotropic glutamate receptor 3; NAA = N-acetyl-aspartate; NAAG = N-acetyl-aspartyl-glutamate; NMDA = N-methyl-D-aspartate; TTX = tetrodotoxin Received October 8, 2008. Revised February 11, 2009. Accepted March 2, 2009. Advance Access publication April 21, 2009 ß 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/ 2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NAAG, NAA and oligodendrocytes Brain 2009: 132; 1496–1508 | 1497 Introduction NAA can be exported to oligodendrocytes, where it is metabolized by the enzyme aspartoacylase, to form acetyl-CoA, which has The speeding of axon potential propagation which is produced by been suggested to be used for myelination (Chakraborty et al., myelination of axons by oligodendrocytes is essential for normal 2001), although this idea has been criticized (Baslow, 2007) on brain function (Fields, 2008). Failure of the development of the grounds that NAA turns over much faster than myelin, myelination, as occurs in genetic leucodystrophies and cerebral and that myelin is still formed in a disorder in which NAA is no palsy, or destruction of myelin, as occurs in multiple sclerosis, longer made. NAAG is broken down to NAA and glutamate by produces mental and physical disability. It has become increasingly glutamatecarboxypeptidases (Berger et al., 1999) located on the clear that activation of glutamate receptors on oligodendrocytes, surface of astrocytes (Fig. 1). or their precursor cells, can lead to loss of myelin. Periventricular In two leucodystrophies there is a defect in the metabolism of leucomalacia, leading to cerebral palsy, can be caused by a NAAG and NAA, associated with a lack of formation of myelin. deficient blood flow to the periventricular white matter and/or Canavan’s disease is caused by a lack of aspartoacylase activity infection, leading to glutamate release that kills precursor and (Fig. 1) in oligodendrocytes (Kumar et al., 2006), which reduces immature oligodendrocytes (Follett et al., 2000; Ka´ rado´ ttir et al., NAA breakdown and thus causes a large rise in NAA and NAAG 2008; Khwaja and Volpe, 2008). In spinal cord injury, secondary levels. Patients have also been reported with a Pelizaeus- ischaemia leads to a release of glutamate by reversed uptake from Merzbacher-like syndrome, in which there is an absence of axons and from oligodendrocytes themselves, which damages myelin similar to that seen when the myelin proteolipid protein oligodendrocytes by activating AMPA/kainate receptors (Li et al., is mutated in Pelizaeus-Merzbacher disease (although no mutation 1999). Oligodendrocytes also express N-methyl-D-aspartate was found in these patients), and this is associated with a large (NMDA) receptors, however, and activation of these receptors by rise of NAAG concentration (Wolf et al., 2008). Because NAA and glutamate released in ischaemia causes demyelination and loss NAAG levels rise in these disorders, and because these agents of axonal action potential propagation (Ka´rado´ ttir et al., 2005; affect neuronal NMDA receptors, we hypothesized that the demyelination occurring in these disorders might reflect NAA Salter and Fern, 2005; Micu et al., 2006; Bakiri et al., 2008). or NAAG acting on oligodendrocyte NMDA receptors. However, Other endogenous molecules may also act on oligodendrocyte the subunit composition of oligodendrocyte NMDA receptors most NMDA receptors. In particular, N-acetyl-aspartate (NAA) and probably differs from that of neuronal ones (Ka´ rado´ ttir et al., N-acetyl-aspartyl-glutamate (NAAG) have been shown to act as 2005; Salter and Fern, 2005; Micu et al., 2006), and so may both agonists and antagonists at neuronal NMDA receptors show a different pharmacological profile. We therefore tested (Westbrook et al., 1986; Sekiguchi et al., 1992; Burlina et al., whether NAAG or NAA can act on oligodendrocyte NMDA 1994; Koenig et al., 1994; Valivullah et al., 1994; Rubin et al., receptors. 1995; Pliss et al., 2000; Bergeron et al., 2005). NAA and NAAG are synthesized in neurons (Baslow, 2007), as shown in Fig. 1. Methods oligodendrocytes aspartate lost in + Preparation Canavan’s acetyl CoA lipids? myelin ? disease Rats (post-natal day 12) were killed by cervical dislocation aspartoacylase in accordance with UK government regulations. Cerebellar slices (225 mm thick) were made in solution containing 124 mM NaCl, 26 mM NaHCO3, 1 mM NaH2PO4, 2.5 mM KCl, 2 mM MgCl2, neurons 2.5 mM CaCl2, 10 mM glucose, bubbled with 95% O2/5% CO2,pH aspartate N-acetylaspartate aspartate N-acetyltransferase NAA L-glutamate ligase 7.4, as well as 1 mM Na-kynurenate to block glutamate receptors. For + + NAAG experiments, slices were superfused at 24 Æ 1C with HEPES-buffered acetyl CoA glutamate solution containing 144 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1 mM NaH2PO4, 2.5 mM CaCl2, 10 mM glucose, pH set to 7.4 with NaOH, glutamate + NAA NAAG glutamatecarboxypeptidases II and III bubbled with 100% O2. Usually MgCl2 was omitted from the solution, astrocytes and glycine (100 mM, to ensure activation of the glycine site of NMDA receptors) and strychnine (5 mM, to block glycine-gated chloride channels) were added. Some experiments, shown in Figs 9 and 10, Figure 1 Metabolic pathways of NAA and NAAG. NAA is were performed in physiological (1 mM) Mg2+ and with no synthesized in neurons from aspartate and acetyl-CoA. It can added glycine. NAA and NAAG were from Tocris, UK. HPLC data then be exported to oligodendrocytes, where it is converted supplied by Tocris showed that 1 mM NAAG contained 50.2 mM back to acetyl-CoA by aspartoacylase (an enzyme lost in glutamate. Canavan’s disease) and may thus be converted into lipids that form part of the myelin. Alternatively, it can be converted to NAAG in neurons and released to the extracellular space, Electrophysiology where it is converted back to NAA by carboxypeptidases expressed on the extracellular surface of astrocytes. White matter cells (avoiding cerebellar nuclei) were whole-cell clamped with pipettes containing a Cs+-based solution comprising 1498 | Brain 2009: 132; 1496–1508 K. Kolodziejczyk et al. 130 mM Cs-gluconate, 4 mM NaCl, 0.5 mM CaCl2, 10 mM HEPES, 8 h incubation with secondary antibody (goat anti-mouse IgG, 10 mM BAPTA, 4 mM MgATP, 0.5 mM Na2GTP, K-Lucifer yellow 2, AlexaFluor 488, Invitrogen, 1:200). Slices were washed 3 Â 30 min pH set to 7.3 with CsOH. Membrane potentials were compensated with PBS and mounted on coverslips using a mounting solution for the –14 mV junction potential measured with the electrode in containing DAPI to label nuclei. the extracellular solution (Fenwick et al., 1982). Series resistance was 10–30 MV. Mature oligodendrocytes were identified from their morphology after Lucifer filling, with a small number of cells also Confocal microscopy being labelled after recording for myelin basic protein (as in Ka´ rado´ ttir et al., 2005; Ka´ rado´ ttir and Attwell, 2006). Granule cells Confocal images of slices were taken for the cell death assay using were identified from their position in the granule cell layer, their small excitation and emission wavelengths as follows: DAPI (excitation soma attached to approximately four dendrites and their high input 364 nm, emission 4385 nm), AlexaFluor 488 (excitation 488 nm, emis- resistance (43GV).
Load more

Recommended publications
  • Synthesis of Conformationally Constrained Glutamate Analogues and Their Preliminary Evaluation As Glutamate Transport Inhibitors
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2002 Synthesis of conformationally constrained glutamate analogues and their preliminary evaluation as glutamate transport inhibitors Travis Taylor Denton The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Denton, Travis Taylor, "Synthesis of conformationally constrained glutamate analogues and their preliminary evaluation as glutamate transport inhibitors" (2002). Graduate Student Theses, Dissertations, & Professional Papers. 9450. https://scholarworks.umt.edu/etd/9450 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.
    [Show full text]
  • Poster Abstracts
    POSTER ABSTRACTS Society of Toxicology (MASOT) www.masot.org Fall 2015 Scientific Meeting October 13th, 2015 Abstract 01 Tracking Inflammatory Macrophage Accumulation in the Lung during Ozone- induced Lung Injury in Mice M Francis, M Mandal, C. Sun, H Choi, JD Laskin, DL Laskin Rutgers University, Piscataway, NJ Ozone induced lung injury is associated with an accumulation of pro- and antiinflammatory macrophages (MP) in the lung which have been implicated in tissue injury and repair. In these studies, we used in vivo tracking techniques to investigate the origin of cell. Initially we generated bone marrow (BM) chimeric mice by adoptive transfer of BM cells from GFP+ mice into irradiated C57BL/6 mice. After 4 weeks, mice were exposed to air or ozone (0.8 ppm, 3 h). Macrophages were isolated from lungs 24- 72 h later, stained with fluorescent labeled antibodies, and analyzed by flow cytometry. Approximately 98% of BM cells were found to be GFP+ while only 5% were GFP+ in control lungs. Ozone exposure resulted in a marked increase in infiltrating mature GFP+CD11b+F4/80+ MP into the lung. Two populations, Ly6CHi proinflammatory and Ly6CLo antiinflammatory were identified. Proinflammatory GFP+Ly6CHi MP increased rapidly after ozone and remained elevated, increases in antiinflammatory GFP+Ly6CLo were transient. To assess potential mechanisms mediating the accumulation of these MP subpopulations in the lung, we used mice lacking Ccr2, a chemokine receptor involved in proinflammatory MP trafficking. Loss of Ccr2 resulted in decreased numbers of infiltrating CD11b+ MP in the lung. This was due to a selective reduction in proinflammatory Ly6CHi MP.
    [Show full text]
  • The Microbiota-Produced N-Formyl Peptide Fmlf Promotes Obesity-Induced Glucose
    Page 1 of 230 Diabetes Title: The microbiota-produced N-formyl peptide fMLF promotes obesity-induced glucose intolerance Joshua Wollam1, Matthew Riopel1, Yong-Jiang Xu1,2, Andrew M. F. Johnson1, Jachelle M. Ofrecio1, Wei Ying1, Dalila El Ouarrat1, Luisa S. Chan3, Andrew W. Han3, Nadir A. Mahmood3, Caitlin N. Ryan3, Yun Sok Lee1, Jeramie D. Watrous1,2, Mahendra D. Chordia4, Dongfeng Pan4, Mohit Jain1,2, Jerrold M. Olefsky1 * Affiliations: 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. 2 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. 3 Second Genome, Inc., South San Francisco, California, USA. 4 Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. * Correspondence to: 858-534-2230, [email protected] Word Count: 4749 Figures: 6 Supplemental Figures: 11 Supplemental Tables: 5 1 Diabetes Publish Ahead of Print, published online April 22, 2019 Diabetes Page 2 of 230 ABSTRACT The composition of the gastrointestinal (GI) microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine (fMLF), are elevated in high fat diet (HFD)- induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon- like peptide-1 (GLP-1). Obese Fpr1-knockout (Fpr1-KO) mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota.
    [Show full text]
  • Microglial Glutathione and Glutamate: Regulation Mechanisms
    Microglial glutathione and glutamate: Regulation mechanisms Victoria Anne Honey Fry UCL Institute of Neurology A thesis submitted for the degree of Doctor of Philosophy (Ph.D.) 1 I, Victoria Fry, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Microglia, the immune cells of the central nervous system (CNS), are important in the protection of the CNS, but may be implicated in the pathogenesis of neuroinflammatory disease. Upon activation, microglia produce reactive oxygen and nitrogen species; intracellular antioxidants are therefore likely to be important in their self-defence. Here, it was confirmed that cultured microglia contain high levels of glutathione, the predominant intracellular antioxidant in mammalian cells. The activation of microglia with lipopolysaccharide (LPS) or LPS + interferon- was shown to affect their glutathione levels. GSH levels in primary microglia and those of the BV-2 cell line increased upon activation, whilst levels in N9 microglial cells decreased. - Microglial glutathione synthesis is dependent upon cystine uptake via the xc transporter, which exchanges cystine and glutamate. Glutamate is an excitatory neurotransmitter whose extracellular concentration is tightly regulated by excitatory amino acid transporters, as high levels cause toxicity to neurones and other CNS cell types through overstimulation of - glutamate receptors or by causing reversal of xc transporters. Following exposure to LPS, increased extracellular glutamate and increased levels of messenger ribonucleic acid - (mRNA) for xCT, the specific subunit of xc , were observed in BV-2 and primary microglial cells, suggesting upregulated GSH synthesis.
    [Show full text]
  • Activation of the Metabotropic Glutamate Receptor Attenuates N
    Proc. Natl. Acad. Sci. USA Vol. 88, pp. 9431-9435, November 1991 Neurobiology Activation of the metabotropic glutamate receptor attenuates N-methyl-D-aspartate neurotoxicity in cortical cultures (trans-1-aminocyclopentyl-1,3-dicarboxylic acid/carbachol/Alzheimer disease/development/neurodegeneration) JAE-YOUNG KOH, ELIZABETH PALMER, AND CARL W. COTMAN* Department of Psychobiology, University of California, Irvine, CA 92717 Communicated by James L. McGaugh, July 15, 1991 (receivedfor review April 3, 1991) ABSTRACT Excitatory amino acid receptor-mediated neu- methylisoxazole-4-propionic acid and kainate receptors) are rotoxicity (excitotoxicity) has been proposed to contribute to directly associated with the specific ligand-gated ionophores neuronal loss in a wide variety of neurodegenerative conditions. that permit influx of cations upon activation (ionotropic Although considerable evidence has accumulated implicating receptor). In contrast, the recently discovered metabotropic N-methyl-D-aspartate (NMDA), kainate, and a-amino-3- glutamate, or trans-1-aminocyclopentyl-1,3-dicarboxylic hydroxy-5-methylisoxazole4propionic acid receptors in the acid (ACPD), receptor (10-12) activates a phospholipase, via processes of excitotoxicity, relatively little research has focused a guanine nucleotide-binding regulatory protein, that hydro- on the ability of other neurotransmitter systems to influence lyzes membrane phospholipid to generate the second mes- sengers diacylglycerol (DAG) and inositol trisphosphate excitotoxic neuronal injury. In the present
    [Show full text]
  • Functional Impact of Interacting Protein on Kainate Receptors: Necab1 and Neto Proteins
    Instituto de Neurociencias de Alicante Universidad Miguel Hernandez Thesis manuscript for: PhD in Neuroscience Functional impact of interacting protein on kainate receptors: NeCaB1 and NeTo proteins. Jon Palacios Filardo Supervised by: Prof. Juan Lerma Alicante, 2014 Agradecimientos/Acknowledgments Agradecimientos/Acknowledgments Ahora que me encuentro escribiendo los agradecimientos, me doy cuenta que esta es posiblemente la única sección de la tesis que no será corregida. De manera que los escribiré tal como soy, tal vez un poco caótico. En primer lugar debo agradecer al profesor Juan Lerma, por la oportunidad que me brindó al permitirme realizar la tesis en su laboratorio. Más que un jefe ha sido un mentor en todos estos años, 6 exactamente, en los que a menudo al verme decía: “Jonny cogió su fusil”, y al final me entero que es el título de una película de cine… Pero aparte de un montón de anécdotas graciosas, lo que guardaré en la memoria es la figura de un mentor, que de ciencia todo lo sabía y le encantaba compartirlo. Sin duda uno no puede escribir un libro así (la tesis) sin un montón de gente alrededor que te enseña y ayuda. Como ya he dicho han sido 6 años conviviendo con unos maravillosos compañeros, desde julio de 2008 hasta presumiblemente 31 de junio de 2014. De cada uno de ellos he aprendido mucho; técnicamente toda la electrofisiología se la debo a Ana, con una paciencia infinita o casi infinita. La biología molecular me la enseñó Isa. La proteómica la aprendí del trío Esther-Ricado-Izabella. Joana y Ricardo me solventaron mis primeras dudas en el mundo de los kainatos.
    [Show full text]
  • Tuesday, Symposium: Cortical Sources . . . 37 Symposium 4
    Tuesday, Symposium: Cortical sources . 37 MET,BOLICPVMP~NG IN INSECT LKSCIE ,WD RESTING MEMBRXW ELECTROGENESIS Comparison of electrical activity and ionic currents in an isolated M.J. KATKOWSKA & B. GRAPEL. N. Copernicus Univ., Inst. of Biology and axon and in an isolated neuron. Environmental Protection. Dept. of Animal Physiology, To&. Poland Stankiewicz M.', Grolleau F.~,Lapied B.~,Kadziela w.', Pelhate M.~ A studj of the literature concerning the resting potential (RP) of insect muscle Inst, of Biology and Environment Protection. N.Copernicus Univ , Torun. Poland reveals a number of apparent departures from the situation found in other (I),Lab.of Neurophysiology. EREA CNRS 120. Angers, France (2). excitable cells. The Insects. adult Colorado beetle and mealworm, and mealworm The comparative approach to investigation of the axonal and larva. chosen to this study differ much in their haemolymph ionic content (e.g neuronal mechanisms underlying rythmogenesis in invertebrates has lead Colorado beetle's haemolymph contains only 2 mmol.l-' of NaC) and so they have to an important conclusion that rythm generation is the result of complex ditferent ion~c requirements for the resting membrane potential (RMP) interactions between cellular, synaptic and network properties. The aim of maintenance and the contnbution of pumps to it. The present study examines the this study is to compare the membrane properties of insect giant axon, tlme dependence of the RP In muscles of studied insects and tries to determine the which propagates action potentials and insect neurosecretory cells called role of metabolic pumping in the genesis of tlus potentla1 using of sodium pump dorsal unpaired median (DUM) neurons involved in the modulation of idubitor - ouabain and in the case of Colorado beetle, K-H pump inhibitor - SCH skeletal and/or visceral muscles via the release of octopamine.
    [Show full text]
  • Seizures and Brain Injury in Neonatal Rats Induced by 1 S,3R-ACPD, a Metabotropic Glutamate Receptor Agonist
    The Journal of Neuroscience, October 1993, 73(10): 4445-4455 Seizures and Brain Injury in Neonatal Rats Induced by 1 S,3R-ACPD, a Metabotropic Glutamate Receptor Agonist John W. McDonald,’ Andrew S. Fix,* Joseph P. Tizzano:* and Darryle D. Schoepp’ ICNS Research Division and *Toxicology Research Laboratories, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 The role of metabotropic excitatory amino acid receptors in receptors, which are coupled to phosphoinositide hydrolysis or seizures and brain injury was examined using the selective modulation of CAMP metabolism, have beencharacterized (Sla- metabotropic agonist 1 S,3R-ACPD [( 1 S,3R)-1 -aminocyclo- deczek et al., 1985; Nicoletti et al., 1986a; Pearce et al., 1986; pentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats. Sys- Sugiyama et al., 1987; Schoepp and Johnson, 1988; Schoepp et temic administration of 1 S,3R-ACPD produced dose-depen- al., 1992b). Nonselective agonistsof metabotropic receptors in- dent convulsions (ED,, = 16 mg/kg, i.p.) that were clude glutamate, ibotenate, and quisqualate (Schoepp et al., stereoselective for the active metabotropic ACPD isomer, 1990a). Recently, more selective metabotropic agonists have since lR,BS-ACPD was less potent (ED,, = 93 mg/kg, i.p.). been developed, including (+)truns-ACPD [(f )-truns- 1-ami- 1 S,3R-ACPD-induced seizures were antagonized by sys- nocyclopentane- 1,3-dicarboxylic acid (Palmer et al., 1989; De- temic administration of dantrolene, an inhibitor of intracel- sai and Conn, 1990)]. Truns-ACPD is a racemic mixture of lular calcium mobilization, but not by the ionotropic gluta- lS,3R and lR, 3S stereoisomers.
    [Show full text]
  • Transiently Selective Activation of Phosphoinositide Turnover in Layer
    The Journal of Neuroscience, December 1995, 15(12): 7916-7928 Transiently Selective Activation of Phosphoinositide Turnover in Layer V Pyramidal Neurons After Specific mGluRs Stimulation in Rat Somatosensory Cortex During Early Postnatal Development J. A. Bevilacqua,’ C. Peter Dowries,* and Pedro R. Lowensteinl ‘Laboratory of Cellular and Molecular Neurobiology, Physiology Unit, School of Molecular and Medical Biosciences, University of Wales College of Cardiff, Cardiff CFl 3US and 2Department of Biochemistry, University of Dundee, Dundee DDl 4HN, United Kingdom Biochemical analysis of muscarinic- and metabotropic-glu- that the neocortex displays a higher susceptibility to experience- tamate receptor stimulated phosphoinositide (PI) turnover induced synaptic modification during early stages of postnatal in rat cortical preparations during the first three weeks of development (Hubel and Wiesel, 1970; Van der Loos and Wool- postnatal development indicates the existence of a tran- sey, 1973; Blakemore and Van Sluyters, 1974; Woolsey and siently increased accumulation of labeled inositol poly- Wann, 1976; Cynader and Mitchell, 1980; Fox, 1992; Schlaggar phosphates during the first postnatal week (Gonzales and et al., 1993; Fox and Zahs, 1994). Studies in the rat somatosen- Crews, 1985; Dudek et al., 1989). We now report for first sory cortex have shown the existence of a narrow period during time the visualization of those neurons responding with in- early postnatal development during which the anatomical and creased PI turnover to glutamatergic or cholinergic-recep- functional structure of the neocortex is highly modifiable in re- tor stimulation in rat somatosensory cortex during early sponse to changes in the afferent input from the peripheral sen- postnatal development utilizing a recently described meth- sory organs, and after which the cortical circuitry remains rel- od (Bevilacqua et al, 1994).
    [Show full text]
  • Activation of Metabotropic Glutamate Receptors Produces Reciprocal
    The Journal of Neuroscience, April 1993, 13(4): 1636-l 641 Activation of Metabotropic Glutamate Receptors Produces Reciprocal Regulation of lonotropic Glutamate and GABA Responses in the Nucleus of the Tractus Solitarius of the Rat Steven R. Glaum and Richard J. Miller Department of Pharmacological and Physiological Sciences, The University of Chicago, Chicago, Illinois 60637 Whole-cell voltage-clamp recordings were made in thin effect was found to be independent of changes in [Ca”], and transverse slices from neurons of the dorsomeclial subdi- could be mimicked by endogenous glutamate released from af- vision of the nucleus of the tractus solitarius (NTS) of the ferent projections to the NTS by high-frequency stimulation of rat. Cells were exposed to either the ionotropic glutamate the tractus solitarius (TS). Furthermore, lS,3R-ACPD reduced receptor agonist (R,S)-a-amino+hydroxy-5methylisoxa- the glutamatergic EPSC and GABAergic IPSC evoked by low- zole-4-propionate (AMPA) or the GABA, receptor agonist frequency stimulation in the region of the TS. These effects muscimol via pressure ejection directed at the cell soma. support the view that the action of glutamate at metabotropic The metabotropic glutamate receptor agonist 1 SJR-1 -ami- receptors plays a key role in synaptic transmission from baro- nocyclopentane-1,3-dicarboxylate (1 S,3/+ACPD; 2-l 00 PM) receptor afferents (Leone and Gordon, 1989; Meeley et al., 1989; reversibly depressed muscimol-evoked currents. Converse- Drewe et al., 1990; Mifflin and Felder, 1990). ly, 1 S,BR-ACPDreversiblypotentiatedAMPA-evokedcurrents. In our previous report, we suggested that the ability of lS,3R- High-frequency stimulation of the tractus solitarius in the ACPD to inhibit synaptic transmission in the NTS might be presence of 6,7-dinitroquinoxaline-2,3-dione and o-2-amino- due to a reduction in the presynaptic release of glutamate and 5phosphonopentanoic acid also produced a reversible de- GABA.
    [Show full text]
  • Glutamate Uptake System in the Presynaptic Vesicle: Glutamic Acid Analogs As Inhibitors and Alternate Substrates*
    Neurochemical Research, VoL 18, No. 1, 1993, pp. 79-85 Glutamate Uptake System in the Presynaptic Vesicle: Glutamic Acid Analogs as Inhibitors and Alternate Substrates* Harry C. Winter ~ and Tetsufumi Ueda 2,3 (accepted March 23, 1992) A variety of naturally occurring amino acids, their isomers, and synthetic analogs were tested for their ability to inhibit uptake of [3H]glutamate into presynaptic vesicles from bovine cerebral cortex. Strongest inhibition (N < lmM) was observed for trans-l-aminocyclopentane-l,3-dicarboxylic acid (t-ACPD) and erythro-4-methyl-L-glutamic acid (MGlu), while 4-methylene-L-glutamic acid (MeGlu) was only moderately inhibitory (Ki = -3mM), indicating that the synaptic vesicle glutamate transloeator has higher affinity for trans-ACPD and MGlu than for glutamate. A few other amino acids, e.g., 4-hydroxyglutamic acid, S-carboxyethyl cysteine, and 5-fluorotryptophan, were slightly inhibitory; all L- and DL-isomers of protein amino acids and longer chain acidic amino acids were without measurable inhibition. Potassium tetrathionate and S-sulfocysteine ex- hibited strong to moderate noncompetitive or irreversible inhibition. Inhibition by t-ACPD, MGlu, or MeGlu was competitive with glutamic acid. Each of these competitive inhibitors was also taken up by the vesicle preparation in an ATP-dependent manner, as indicated by their being recovered unchanged from filtered vesicles. Similar results were obtained with reconstituted vesicles, while glutamate uptake by partially purified rat synaptosomes was inhibited only by MGIu. These results indicate that the glutamate translocator of presynaptic vesicles has stringent structural requirements distinct from those of the plasma membrane translocator and the metabotropic type of postsynaptic glutamate receptor.
    [Show full text]
  • 7Th International Congress on Amino Acids and Proteins Vienna, Austria
    Amino Acids (2001) 21: 1–90 7th International Congress on Amino Acids and Proteins Vienna, Austria August 6–10, 2001 Abstracts Co-Presidents: Steve Schaffer, Mobilel, AL, U.S.A. Michael Fountoulakis, Basel, Switzerland Gert Lubec, Vienna, Austria Contents Analysis................................................................................ 3 Biology ................................................................................ 10 Proteomics . 14 Medicine . 22 Metabolism/Nutrition . 25 Neurobiology . 35 Neuroscience . 45 Plant Amino Acids . 56 Physiology/Exercise and Sport . 59 Polyamines . 63 Synthesis . 68 Taurine ................................................................................ 74 Amino Acids Transport . 79 Addendum . 86 3 Analysis Fully automated HPLC based analysis of cysteine and related used for calculation of the degree of substitution in case of compounds in plasma using on line microdialysis as sample peptide-conjugates. The results of amino acid analysis were preparation verified by the data of ES mass spectrometry method. [This study was supported by grants from Hungarian E. Bald Research Fund (OTKA) T 030838, T025834, T032425, F034886 Department of Environmental Chemistry, University of ´Lodz´, and from the Ministry of Education (FKFP/0153/2001).] Poland Low molecular weight thiols play important roles in metabolism and homeostasis. While plasma thiols, including Free and bound cysteine in homocystinuria: assessment of metabolically related cysteine, glutathione, and homocysteine, cysteine and glutathione status are being investigated as potential indicators of health status A. Briddon1, I. P. Hargreaves1, and P. J. Lee2 and disease risk, trace levels, poor stability, and the lack of 1 structural properties necessary for the production of signals Department of Clinical Biochemistry, and compatible with common detection methods have hampered 2 Metabolic Unit, The National Hospital for Neurology and their accurate assessment. The facile oxidation of sulfhydryl Neurosurgery, London, U.K.
    [Show full text]