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PubMed1975

Gamma-aminobutric acid and glutamate decarboxylas (l-glutamate 1-carboxy-lyase e.c. 4.1.1.15) in the nervous system of the cockroach, periplaneta americana.i.regional distribution and properties of the enzyme.

Both the central and peripheral nervous system of the cockroach Periplaneta americana contain gamma-aminobutyric acid (GABA) and glutamate decarboxylase (GAD). In the central ganglia of the cockroach, an average of more that 60 mumoles of GABA are formed from glutamate (Glu) per gram wet weight of tissue per hour. This activity level of the GAD apoenzyme is considerably higher than that found in the central nervous system of crustaceans, amphibians, avians and mammals but is similar to that reported for nervous system tissues from other insect species. A comparison of properties of the crude cockroach enzyme with GAD from crustacean and mammalian origin revealed both similarities and differences: whereas crude cockroach GAD has cofactor requirements and an affinity for Glu substrate (Km 2.8 X 10-2) which are similar to GAD from lobster and mouse, it is uniquely inhibited by both Cl-and by GABA. The GAD from cockroach nervous tissues has two apparent pH optima of which the lower one is preferentially inhibited by a compound which is found in the nerve sheath and the fat body tissue adjacent to ganglia and axons.

Aminobutyrates↗
PubMed1982

N-acetyl-L-aspartic acid, N-acetyl-alpha-L-aspartyl-L-glutamic acid and beta-citryl-L-glutamic acid in human urine.

N-Acetyl-L-aspartic acid (NA-Asp), N-acetyl-alpha-L-aspartyl-L-glutamic acid (NA-Asp-Glu) and beta-citryl-L-glutamic acid (beta-CG), which are known to occur in the brain, have been isolated from human urine. Their identities were proved by comparing them with synthetic NA-Asp, NA-Asp-Glu and beta-CG using electrophoretic and chromatographic methods and by acid hydrolysis. A method was developed for the quantitation of NA-Asp, NA-Asp-Glu and beta-CG in human urine. It consists of ion-exchange chromatography followed by gas-chromatographic analysis. The amounts of urinary excretion of NA-Asp, NA-Asp-Glu and beta-CG were 41.2 +/- 10.1 (n = 27), 20.8 +/- 9.6 (n = 27) and 30.2 +/- 13.2 (n = 21) mumol/g creatinine in adult males, and 62.2 +/- 16.3 (n = 27), 24.0 +/- 8.2 (n = 27) and 40.5 +/- 21.1 (n = 24) mumol/g creatinine in adult females, respectively.

Adult↗
PubMed1988

The glutamate-induced chloride current in Aplysia neurones lacks pharmacological properties seen for excitatory responses to glutamate.

The pharmacological properties of the L-glutamate (Glu)-induced chloride current (ICl) in enzymatically isolated Aplysia neurones were examined using the 'concentration clamp' technique. The Glu-ICl did not cross-desensitize with the ICl evoked by gamma-aminobutyric acid or acetylcholine. Quisqualate, kainate (one out of eight) and N-methyl-D-aspartate (one out of nine) induced a small, non-desensitizing ICl in Glu-responding neurones. The quisqualate- and kainate-ICl did not cross-desensitize with the Glu-ICl. L-Aspartate did not induce a ICl in 11 neurones tested, which showed a Glu-ICl. Glutamate diethyl ester, Joro Spider toxin and ketamine did not suppress the Glu-ICl. Concanavalin A had no effect on the time course of desensitization. These results suggest that the Glu receptor-Cl channel complex in Aplysia neurones has pharmacological properties which differ from those of the excitatory Glu receptor-channel complexes in the crustacean muscle fibres and in the central neurones of vertebrates.

Acetylcholine↗
PubMed2000

Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice.

In metabotropic glutamate receptor 2 (mGlu(2)) knockout mice, the group 2 metabotropic glutamate receptor agonist LY314582 (20 mg/kg, i.p.), a racemate of LY354740, inhibits neither spontaneous nor phencyclidine (PCP)-induced (2.5 mg/kg, s.c.) locomotor activity. Since LY314582 attenuated spontaneous and PCP-induced locomotor activity in wild-type control mice, these data indicate that the effects of LY314582 are mediated via the mGlu(2) receptor and not via the mGlu(3) receptor.

Analysis of Variance↗
PubMed1996

Apparent independent action of nimodipine and glutamate antagonists to protect cultured neurons against glutamate-induced damage.

A disturbed cellular calcium homeostasis is suggested to play a pivotal role in neuronal damage. Energy deficiency causes depolarization of the neuronal membrane and Ca2+ enters the cells through different ion channels, the voltage-sensitive L-type Ca2+ channels and the NMDA-operated channels being the main gates. In the present study we used primary cultures of rat hippocampal neurons to demonstrate that the dihydropyridine calcium antagonist nimodipine, the non-competitive NMDA antagonists dizocilpine and memantine, as well as the AMPA antagonist NBQX (2,3-dihydroxy-6-nitro -7-sulfamoyl-benzo(F)quinoxaline), attenuate the glutamate-induced neuronal damage dose-dependently. Nimodipine applied simultaneously with NMDA-antagonists and NBQX, respectively, resulted in somewhat greater neuroprotection of glutamate-treated neurons compared with the effects of these agents applied singly. The type of interaction is best described by an independent action in combination, which means that the relative effects of nimodipine were not enhanced. Therefore, it can be considered as a lack of potentiation.

Animals↗
PubMed1997

LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors.

The novel compound LY354740 is a conformationally constrained analog of glutamate, which was designed for interaction at metabotropic glutamate (mGlu) receptors. In this paper the selectivity of LY354740 for recombinant human mGlu receptor subtypes expressed in non-neuronal (RGT) cells is described. At human mGlu2 receptors, LY354740 produced > 90% suppression of forskolin-stimulated cAMP formation with an EC50 of 5.1 +/- 0.3 nM. LY354740 was six-fold less potent in activating human mGlu3 receptors (EC50 = 24.3 +/- 0.5 nM). LY354740 inhibition of forskolin-stimulated cAMP formation in human mGlu2 receptor-expressing cells was blocked by competitive mGlu receptor antagonists, including (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) and LY307452 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid). LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM). When tested at group I phosphoinositide-coupled human mGlu receptors (mGlu1a and mGlu5a), LY354740 did not activate or inhibit mGlu receptor agonist-evoked phosphoinositide hydrolysis at up to 100,000 nM. Electrophysiological experiments also demonstrated that LY354740 also had no appreciable activity in cells expressing human recombinant AMPA (GluR4) and kainate (GluR6) receptors. Thus, LY354740 is a highly potent, efficacious and selective group II (mGlu2/3) receptor agonist, useful to explore the functions of these receptors in situ.

Bridged Bicyclo Compounds↗
PubMed1998

Comparative effect of L-CCG-I, DCG-IV and gamma-carboxy-L-glutamate on all cloned metabotropic glutamate receptor subtypes.

In a previous study we reported that the addition of a carboxylic group to the mGlu receptor agonist aminocyclopentane-1,3-dicarboxylate (ACPD) changes its properties from agonist to antagonist at both mGlu1 and mGlu2 receptors, and resulted in an increase in affinity at mGlu4 receptors, with isomers being either agonists or antagonists. In the present study, the effect of gamma-carboxy-L-glutamic acid (Gla) and (2S,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), two carboxylic derivatives of non-selective agonists, were examined on all cloned mGlu receptors. We found that this additional carboxylic group on glutamate prevents its interaction with group-I mGlu receptors and generates a potent group-II antagonist (K(B) = 55 microM on mGlu2). At group-III mGlu receptors, Gla was found to be either an antagonist (mGlu7 and mGlu8 receptors) or a partial agonist (mGlu4 and mGlu6 receptors). We show here that L-CCG-I is a general mGlu receptor agonist activating all cloned receptors. We also confirm that DCG-IV, which corresponds to L-CCG-I with an additional carboxylic group, is a selective group-II agonist. However, this additional COOH group changes the properties of L-CCG-I from an agonist to an antagonist at all group-III receptors, making this compound one of the most potent group-III mGlu receptor antagonist known so far. These observations will be useful for the development of more potent and selective mGlu receptor agonists and antagonists.

1-Carboxyglutamic Acid↗
PubMed2000

Blockade of pilocarpine-induced cerebellar phosphoinositide hydrolysis with metabotropic glutamate antagonists: evidence for an indirect control of granule cell glutamate release by muscarinic agonists.

The ability in vivo of the muscarinic agonist, pilocarpine, to increase phosphoinositol (PI) hydrolysis in lithium pretreated rats was investigated by measuring the accumulation of [(3)H]inositol phosphates (IP). As expected, 20 mg/kg s.c. pilocarpine, a muscarinic agonist, increased PI hydrolysis in the striatum, frontal cortex and hippocampus. Somewhat surprisingly, an increase in IP was also found in the cerebellar homogenates. In all four tissues the pilocarpine-induced effect could be completely inhibited by pretreatment with the muscarinic antagonist scopolamine (1.2 mg/kg i. p.). It was also found that the cerebellar but not the hippocampal pilocarpine-induced rise in PI hydrolysis could be blocked by the metabotropic glutamate (mGlu) receptor antagonist, LY341495 (100 nmol, i.c.v.). The same dose of LY341495 was found to also block both the cerebellar and hippocampal increase in IP formed by stimulation with the group I mGlu receptor agonist 3, 5-dihydroxyphenylglycine (1 micromol, i.c.v.). Given this data and the current information on the distribution of muscarinic and mGlu receptors in the cerebellum, it is suggested that these results may be a reflection of pilocarpine acting at M(2) receptors to indirectly increase glutamate release from parallel fibers by inhibition of gamma-aminobutyric acid-releasing Golgi cells.

Amino Acids↗
PubMed1983

Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood. Part I. Glutamic acid decarboxylase activity in cerebrospinal fluid of normal infants and children.

Glutamic acid decarboxylase (GAD) activity in the cerebrospinal fluid (CSF) of normal infants (n:14) and children (n:28) was determined by measuring the amount of 14CO2 released from L-[1-14C]-glutamic acid. The mean GAD activity in CSF of infants and children was 5.2 +/- 2.5 pmol CO2 formed/hr/ml. Dividing these subjects into 4 groups according to age, GAD activities in CSF were 5.4 +/- 1.6 pmol CO2 formed/hr/ml in neonates (0-1 m), 3.6 +/- 1.6 pmol CO2 formed/hr/ml in infants (2-12 m), 3.9 +/- 1.1 pmol CO2 formed/hr/ml in young children (2-6 yr) and 7.1 +/- 2.3 pmol CO2 formed/hr/ml in school children (7-16 yr), respectively. In neonates and school children, GAD activities were significantly higher (p less than 0.001) than those in the other age groups. In infants under 6 months of age, a significantly negative correlation between GAD activity in CSF and their ages was recognized (r = -0.52, p less than 0.001). In infants and children ranging from 6 months to 16 years of age, a significantly positive correlation between GAD activity in CSF and their ages was found (r = 0.67, p less than 0.001). These data suggest that high GAD activity in neonates may be due to hypoxia at birth and the activity gradually increases from 6 months to 15 years of age.

Adolescent↗
PubMed1999

Competitive inhibition of a glutamate carboxypeptidase by phosphonamidothionate derivatives of glutamic acid.

Several N-thiophosphonyl-glutamates were found to be potent competitive inhibitors of a zinc-dependent glutamyl hydrolase, carboxypeptidase G (CPG). Weak inhibition exhibited by an analogous N-phosphonyl-glutamate suggests that the enhanced potency of the phosphonamidothioates is due to the presence of their sulfur ligand and its favorable interactions with active site features, presumably zinc(II).

Carboxypeptidases↗
PubMed2003

N-methyl-D-glutamate and N-methyl-L-glutamate in Scapharca broughtonii (Mollusca) and other invertebrates.

The presence of N-methyl-D-glutamate (NMDG) and N-methyl-L-glutamate (NMLG) has been demonstrated in the tissues of Scapharca broughtonii, which are known to contain N-methyl-D-aspartate (NMDA). To our knowledge, this is the first report on the natural occurrence of NMDG and the occurrence of NMLG in eukaryotes. These compounds were identified according to the following findings; (a) their derivatives with (+)- and (-)-l-(9-fluorenyl)ethyl chloroformate (FLEC) showed identical behaviors with those of authentic NMDG and NMLA, respectively, on high-performance liquid chromatography (HPLC), (b) the HPLC peak of NMDG disappeared when the extract, as well as the authentic compound, was treated with D-aspartate oxidase before derivatization, (c) they behaved identically with authentic compounds on thin-layer chromatography and differently from NMDA. Both or either of NMDG and NMLG were also detected in several mollusks and other animals. Concentrations of the enantiomers were comparable in the tissues of S. broughtonii and a few other species.

Amino Acid Oxidoreductases↗
PubMed1994

Flow injection assay for the neurotoxin beta-ODAP using an immobilized glutamate oxidase reactor with prereactors to eliminate glutamate interferences.

The neurotoxic amino acid, beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-ODAP,ODAP) was oxidized by immobilized glutamate oxidase (GlOD) to produce hydrogen peroxide. The peroxide reacts with Trinder reagent in a reactor with immobilized horseradish peroxidase to form a red-colored quinone imine dye, which was detected spectrophotometrically at 512 nm. Determinations were made in a flow injection (FI) setup consisting of four packed-bed enzyme reactors containing GlOD (20 microL), catalase (20 microL), GlOD (250 microL), and peroxidase (50 microL) in series. Glutamate is oxidized quantitatively in the first reactor, but the hydrogen peroxide is destroyed in the second so that interferences from this substrate are removed. This step destroys only a few percent of the ODAP in the sample. Most of the remaining ODAP is oxidized in the third reactor. Injections of 20-microL ODAP standards gave a response curve which was linear within the range 10-650 microM. Phosphate buffer extracts of grass peas (lathyrus sativus) were purified by centrifugation and membrane filtration. Samples were injected into the FI setup to assay the toxin at a rate of 20 samples per hour. The beta-ODAP content of a batch of dry seed corresponded to 0.74% (w/w) with a relative standard deviation of 2.8%. Thermal treatment of ODAP standards at 80-90 degrees C reduced the response to 62% of that before heating. The decrease is due to beta<-->alpha isomerization, and the experiment thus confirms that the method is selective for the toxic beta-isomer.

Amino Acid Oxidoreductases↗
PubMed2005

Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3.

A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.

Animals↗
PubMed2005

Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents.

Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds 3 and 4 were obtained from 2,4-diamino-5-methylpyrrolo[2,3-d]pyrimidine 7 and 2-amino-4-oxo-5-methylpyrrolo[2,3-d]pyrimidine 12, respectively, in a concise three-step sequence. Compound 3 is the first example, to our knowledge, of a 2,4-diamino classical antifolate that has potent inhibitory activity against both human dihydrofolate reductase (DHFR) and human thymidylate synthase (TS). Compound 4 was a dual DHFR-TS inhibitor against the bifunctional enzyme derived from Toxoplasma gondii (tg). Further evaluation of the mechanism of action of 3 implicated DHFR as its primary intracellular target. Both 3 and 4 were folylpolyglutamate synthetase (FPGS) substrates. Compound 3 also inhibited the growth of several human tumor cell lines in culture with GI50 < 10(-8) M. This study shows that the pyrrolo[2,3-d]pyrimidine scaffold is conducive to dual DHFR-TS and tumor inhibitory activity, and the potency is determined by the 4-position substituent.

Animals↗
PubMed1997

Biosensor for neurotransmitter L-glutamic acid designed for efficient use of L-glutamate oxidase and effective rejection of interference.

An amperometric biosensor for L-glutamic acid (Glu) was constructed by the adsorption and dip coating of L-glutamate oxidase (GluOx, 200 U ml-1 phosphate buffer, pH 7.4) onto 60-micron radius Teflon-coated Pt wire (1 mm exposed length). The enzyme was then trapped on the surface by electropolymerisation of o-phenylenediamine that also served to block electroactive interference. This procedure afforded electrodes with similar substrate sensitivity compared with the classical approach of immobilising enzyme from a solution of monomer, and represents an approximately 10,000-fold increase in the yield of biosensors from a batch of enzyme. A number of strategies were examined to enhance the sensitivity and selectivity of the Pt/PPD/GluOx sensors operating at 0.7 V versus SCE. Pre-coating the Pt with lipid and incorporation of the protein bovine serum albumin into the polymer matrix were found to improve the performance of the electrode. The sensors had a fast response time, high sensitivity to Glu, with an LOD of about 0.3 mumol l-1, and possessed selectivity characteristics suggesting that monitoring Glu in biological tissues in vivo may be feasible.

Amino Acid Oxidoreductases↗
PubMed2005

Glutamate-induced glutamate release: a proposed mechanism for calcium bursting in astrocytes.

Here we present a new model for the generation of complex calcium-bursting patterns in astrocytes, a type of brain cell recently implicated in a variety of neural functions including memory formation. The model involves two positive feedback processes, in which the key feedback species are calcium ion and glutamate. The latter is the most abundant excitatory neurotransmitter in the brain and has been shown to be involved in bidirectional communication between astrocytes and nearby neurons. The glutamate feedback process considered here is shown to be critical for the generation of complex bursting oscillations in the astrocytes and to, perhaps, code for information which may be passed from neuron to neuron via the astrocyte. These processes may be involved in memory storage and formation as well as in mechanisms which lead to dynamical diseases such as epilepsy.

Animals↗
PubMed2006

Phosphorylation of glutamate receptor interacting protein 1 regulates surface expression of glutamate receptors.

The number of synaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors (AMPARs) controls the strength of excitatory transmission. AMPARs cycle between internal endosomal compartments and the plasma membrane. Interactions between the AMPAR subunit GluR2, glutamate receptor interacting protein 1 (GRIP1), and the endosomal protein NEEP21 are essential for correct GluR2 recycling. Here we show that an about 85-kDa protein kinase phosphorylates GRIP1 on serine 917. This kinase is present in NEEP21 immunocomplexes and is activated in okadaic acid-treated neurons. Pulldown assays and atomic force microscopy indicate that phosphorylated GRIP shows reduced binding to NEEP21. AMPA or N-methyl-D-aspartate stimulation of hippocampal neurons induces delayed phosphorylation of the same serine 917. A wild type carboxy-terminal GRIP1 fragment expressed in hippocampal neurons interferes with GluR2 surface expression. On the contrary, a S917D mutant fragment does not interfere with GluR2 surface expression. Likewise, coexpression of GluR2 together with full-length wild type GRIP1 enhances GluR2 surface expression in fibroblasts, whereas full-length GRIP1-S917D had no effect. This indicates that this serine residue is implicated in AMPAR cycling. Our results identify an important regulatory mechanism in the trafficking of AMPAR subunits between internal compartments and the plasma membrane.

Animals↗
PubMed1971

Specific immune response genes of the guinea pig. II. Relationship between the poly-L-lysine gene and the genes controlling immune responsiveness to copolymers of L-glutamic acid and L-alanine and L-glutamic acid and L-tyrosine in random-bred Hartley guinea pigs.

The ability of guinea pigs to make immune responses to GA, a linear random copolymer of L-glutamic acid and L-alanine, GT, a random linear copolymer of L-glutamic acid and L-tyrosine, and PLL, a linear homopolymer of L-lysine, is controlled by different autosomal dominant genes specific for each of those polymers. We have investigated the relationship between the PLL gene and the GA and GT immune response genes by simultaneously immunizing random-bred Hartley strain guinea pigs with GA and PLL, GT and PLL, or GA and GT. In most Hartley guinea pigs the ability to respond immunologically to GA and to PLL is inherited together; that is, most animals responding to GA respond to PLL and vice versa. However, a few animals respond to either GA or to PLL but not both, demonstrating that the GA and PLL immune response genes are not identical but linked in most Hartley animals. Conversely, when simultaneously immunized with GT and PLL, most Hartley guinea pigs respond to either PLL or GT but not both, indicating that GT and PLL responsiveness tends to segregate away from each other. Thus, the GT and PLL immune response genes also are not inherited independently but, rather, behave as alleles or pseudoalleles. Similar results are observed when Hartley guinea pigs are simultaneously immunized with GA and GT. The ability to respond to GA segregates away from the ability to respond to GT. Our studies demonstrated that the specific immune response genes thus far identified in guinea pigs controlling the ability to respond to GA, GT, and PLL, respectively, are found on the same chromosome. In most Hartley animals, the GA and PLL immune response genes are often linked, i.e. occur on the same chromosome strand, and tend to behave as alleles or pseudoalleles to the GT immune response gene.

Alanine↗