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1-14 of 14
Keyword: glutamate
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Articles
Biochem Soc Trans (2019) 47 (4): 1197-1207.
Published: 05 August 2019
...Ana Pavić; Alexandra O. M. Holmes; Vincent L. G. Postis; Adrian Goldman Glutamate transporters play important roles in bacteria, archaea and eukaryotes. Their function in the mammalian central nervous system is essential for preventing excitotoxicity, and their dysregulation is implicated in many...
Abstract
Glutamate transporters play important roles in bacteria, archaea and eukaryotes. Their function in the mammalian central nervous system is essential for preventing excitotoxicity, and their dysregulation is implicated in many diseases, such as epilepsy and Alzheimer's. Elucidating their transport mechanism would further the understanding of these transporters and promote drug design as they provide compelling targets for understanding the pathophysiology of diseases and may have a direct role in the treatment of conditions involving glutamate excitotoxicity. This review outlines the insights into the transport cycle, uncoupled chloride conductance and modulation, as well as identifying areas that require further investigation.
Articles
Biochem Soc Trans (2013) 41 (6): 1546-1550.
Published: 20 November 2013
... activity and brain development. 1 To whom correspondence should be addressed (email hwolosker@tx.technion.ac.il ). 17 9 2013 © The Authors Journal compilation © 2013 Biochemical Society 2013 gliotransmission glutamate long-term potentiation (LTP) neurotoxicity N -methyl- D...
Abstract
D -Serine is a physiological co-agonist of NMDARs ( N -methyl- D -aspartate receptors) required for neurotransmission, synaptic plasticity and neurotoxicity. There is no consensus, however, on the relative roles of neurons and astrocytes in D -serine signalling. The effects of D -serine had been attributed to its role as a gliotransmitter specifically produced and released by astrocytes. In contrast, recent studies indicate that neurons regulate their own NMDARs by releasing D -serine via plasma membrane transporters and depolarization-sensitive pathways. Only a minority of astrocytes contain authentic D -serine, whereas neuronal D -serine accounts for up to 90% of the total D -serine pool. Neuronal and glial D -serine production requires astrocytic L -serine generated by a 3-phosphoglycerate dehydrogenase-dependent pathway. These findings support a model whereby astrocyte-derived L -serine shuttles to neurons to fuel the synthesis of D -serine by serine racemase. We incorporate these new findings in a revised model of serine dynamics, called the glia–neuron serine shuttle, which highlights the role of glia–neuron cross-talk for optimal NMDAR activity and brain development.
Articles
Biochem Soc Trans (2013) 41 (6): 1518-1524.
Published: 20 November 2013
... homoeostasis. GS (glutamine synthetase), which catalyses the ATP-dependent condensation of ammonia and glutamate to form glutamine, is an enzyme particularly found in astrocytes. GS plays a pivotal role in glutamate and glutamine homoeostasis, orchestrating astrocyte glutamate uptake/release and the glutamate...
Abstract
The multifunctional properties of astrocytes signify their importance in brain physiology and neurological function. In addition to defining the brain architecture, astrocytes are primary elements of brain ion, pH and neurotransmitter homoeostasis. GS (glutamine synthetase), which catalyses the ATP-dependent condensation of ammonia and glutamate to form glutamine, is an enzyme particularly found in astrocytes. GS plays a pivotal role in glutamate and glutamine homoeostasis, orchestrating astrocyte glutamate uptake/release and the glutamate–glutamine cycle. Furthermore, astrocytes bear the brunt of clearing ammonia in the brain, preventing neurotoxicity. The present review depicts the central function of astrocytes, concentrating on the importance of GS in glutamate/glutamine metabolism and ammonia detoxification in health and disease.
Articles
Biochem Soc Trans (2010) 38 (2): 457-459.
Published: 22 March 2010
... spontaneous action potentials, allowing the presynaptic control of glutamate exocytosis to be studied. Recent developments have greatly increased the sensitivity with which the bioenergetics of the intra-synaptosomal mitochondria can be investigated. 1 email dnicholls@buckinstitute.org 23 8...
Abstract
Synaptosomes (isolated nerve terminals) have been studied for more than 40 years. The preparation allows aspects of transmitter metabolism and release to be studied ex vivo from specific brain regions of animals of any age. Conditions can be devised to enable the terminals to fire spontaneous action potentials, allowing the presynaptic control of glutamate exocytosis to be studied. Recent developments have greatly increased the sensitivity with which the bioenergetics of the intra-synaptosomal mitochondria can be investigated.
Articles
Biochem Soc Trans (2009) 37 (6): 1317-1322.
Published: 19 November 2009
...Peter R. Moult Glutamate and GABA (γ-aminobutyric acid) are the predominant excitatory and inhibitory neurotransmitters in the mammalian CNS (central nervous system) respectively, and as such have undergone intense investigation. Given their predominance, it is no wonder that the reciprocal...
Abstract
Glutamate and GABA (γ-aminobutyric acid) are the predominant excitatory and inhibitory neurotransmitters in the mammalian CNS (central nervous system) respectively, and as such have undergone intense investigation. Given their predominance, it is no wonder that the reciprocal receptors for these neurotransmitters have attracted so much attention as potential targets for the promotion of health and the treatment of disease. Indeed, dysfunction of these receptors underlies a number of well-characterized neuropathological conditions such as anxiety, epilepsy and neurodegenerative diseases. Although intrinsically linked, the glutamatergic and GABAergic systems have, by and large, been investigated independently, with researchers falling into the ‘excitatory’ or ‘inhibitory’ camps. Around 70 delegates gathered at the University of St Andrews for this Biochemical Society Focused Meeting aimed at bringing excitation and inhibition together. With sessions on behaviour, receptor structure and function, receptor trafficking, activity-dependent changes in gene expression and excitation/inhibition in disease, the meeting was the ideal occasion for delegates from both backgrounds to interact. This issue of Biochemical Society Transactions contains papers written by those who gave oral presentations at the meeting. In this brief introductory review, I put into context and give a brief overview of these contributions.
Articles
Biochem Soc Trans (2009) 37 (6): 1347-1354.
Published: 19 November 2009
...Timothy O'Leary; David J.A. Wyllie Subtypes of NMDARs ( N -methyl- D -aspartate receptors) display differences in their pharmacological and biophysical properties. The differences are, to a large extent, determined by the identities of the GluN2 (glutamate-binding) NMDAR subunits that are co...
Abstract
Subtypes of NMDARs ( N -methyl- D -aspartate receptors) display differences in their pharmacological and biophysical properties. The differences are, to a large extent, determined by the identities of the GluN2 (glutamate-binding) NMDAR subunits that are co-expressed with GluN1 (glycine-binding) subunits, which form the final tetrameric NMDAR assembly. Of the four GluN2 subunits that exist (termed A–D), NMDARs composed of GluN1/GluN2A and GluN1/GluN2D subunits display the greatest differences in their sensitivities to a variety of agonists, antagonists and channel blockers as well as showing marked differences in their single-channel conductances and deactivation kinetics. Here, we describe a series of experiments where we have generated and studied two chimaeric GluN2A/GluN2D subunits. The first chimaera, referred to as GluN2A(2D-M1M2M3), replaces the membrane-associated regions M1, M2 and M3 of the GluN2A subunit with the corresponding regions found in the GluN2D subunit. The second chimaera, GluN2A(2D-S1M1M2M3S2), replaces the same three membrane-associated regions of the GluN2A subunit plus the LBD (ligand-binding domain) with the corresponding regions of the GluN2D subunit. Our results show that the identity of the GluN2 LBD not only controls glutamate potency, but also influences the potency of the NMDAR co-agonist glycine, whereas the single-channel conductance and the duration of single activations of ion channels can be predicted by the identities of the M1–M3 regions and the LBD.
Articles
Biochem Soc Trans (2009) 37 (6): 1389-1393.
Published: 19 November 2009
...Sarah M. Mizielinska; Sam M. Greenwood; Hemanth Tummala; Christopher N. Connolly Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system playing critical roles in basal synaptic transmission and mechanisms of learning and memory. Under normal conditions, glutamate...
Abstract
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system playing critical roles in basal synaptic transmission and mechanisms of learning and memory. Under normal conditions, glutamate is sequestered within synaptic vesicles (~100 mM) with extracellular glutamate concentrations being limited (<1 μM), via retrieval by plasma-membrane transporters on neuronal and glial cells. In the case of central nervous system trauma, stroke, epilepsy, and in certain neurodegenerative diseases, increased concentrations of extracellular glutamate (by vesicular release, cell lysis and/or decreased glutamate transporter uptake/reversal) stimulate the overactivation of local ionotropic glutamate receptors that trigger neuronal cell death (excitotoxicity). Other natural agonists, such as domoic acid, alcohol and auto-antibodies, have also been reported to induce excitotoxicity.
Articles
Biochem Soc Trans (2009) 37 (6): 1423-1425.
Published: 19 November 2009
... receptor (GABA A R) glutamate glycine malt whisky N -methyl- D -aspartate receptor (NMDAR) At the recent Biochemical Society Meeting ‘Neuronal glutamate and GABA A receptor function in health and disease’ held at St Andrews in July 2009, delegates were invited to a malt whisky tasting evening...
Abstract
NMDARs ( N -methyl- D -aspartate receptors) are considered to be a target for the inhibitory actions of ethanol. While profound inhibition of both native and recombinant NMDARs can be observed following the application of high concentrations of ethanol the levels of inhibition seen with lower concentrations of ethanol are more modest. Here, we report the effects of inhibiting NMDAR-mediated responses with ethanol concentrations that are experienced during the social consumption of alcohol comparing levels of inhibition seen with ‘pure’ ethanol with those produced by ethanol contained in three popular single malt whiskies.
Articles
Biochem Soc Trans (2009) 37 (6): 1385-1388.
Published: 19 November 2009
...David G. Nicholls Chronic exposure to glutamate (glutamate excitotoxicity) exacerbates neuronal damage in the aftermath of stroke and is implicated in a variety of neurodegenerative disorders. Mitochondria play a central role in the survival or death of the exposed neuron. Calcium, oxidative stress...
Abstract
Chronic exposure to glutamate (glutamate excitotoxicity) exacerbates neuronal damage in the aftermath of stroke and is implicated in a variety of neurodegenerative disorders. Mitochondria play a central role in the survival or death of the exposed neuron. Calcium, oxidative stress and ATP insufficiency play closely interlocked roles that may be investigated with primary neuronal cultures.
Articles
Biochem Soc Trans (2007) 35 (2): 433-436.
Published: 20 March 2007
...G.P. Reynolds; M.K. Harte There is an accumulation of evidence for abnormalities in schizophrenia of both the major neurotransmitter systems of the brain – those of GABA (γ-aminobutyric acid) and glutamate. Initial studies have found deficits in the putative neuronal marker, N -acetylaspartate, in...
Abstract
There is an accumulation of evidence for abnormalities in schizophrenia of both the major neurotransmitter systems of the brain – those of GABA (γ-aminobutyric acid) and glutamate. Initial studies have found deficits in the putative neuronal marker, N -acetylaspartate, in a number of brain regions in schizophrenia. The animal models have provided some interesting correlates and discrepancies with these findings. The deficit in inhibitory interneurons within structures implicated in schizophrenic symptomatology may well have direct functional relevance, and can be induced by animal models of the disease such as subchronic phencyclidine administration or social isolation. Their association with these animal models suggests an environmental involvement. A loss of glutamatergic function in schizophrenia is supported by decreases in markers for the neuronal glutamate transporter in striatal structures that receive cortical glutamatergic projections. Deficits in the VGluT1 (vesicular glutamate transporter-1) in both striatal and hippocampal regions support this observation, and the association of VGluT1 density with a genetic risk factor for schizophrenia points to genetic influences on these glutamatergic deficits. Further studies differentiating neuronal loss from diminished activity and improved models allowing us to determine the temporal and causal relationships between GABAergic and glutamatergic deficits will lead to a better understanding of the processes underlying the neuronal pathology of schizophrenia.
Articles
Biochem Soc Trans (2006) 34 (6): 1356-1361.
Published: 25 October 2006
...R. Simon; Z. Xiong Intracellular calcium toxicity remains the central feature in the pathophysiology of ischaemic cell death in brain. Glutamate-gated channels have been thought to be the major sites of ischaemia-induced toxic calcium entry, but the failure of glutamate antagonists in clinical...
Abstract
Intracellular calcium toxicity remains the central feature in the pathophysiology of ischaemic cell death in brain. Glutamate-gated channels have been thought to be the major sites of ischaemia-induced toxic calcium entry, but the failure of glutamate antagonists in clinical trials has suggested that glutamate-independent mechanisms of calcium entry during ischaemia must exist and may prove central to ischaemic injury. We have shown that ASICs (acid-sensing ion channels) in brain are glutamate-independent vehicles of calcium flux and transport calcium in greater measure in the setting of the two major neurochemical components of ischaemia: acidosis and substrate depletion. Pharmacological blockade of ASICs markedly attenuates stroke injury with a robust therapeutic time window of 5 h following stroke onset. Here, we describe this new mechanism of calcium toxicity in brain ischaemia and offer a potential new therapy for stroke.
Articles
Biochem Soc Trans (2004) 32 (6): 1032-1036.
Published: 26 October 2004
...F.J.S. Lee; F. Liu Considerable evidence has accumulated describing a complex interaction between the dopaminergic and glutamatergic pathways. Efforts to describe the mechanisms underlying this complex interaction have implicated a functional interaction between dopamine and glutamate receptors...
Abstract
Considerable evidence has accumulated describing a complex interaction between the dopaminergic and glutamatergic pathways. Efforts to describe the mechanisms underlying this complex interaction have implicated a functional interaction between dopamine and glutamate receptors. Classically, the interaction between D 1 and NMDA ( N -methyl- D -aspartate) receptors has been proposed to involve the activation of second-messenger signalling cascades after receptor stimulation. However, in recent years, another paradigm has emerged which involves the direct interaction between D 1 and NMDA receptors. The physical association between D 1 and NMDA receptors is unique in that two different regions of the D 1 C-terminus are able to couple specifically and physically with two different NMDA subunits. The selective modulation of multiple NMDA receptor-mediated functions by direct interactions with D 1 receptors may form a new avenue to identify specific targets for therapeutics to modulate NMDA receptor-governed synaptic plasticity, neuronal development and disease states.
Articles
Biochem Soc Trans (2004) 32 (6): 1068-1069.
Published: 26 October 2004
.... 1 To whom correspondence should be addressed (email pkm22@mole.bio.cam.ac.uk ). 13 7 2004 © 2004 The Biochemical Society 2004 cytochrome oxidase glia glutamate hypoxia inducible nitric oxide synthase (iNOS) Both NO (nitric oxide) and hypoxia acutely inhibit...
Abstract
NO (nitric oxide) acutely and potently inhibits mitochondrial cytochrome oxidase in competition with oxygen, thereby raising the apparent K M for oxygen of mitochondria and neurons into the physiological or pathological range. We find that NO from an NO donor or glial inducible NOS (nitric oxide synthase) highly sensitizes neurons to hypoxia-induced death, probably via the NO–oxygen competition at cytochrome oxidase. Thus the NO from neuronal NOS during excitotoxicity or the NO from inducible NOS during inflammation may sensitize the brain to hypoxic/ischaemic damage.
Articles
Biochem Soc Trans (2001) 29 (6): 717-722.
Published: 01 November 2001
... ionic dependence, kinetics of transport and specificity of inhibitors. Almost 90°% of l cystine transport is by a low-affinity, sodium-dependent mechanism ( K m = 473 ± 146 μM), that is mediated by the X AG -family of glutamate transporters. Both l glutamate (IC 50 = 9.1 ± 0.4 μM) and l cysteine...
Abstract
The transport of l -cystine into cells of the mammalian brain is an essential step in the supply of cysteine for synthesis of the antioxidant glutathione. Uptake of l cystine in rat brain synaptosomes occurs by three mechanisms that are distinguishable on the basis of their ionic dependence, kinetics of transport and specificity of inhibitors. Almost 90°% of l cystine transport is by a low-affinity, sodium-dependent mechanism ( K m = 473 ± 146 μM), that is mediated by the X AG -family of glutamate transporters. Both l glutamate (IC 50 = 9.1 ± 0.4 μM) and l cysteine sulphinate (IC 50 = 16.4 ± 3.6 μM) are non-competitive inhibitors of sodium-dependent l [ 14 C]cystine transport, whereas l trans -pyrrolidine-2,4-dicarboxylic acid (IC 50 = 5.6 ± 2.0 μM), l serine- O -sulphate (IC 50 = 13.2 ± 5.4 μM), kainate (IC 50 = 215 ± 78 μM) and l cysteine (IC 50 = 363 ± 63 μM) are competitive inhibitors. l Cystine has no effect on the sodium-dependent uptake of D-[ 3 H]aspartate. These results suggest that l cystine binds to a site that is different from the l glutamate recognition site on X AG -glutamate transporters. In rat brain slices, sodium-dependent transport of both l glutamate and l cystine is necessary for maintaining glutathione levels. Uptake of l cystine is sensitive to inhibition by an increased extracellular concentration of l glutamate, which has important implications for understanding conditions that may initiate oxidative stress.