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PubMed1990

A potent metabotropic glutamate receptor agonist: electrophysiological actions of a conformationally restricted glutamate analogue in the rat spinal cord and Xenopus oocytes.

The (2S,3S,4S) isomer of alpha-(carboxycyclopropyl)glycine (L-CCG-I), a conformationally restricted glutamate analogue, caused a marked depolarization of motoneurons in the isolated rat spinal cord, which was almost insensitive to CPP and CNQX. Depolarizing responses to L-CCG-I were markedly decreased by reducing the temperature of the bathing fluid. Similar results were obtained in the case of trans-ACPD, which is a metabotropic glutamate receptor agonist, but the depolarizing action of L-CCG-I was more potent than that of trans-ACPD. In Xenopus oocytes injected with poly(A)+ mRNA extracted from the rat brain, L-CCG-I induced significant oscillatory chloride currents, suggesting that L-CCG-I is a potent agonist for metabotropic-type glutamate receptors.

Amino Acids, Dicarboxylic↗
PubMed1995

Neuroprotective effect of phenylsuccinate, an inhibitor of cytosolic glutamate formation from glutamine, under anoxic conditions but not during exposure to exogenous glutamate.

Phenylsuccinate is an inhibitor of cytosolic glutamate formation from extracellular glutamine in cultured cerebellar granule cell neurons, a glutamatergic preparation. It prevents anoxic cell death in these cells as indicated by decreased lactate dehydrogenase (LDH) release and by the morphological appearance of the cells after the insult. In contrast, it does not prevent neurotoxicity by added glutamate because it is not an antagonist of the glutamate receptor.

Animals↗
PubMed2005

Synthesis and pharmacological evaluation of side chain modified glutamic acid analogues of the neuroprotective agent glycyl-L-prolyl-L-glutamic acid (GPE).

The synthesis of eight GPE* analogues, wherein the gamma-carboxylic moiety of the glutamic residue has been modified, is described by coupling readily accessible N-benzyloxycarbonyl-glycyl-L-proline with various analogues of glutamic acid. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glutamate residue on the observed neuroprotective properties of the endogenous tripeptide GPE.

Animals↗
PubMed2005

Sulfhydryl modification of cysteine mutants of a neuronal glutamate transporter reveals an inverse relationship between sodium dependent conformational changes and the glutamate-gated anion conductance.

In the central nervous system, glutamate transporters remove the neurotransmitter from the synaptic cleft. The electrogenic transport of glutamate is coupled to the electrochemical sodium, proton and potassium gradients. Moreover, these transporters mediate a sodium- and glutamate-dependent uncoupled chloride conductance. In contrast to the wild type, the uptake of radiolabeled substrate of the G283C mutant is inhibited by [2-(trimethylammonium)ethyl]methanethiosulfonate, a membrane impermeant sulfhydryl reagent. In the wild type and the unmodified mutant, substrate-induced currents are inwardly rectifying and reflect the sum of the coupled electrogenic flux and the anion conductance. However, the sulfhydryl-modified G283C mutant exhibits currents that are non-rectifying and reverse at the equilibrium potential for chloride. These properties are similar to those of the I421C mutant after sulfhydryl modification. Importantly, in contrast to I421C, the modification of G283C does not cause an increase of the magnitude of the anion conductance and a decrease of the apparent substrate affinity. Moreover, in the G283C/I421C double mutant the phenotype of I421C is dominant. Sulfhydryl modification of I421C, but not of G283C, abolishes the sodium dependent transient currents. The results indicate the existence of multiple transitions between the coupled transport cycle and anion conducting states.

Amino Acid Transport System X-AG↗
PubMed2000

Evidence that reversed glutamate uptake contributes significantly to glutamate release following experimental injury to the rat spinal cord.

Released excitatory amino acids contribute significantly to secondary damage following spinal cord injury. Reversal of normal transport due to cell membrane depolarization may contribute to this release. We tested this by administering dihydrokainic acid (DHK), a non-transported glutamate uptake blocker, into the rat spinal cord by microdialysis in association with contusion spinal cord injury. Glutamate release in response to injury was reduced by 34% (P<0.05) when 3 mM DHK was administered within the microdialysis fiber, suggesting that reversed transport is an important contributor to glutamate release upon spinal cord injury.

Animals↗
PubMed2000

Bilirubin does not modulate ionotropic glutamate receptors or glutamate transporters.

Bilirubin, a product of haemoglobin metabolism, has been suggested to damage neurons by increasing activation of N-methyl-D-aspartate (NMDA) receptors when it reaches high levels in the blood [15,19], as occurs in neonatal jaundice [7]. Bilirubin is also generated in the brain following synthesis of the messenger carbon monoxide (CO) by haem oxygenase, and haem oxygenase is upregulated in Alzheimer's disease [23]. We examined the effect of bilirubin on currents generated by NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in hippocampal pyramidal cells, and on glutamate transporter currents in retinal glial cells. Bilirubin did not modulate either receptor-gated currents or transporter currents. These data show the negative, but important result that bilirubin does not induce neuronal death by acting directly on NMDA or AMPA receptors, nor indirectly by blocking glutamate uptake and raising the extracellular concentration of glutamate.

ATP-Binding Cassette Transporters↗
PubMed1998

Patch-clamp, ion-sensing, and glutamate-sensing techniques to study glutamate transport in isolated retinal glial cells.

We have described how a combination of electrical, ion-sensing, and glutamate-sensing techniques has advanced our understanding of glutamate uptake into isolated salamander retinal glial cells. The next steps in understanding glutamate transport will inevitably depend strongly on molecular biological methods, as described elsewhere in this book, but will also require more detailed study of transporters in their normal environment, perhaps by using patch-clamping or imaging techniques to study cells in situ.

ATP-Binding Cassette Transporters↗
PubMed2003

Expression of glutamate transporter, GABRA6, serine proteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease.

Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and gamma-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and gamma-aminobutyric acid-A receptor, subunit alpha6 (GABRA6) were lower 9.7- and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.

Amino Acid Transport System X-AG↗
PubMed1997

Phosphorylation of serine residues 3, 6, 10, and 13 distinguishes membrane anchored from soluble glutamic acid decarboxylase 65 and is restricted to glutamic acid decarboxylase 65alpha.

GAD65, the smaller isoform of the gamma-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase is detected as an alpha/beta doublet of distinct mobility on SDS-polyacrylamide gel electrophoresis. Glutamic acid decarboxylase (GAD) 65 is reversibly anchored to the membrane of synaptic vesicles in neurons and synaptic-like microvesicles in pancreatic beta-cells. Here we demonstrate that GAD65alpha but not beta is phosphorylated in vivo and in vitro in several cell types. Phosphorylation is not the cause of the alpha/beta heterogeneity but represents a unique post-translational modification of GAD65alpha. Two-dimensional protein analyses identified five phosphorylated species of three different charges, which are likely to represent mono-, di-, and triphosphorylated GAD65alpha in different combinations of phosphorylated serines. Phosphorylation of GAD65alpha was located at serine residues 3, 6, 10, and 13, shown to be mediated by a membrane bound kinase, and distinguish the membrane anchored, and soluble forms of the enzyme. Phosphorylation status does not affect membrane anchoring of GAD65, nor its Km or Vmax for glutamate. The results are consistent with a model in which GAD65alpha and -beta constitute the two subunits of the native GAD65 dimer, only one of which, alpha, undergoes phosphorylation following membrane anchoring, perhaps to regulate specific aspects of GAD65 function in the synaptic vesicle membrane.

Amino Acid Sequence↗
PubMed1998

Folylpoly-gamma-glutamate carboxypeptidase from pig jejunum. Molecular characterization and relation to glutamate carboxypeptidase II.

Jejunal folylpoly-gamma-glutamate carboxypeptidase hydrolyzes dietary folates prior to their intestinal absorption. The complete folylpoly-gamma-glutamate carboxypeptidase cDNA was isolated from a pig jejunal cDNA library using an amplified homologous probe incorporating primer sequences from prostate-specific membrane antigen, a protein capable of folate hydrolysis. The cDNA encodes a 751-amino acid polypeptide homologous to prostate-specific membrane antigen and rat brain N-acetylated alpha-linked acidic dipeptidase. PC3 transfectant membranes exhibited activities of folylpoly-gamma-carboxypeptidase and N-acetylated alpha-linked acidic dipeptidase, while immunoblots using monoclonal antibody to native folylpoly-gamma-glutamate carboxypeptidase identified a glycoprotein at 120 kDa and a polypeptide at 84 kDa. The kinetics of native folylpoly-gamma-carboxypeptidase were expressed in membranes of PC3 cells transfected with either pig folylpoly-gamma-carboxypeptidase or human prostate-specific membrane antigen. Folylpoly-gamma-carboxypeptidase transcripts were identified at 2.8 kilobase pairs in human and pig jejunum, human and rat brain, and human prostate cancer LNCaP cells. Thus, pig folylpoly-gamma-carboxypeptidase, rat N-acetylated alpha-linked acidic dipeptidase, and human prostate-specific membrane antigen appear to represent varied expressions of the same gene in different species and tissues. The discovery of the jejunal folylpoly-gamma-carboxypeptidase gene provides a framework for future studies on relationships among these proteins and on the molecular regulation of intestinal folate absorption.

Amino Acid Sequence↗
PubMed2004

The chloride permeation pathway of a glutamate transporter and its proximity to the glutamate translocation pathway.

Excitatory amino acid transporters (EAATs) regulate glutamate concentrations in the brain to maintain normal excitatory synaptic transmission. A widely accepted view of transporters is that they consist of a pore with alternating access to the intracellular and extracellular solutions, which serves to couple ion movement to the movement of substrate. However, recent observations that EAATs, and also a number of other neurotransmitter transporters, can also function as ligand-gated chloride channels have blurred the distinctions between transporters and ion channels. Here we show that mutations in the second transmembrane domain (TM2) of EAAT1 alter anion permeation properties without affecting glutamate transport and that a number of TM2 residues are accessible to the external aqueous solution. Furthermore, we demonstrate that the extracellular edge of TM2 is in close proximity to a membrane-associated domain that influences glutamate transport. This study will provide the foundation for beginning to understand how transporters can function as both transporters and ion channels.

Amino Acid Sequence↗
PubMed1971

Specific immune response genes of the guinea pig. I. Dominant genetic control of immune responsiveness to copolymers of L-glutamic acid and L-alanine and L-glutamic acid and L-tyrosine.

The immunogenicity of three random copolymers of amino acids with L-glutamic acid and L-alanine (GA), L-glutamic acid and L-tyrosine (GT), or L-glutamic acid, L-alanine, and L-tyrosine (GAT), administered in complete Freund's adjuvant, was studied in several inbred and random-bred guinea pig strains. The animals were tested for delayed sensitivity and their sera were assayed for the presence of antibody directed against the immunizing polymer. All of the guinea pigs developing delayed hypersensitivity also had significant antibody levels in their sera. Inbred strain 2 guinea pigs responded to immunization with GA, but failed to form detectable responses to GT. Inbred strain 13 animals, on the other hand, responded to GT, but not to GA. The (2 x 13)F(1) hybrids responded to both GA and GT with both delayed hypersensitivity and circulating antibody. Thus, the ability of these inbred guinea pigs to respond immunologically to GA or GT is controlled by distinct autosomal dominant genes. A variable percentage of random-bred guinea pigs, depending on their source as well as their strain, responded to immunization with GA and with GT. All guinea pigs, both inbred and random bred, responded to immunization with GAT. The ability to respond immunologically to GAT, therefore, does not seem to be under simple genetic control. However, the levels of anti-GAT antibody found in the sera of animals lacking the ability to respond to GA were much lower than those detected in GA responder animals.

Alanine↗
PubMedDate not supplied

Enhancement of glutamate release by L-fucose changes effects of glutamate receptor antagonists on long-term potentiation in the rat hippocampus.

In previous studies L-fucose has been shown to facilitate long-term memory formation and to enhance and prolong long-term potentiation (LTP). To search for possible presynaptic or postsynaptic mechanisms that are affected by L-fucose, we examined the effect of L-fucose on (1) inhibition of LTP induction via glutamate receptors by antagonists, (2) paired-pulse facilitation, and (3) presynaptic transmitter release. Coapplication of 0.2 mM L-fucose with the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate (AP5), or coapplication of 0.2 mM L-fucose in the presence of an inhibitor for class I/II metabotropic glutamate receptors, (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), reversed LTP blockade in the CA1-region of hippocampal slices. In contrast, L-fucose had no effect on the LTP blockade by the noncompetitive NMDA ion-channel blocker (5R,10S)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801). Paired-pulse facilitation, which is a primarily presynaptic phenomenon of short-term plasticity, was decreased in the presence of 0.2 mM L-fucose. Furthermore, L-fucose enhanced the K(+)-stimulated release of [(3)H]-D-aspartate from preloaded hippocampal slices in a concentration-dependent manner. These observations demonstrate an influence of L-fucose on transmitter release that in turn can increase transmitter availability at postsynaptic glutamate receptors. This effect of L-fucose may contribute to the LTP facilitation seen in vitro and in vivo as well as to improvement in memory formation.

2-Amino-5-phosphonovalerate↗
PubMed1987

Use of a bioreactor consisting of sequentially aligned L-glutamate dehydrogenase and L-glutamate oxidase for the determination of ammonia by chemiluminescence.

A chemiluminometric method for the automated flow injection analysis of ammonia is described. The essence of the invention is the use of a bioreactor consisting of both immobilized L-glutamate dehydrogenase (GLDH) and L-glutamate oxidase (GLXD), which are sequentially aligned in this order in a minicolumn measuring 2.0 X 20 mm. The unidirectional constant flow of liquid through the column reactor minimizes the reversed diffusion of the solutes so that the following sequence of reactions is ensured. Thus, ammonia to be determined is first transformed by GLDH into L-glutamate, which then produces hydrogen peroxide by GLXD. Hydrogen peroxide in the effluent from the column is then determined by its chemiluminescence upon admixing with luminol and potassium ferricyanide. The present method gives linearity of the standard curve for ammonia up to 1.0 mM. It is at least 100 times more sensitive than the conventional method for ammonia assay using ultraviolet absorption measurement.

Amino Acid Oxidoreductases↗
PubMed1992

Amitriptyline prevents N-methyl-D-aspartate (NMDA)-induced toxicity, does not prevent NMDA-induced elevations of extracellular glutamate, but augments kainate-induced elevations of glutamate.

The effect of amitriptyline on kainate- and N-methyl-D-aspartate (NMDA)-induced toxicity and release of amino acids from cerebellar granule neurons was studied. The ED50 for amitriptyline, imipramine, and nortriptyline protection against NMDA-induced toxicity was 6.9, 6.5, and 1.3 microM, respectively. None of these compounds protected against kainate-induced toxicity. Even though amitriptyline was protective against NMDA-induced toxicity, it had no effect on the NMDA-induced increase in extracellular levels of glutamate or aspartate from these cells, indicating a dissociation between NMDA receptor activation (as indicated by glutamate content elevations) and NMDA-induced toxicity. However, kainate and quisqualate treatment resulted in elevations of glutamate and taurine levels that were further augmented in the presence of 25 microM amitriptyline. These findings confirm the reports of others that tricyclic antidepressants have neuroprotective effects related to the NMDA receptor and expand on these reports by showing that even though there is protection against toxicity, the NMDA receptor is nevertheless activated, suggesting an involvement of these compounds at sites removed from the receptor. Furthermore, this is the first report showing an interaction of tricyclic antidepressants with the function of non-NMDA receptors.

Amitriptyline↗
PubMed1966

Occurrence of hydroxypyruvate-L-glutamate transaminase in Escherichia coli and its separation from hydroxypyruvate-phosphate-L-glutamate transaminase.

Blatt, L. (University of Wisconsin, Madison), F. E. Dorer, and H. J. Sallach. Occurrence of hydroxypyruvate-l-glutamate transaminase in Escherichia coli and its separation from hydroxypyruvate-phosphate-l-glutamate transaminase. J. Bacteriol. 92:668-675. 1966.-The formation of l-serine from hydroxypyruvate by a transamination reaction with l-glutamate has been demonstrated in extracts of Escherichia coli. The level of activity with hydroxypyruvate is approximately one-tenth that observed with hydroxypyruvate-phosphate in cell-free extracts. The transamination of hydroxypyruvate, but not hydroxypyruvate-phosphate, is inhibited by inorganic phosphate. No marked differences in the levels of activity with hydroxypyruvate were observed in extracts from bacteria grown under different conditions. Heat treatment of enzyme preparations at 65 C rapidly destroys the activity with hydroxypyruvate-phosphate, but not that with hydroxypyruvate. Fractionation of extracts with lithium sulfate and alumina Cgamma resulted not only in a 10-fold purification, but also in a complete separation of the two activities, thereby establishing that two different enzymes are involved in the transamination of hydroxypyruvate and hydroxypyruvate-phosphate. Hydroxypyruvate transaminase is present in two mutants that require serine for growth. The inability of hydroxypyruvate to replace the growth requirement for serine, even to a limited extent, was shown to be due to the inability of the bacteria to accumulate this compound actively.

Alanine↗
PubMedDate not supplied

[Glutamate-related excitotoxicity neuroprotection with memantine, an uncompetitive antagonist of NMDA-glutamate receptor, in Alzheimer's disease and vascular dementia].

AIM: To review the therapeutic efficacy of memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA)-glutamate receptor. DEVELOPMENT: Alzheimer's disease (AD) is the most common neurodegenerative disorder and cause of dementia with ageing worldwide. The main AD symptoms are a gradual loss of cognitive function and a functional impairment. Glutamatergic excitatory neurotransmission, an important process in learning and memory, is severely disrupted in AD, probably due to the oxidative stress associated with the beta-amyloid peptide (1-42) increase. The glutamate-related excitotoxicity, mainly mediated by NMDA subtype of the glutamate receptors, is a common clue of pathogenesis for neurodegenerative disorders. CONCLUSIONS: Memantine, a moderate-affinity, voltage-dependent, uncompetitive antagonist of NMDA receptor, shows neuroprotective effects in patients with moderate-to-severe AD. Memantine is a drug with neuroprotective and cognition-enhanced properties, which can be combined with other treatments for AD. Thus, memantine does not stop or reverse AD, but its moderating effect in protecting the brain from the toxic levels of calcium, allows normal signaling among brain neurons. The efficacy and safety profile of memantine have been reported in several clinical trials for treatment of AD and vascular dementia.

Alzheimer Disease↗
PubMed1977

Nicotinamide adenine dinucleotide-specific glutamate dehydrogenase of Neurospora. IV. The COOH-terminal 669 residues of the peptide chain; comparison with other glutamate dehydrogenases.

A sequence is presented for the COOH-terminal 669 residues of the NAD-specific glutamate dehydrogenase of Neurospora crassa. Comparison of this sequence with those of the vertebrate glutamate dehydrogenases of chicken and bovine liver and with the NADP-specific enzyme of Neurospora shows some similarities in sequences around residues previously identified as important for the function of these enzymes. These are: (a) the reactive lysine residue of low pK in the NADP and the vertebrate enzymes; (b) the tyrosine residue of the NADP enzyme that is readily nitrated by tetranitromethane with inactivation, a residue protected by NADP or by NMN; and (c) the arginine residue of the NADP-enzyme that is reactive with 1,2-cyclohexanedione with inactivation. Despite these similarities, comparison of the sequence of the NAD-enzyme with those of the other glutamate dehydrogenases of known sequences revealed relatively little overall homology as determined by computer analysis.

Amino Acid Sequence↗