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PubMed1976

Glutamate transport in membrane vesicles of the wild-type strain and glutamate-utilizing mutants of Escherichia coli.

A highly specific energy-dependent glutamate transport system was demonstrated in membrane vesicles of glutamate-utilizing Escherichia coli K-12 mutants. The glutamate transport activity of membranes from the parent strain, unable to grow on glutamate, was very low. With ascorbate-phenazine methosulfate as the electron donor, mutant preparations displayed 17 to 20 times higher activity than did the wild type. However, the affinity of the mutant carrier for L-glutamate remained the same as in the parent strain. Comparative inhibition analysis of glutamate transport in whole cells and membrane vesicles and of in vitro binding of glutamate to a specific periplasmic-binding protein suggests that under certain conditions the latter may be a component of the E. coli K-12 glutamate transport system.

Amino Acids↗
PubMed1972

Effect of insulin on muscle glutamate uptake. Whole blood versus plasma glutamate analysis.

For decades, investigators concerned with protein metabolism in man have performed detailed amino acid analyses of human plasma obtained under a wide range of experimental situations. A large body of information has been used to calculated rates of protein synthesis and proteolysis. During the course of an investigation of the effect of intrabrachial artery infusion of insulin (70 muU/min per kg body weight) on glutamate uptake by human forearm muscle, it was discovered that plasma arterio-deep venous glutamate difference analysis failed to document any increase in the uptake of this amino acid, suggesting that insulin had little influence on glutamate uptake by muscle. However, whole blood glutamate analyses, performed on the same blood samples, revealed that (a) the resting muscle uptake of glutamate is smaller than previously reported and (b) insulin is capable of markedly increasing glutamate uptake by muscle from whole blood. Since the hematocrit was obtained on all samples, detailed analyses of the various compartments in which glutamate could be found were performed. It was determined that circulating blood cells have a dynamic role in glutamate transport. These data underscore the need for both whole blood and plasma amino acid analysis in investigations concerned with protein synthesis and/or amino acid flux, for analysis of plasma samples alone could be misleading as illustrated in the present study.

Blood Cells↗
PubMed2003

Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration.

T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.

Amino Acid Sequence↗
PubMed1998

The striatal neurotensin receptor modulates striatal and pallidal glutamate and GABA release: functional evidence for a pallidal glutamate-GABA interaction via the pallidal-subthalamic nucleus loop.

In the present study, we used dual-probe microdialysis to investigate the effects of intrastriatal perfusion with neurotensin (NT) on striatal and pallidal glutamate and GABA release. The role of the pallidal GABAA receptor in the intrastriatal NT-induced increase in pallidal glutamate release was also investigated. Intrastriatal NT (100 and 300 nM) increased striatal glutamate and GABA (100 nM, 155 +/- 9 and 141 +/- 6%, respectively; 300 nM, 179 +/- 8 and 166 +/- 11%, respectively) release, as well as pallidal glutamate and GABA (100 nM, 144 +/- 8 and 130 +/- 5%; 300 nM, 169 +/- 9 and 157 +/- 8%, respectively) release. These effects were dose-dependently antagonized by the NT receptor antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2, 6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1 .1.3. 7)-decan-2-carboxylic acid (SR48692). Intrasubthalamic injection of the GABAA receptor antagonist (-)-bicuculline (10 pmol/100 nl, 30 sec) rapidly increased pallidal glutamate release, whereas the intrastriatal NT-induced increase in pallidal glutamate release was counteracted by intrapallidal perfusion with (-)-bicuculline, suggesting that an increase in striopallidal GABA-mediated inhibition of the GABAergic pallidal-subthalamic pathway results in an increased glutamatergic drive in the subthalamic-pallidal pathway. These results demonstrate a tonic pallidal GABA-mediated inhibition of excitatory subthalamic-pallidal neurons and strengthen the evidence for a functional role of NT in the regulation of glutamate and GABA transmission in the basal ganglia. The ability of intrastriatal SR48692 to counteract the NT-induced increase in both striatal and pallidal glutamate and GABA release suggests that blockade of the striatal NT receptor may represent a possible new therapeutic strategy in the treatment of those hypokinetic disorders implicated in disorders of the indirect pathway mediating motor inhibition.

Animals↗
PubMed2004

Developmental expression of glutamate transporters and glutamate dehydrogenase in astrocytes of the postnatal rat hippocampus.

Glutamate is the major excitatory transmitter in the CNS and plays distinct roles in a number of developmental events. Its extracellular concentration, which mediates these activities, is regulated by glutamate transporters in glial cells and neurons. In the present study, we have used nonradioactive in situ hybridization, immunocytochemistry, and immunoblotting to show the cellular and regional expression of the high-affinity glutamate transporters GLAST (EAAT1) and generic GLT1 (EAAT2; glial form of GLT1) in the rat hippocampus during postnatal development (P1-60). The results of transporter expression were compared with the localization and activity pattern of glutamate dehydrogenase (GDH), an important glutamate-metabolizing enzyme. The study showed that both transporters and GDH were demonstrable at P1 (day of birth). The expression of GLAST (detected by in situ hybridization and immunocytochemistry) in the early postnatal development was higher than GLT1. Thereafter, the expression of both transporters increased, showing adult levels at between P20 and P30 (detected by in situ hybridization and immunoblotting). At these time points, the expression of GLT1 appeared to be significantly higher than the GLAST expression. GLT1 and GLAST proteins were demonstrable only in astrocytes. The increase of GDH activities (steepest increase from P5-P8), which were localized preferentially in astrocytes, was in agreement with the increase of transporter expression, preferentially with that of GLT1. These observations suggest that the extent of glutamate transporter expression and of glutamate-metabolizing GDH activity in astrocytes is intimately correlated with the formation of glutamatergic synapses in the developing hippocampus.

Aging↗
PubMed2004

Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation.

Metabotropic glutamate receptors (mGluR) are present in cells of the nervous system, where they are activated by one of the main neurotransmitters, glutamate. They are also expressed in cells outside the nervous system. We identified and characterized two receptors belonging to group I mGluR, mGlu1R and mGlu5R, in human cell lines of lymphoid origin and in resting and activated lymphocytes from human peripheral blood. Both are highly expressed in the human Jurkat T cell line, whereas mGlu5R is expressed only in the human B cell line SKW6.4. In blood lymphocytes, mGlu5R is expressed constitutively, whereas mGlu1R is expressed only upon activation via the T cell receptor-CD3 complex. Group I receptors in the central nervous system are coupled to phospholipase C, whereas in blood lymphocytes, activation of mGlu5R does not trigger this signaling pathway, but instead activates adenylate cyclase. On the other hand, mGlu5R does not mediate ERK1/2 activation, whereas mGlu1R, which is coupled neither to phospholipase C nor to calcium channels and whose activation does not increase cAMP, activates the mitogen-activated protein kinase cascade. The differential expression of mGluR in resting and activated lymphocytes and the different signaling pathways that are triggered when mGlu1Rs or mGlu5Rs are activated point to a key role of glutamate in the regulation of T cell physiological function. The study of the signaling pathways (cAMP production and ERK1/2 phosphorylation) and the proliferative response obtained in the presence of glutamate analogs suggests that mGlu1R and mGlu5R have distinct functions. mGlu5R mediates the reported inhibition of cell proliferation evoked by glutamate, which is reverted by the activation of inducible mGlu1R. This is a novel non-inhibitory action mechanism for glutamate in lymphocyte activation. mGlu1R and mGlu5R thus mediate opposite glutamate effects in human lymphocytes.

B-Lymphocytes↗
PubMed1990

Glutamate-dependent active-site labeling of brain glutamate decarboxylase.

A major regulatory feature of brain glutamate decarboxylase (GAD) is a cyclic reaction that controls the relative amounts of holoenzyme and apoenzyme [active and inactive GAD with and without bound pyridoxal 5'-phosphate (pyridoxal-P, the cofactor), respectively]. Previous studies have indicated that progression of the enzyme around the cycle should be stimulated strongly by the substrate, glutamate. To test this prediction, the effect of glutamate on the incorporation of pyridoxal-P into rat-brain GAD was studied by incubating GAD with [32P]pyridoxal-P, followed by reduction with NaBH4 to link irreversibly the cofactor to the enzyme. Adding glutamate to the reaction mixture strongly stimulated labeling of GAD, as expected. 4-Deoxypyridoxine 5'-phosphate (deoxypyridoxine-P), a close structural analogue of pyridoxal-P, was a competitive inhibitor of the activation of glutamate apodecarboxylase by pyridoxal-P (Ki = 0.27 microM) and strongly inhibited glutamate-dependent labeling of GAD. Analysis of labeled GAD by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis showed two labeled proteins with apparent molecular masses of 59 and 63 kDa. Both proteins could be purified by immunoaffinity chromatography on a column prepared with a monoclonal antibody to GAD, and both were labeled in a glutamate-dependent, deoxypyridoxine-P-sensitive manner, indicating that both were GAD. Three peaks of GAD activity (termed peaks I, II, and III) were separated by chromatography on phenyl-Sepharose, labeled with [32P]pyridoxal-P, purified by immunoaffinity chromatography, and analyzed by SDS-polyacrylamide gel electrophoresis. Peak I contained only the 59-kDa labeled protein. Peaks II and III contained the both the 59- and 63-kDa proteins, but in differing proportions.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed2005

Loss of metabotropic glutamate receptor-mediated regulation of glutamate transport in chemically activated astrocytes in a rat model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurones accompanied by intense gliosis in lesioned areas of the brain and spinal cord. Glutamate-mediated excitotoxicity resulting from impaired astroglial uptake constitutes one of the current pathophysiological hypotheses explaining the progression of the disease. In this study, we examined the regulation of glutamate transporters by type 5 metabotropic glutamate receptor (mGluR5) in activated astrocytes derived from transgenic rats carrying an ALS-related mutated human superoxide dismutase 1 (hSOD1(G93A)) transgene. Cells from transgenic animals and wild-type littermates showed similar expression of glutamate-aspartate transporter and glutamate transporter 1 (GLT-1) after in vitro activation, whereas cells carrying the hSOD1 mutation showed a three-fold higher expression of functional mGluR5, as observed in the spinal cord of end-stage animals. In cells from wild-type animals, (S)-3,5-dihydroxyphenylglycine (DHPG) caused an immediate protein kinase C (PKC)-dependent up-regulation of aspartate uptake that reflected the activation of GLT-1. Although this effect was mimicked in both cultures by direct activation of PKC using phorbol myristate acetate, DHPG failed to up-regulate aspartate uptake in cells derived from the transgenic rats. The failure of activated mGluR5 to increase glutamate uptake in astrocytes derived from this animal model of ALS supports the theory of glutamate excitotoxicity in the pathogenesis of the disease.

Amyotrophic Lateral Sclerosis↗
PubMed1985

[Molecular organization of glutamate-sensitive chemoexcitable membranes of nerve cells. Function of glutamate-binding proteins of the central nervous system when incorporated into liposomes].

The functioning of the glutamate-binding protein of rat brain cortex synaptic membranes was studied by its incorporation into liposomes. The optimal conditions for the receptor protein incorporation were established and the kinetics of 22Na+ and 86Rb+ incorporation into the liposomes in the presence of L-glutamate were analyzed. Modelling of the CNS glutamate receptor functions was found to be dependent on the lipid composition and amount of the incorporated membrane protein. The selective transport of 22Na+ into the liposomes was stimulated in the presence of 10(-4) M glutamate. Addition of monoclonal antibodies against glutamate-binding proteins blocked the incorporation of Na+ into the liposomes. The experimental results are suggestive of the nativity of the liposome-incorporated membrane protein, which is capable of binding glutamate and regulating selective transport of Na+. It was assumed that the glutamate receptor macromolecule represents an integral complex made up of several low molecular weight subunits of glucoprotein nature that form a selective ionic channel.

Animals↗
PubMed2002

The effect of dietary carbohydrate on the rise in plasma glutamate concentrations following oral glutamate ingestion in rats.

Plasma glutamate concentrations were examined in male rats following oral intubation of monosodium L-glutamic acid (MSG, 250 mg/kg) soon after ingesting one of several meals differing in carbohydrate content. Intubation of MSG alone produced a 4-fold rise in plasma glutamate that peaked at 15 min, and returned to baseline by 60 min. Red blood cell glutamate concentrations were unchanged. The ingestion of a meal lacking carbohydrate produced a modest attenuation of the post-MSG intubation rise in plasma glutamate concentrations. This attenuating effect increased progressively with the carbohydrate content of the meal (and as the protein content declined, to maintain isocaloric meals), though as little as 5% carbohydrate marked attenuated the plasma glutamate rise. This effect diminished as the time interval between the meal and MSG intubation increased from 1 to 4 hrs. Similar, but not identical effects were noted when meals substituted fat (instead of protein) for carbohydrate. The intubation of MSG alone produced a slight increase in plasma alanine concentrations over the 60-min post-intubation period examined. The ingestion of any of the meals just prior to intubation did not influence this effect. Overall, the results indicate that although the ingestion of carbohydrate can markedly attenuate the rise in plasma glutamate that follows MSG consumption in rats, this effect is also influenced by the other macronutrients present. The absence of notable, meal related changes in plasma alanine suggests that this parameter does not provide a useful indication of gut glutamate transamination.

Journal Article↗
PubMed1996

Glutamate release evoked by glutamate receptor agonists in cultured chick retina cells: modulation by arachidonic acid.

We studied the effect of ionotropic glutamate receptor agonists on the release of endogenous glutamate or of [3H]D-aspartate from reaggregate cultures (retinospheroids) or from monolayer cultures of chick retinal cells, respectively. Kainate increased the fluorescence ratio of the Na+ indicator SBFI and stimulated a dose-dependent release of glutamate in low (0.1 mM) Ca2+ medium, as measured using a fluorometric assay. Under the same experimental conditions, the release evoked by N-methyl-D-aspartate (NMDA; 400 microM) was about half of that evoked by the same kainate concentration; alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA; 400 microM) did not trigger a significant response. In the presence of 1 mM CaCl2, all of the agonists increased the [Ca2+]i, as determined with the fluorescence dye Indo-1, but the glutamate release evoked by NMDA and kainate was significantly lower than that measured in 0.1 mM CaCl2 medium. Inhibition by Ca2+ of the kainate-stimulated release of glutamate was partially reversed by the phospholipase A2 inhibitor oleiloxyethyl phosphorylcholine (OPC), suggesting that the effect was mediated by the release of arachidonic acid, which inhibits the glutamate carrier. Accordingly, kainate, NMDA, and AMPA stimulated a Ca(2+)-dependent release of [3H]arachidonic acid, and the direct addition of the exogenous fatty acid to the medium decreased the release of glutamate evoked by kainate in low (0.1 mM) CaCl2 medium. In monolayer cultures, we showed that NMDA, kainate, and AMPA also stimulated the release of [3H]D-aspartate, but in this case release in the presence of 1 mM CaCl2 was significantly higher than that evoked in media with no added Ca2+. The ranking order of efficacy for stimulation of Ca(2+)-dependent release of [3H]D-aspartate was NMDA > > kainate > AMPA.

Animals↗
PubMed1998

Glutamate-stimulated neuropeptide Y mRNA expression in the rat dentate gyrus: a prominent role of metabotropic glutamate receptors.

The influence of intrahippocampal injections of glutamate receptor agonists on neuropeptide Y (NPY) mRNA expression was investigated in granule cells and interneurons of the rat dentate gyrus. One day after local injection of non-neurodegenerative doses (20 and 70 nmol) of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)ACPD], NPY mRNA levels were more than doubled in ipsilateral granule cells and interneurons. Doses of 200 and 400 nmol caused up to 15.9- and 4.6-fold mRNA increases in granule cells and interneurons, respectively. The group I metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG; 50 nmol), but not the group III receptor agonist L(+)-2-amino-4-phosphonobutyrate (L-AP4; 20 and 200 nmol) exerted a similar action. The general metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; 200 nmol), the group I receptor antagonist (S)-4-carboxyphenylglycine (4-CPG; 200 nmol) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (1 mg/kg; i.p.) partially blocked the (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate-induced increase in NPY mRNA in granule cells, but not in interneurons. (S)-4-carboxyphenylglycine (200 nmol) by itself increased NPY mRNA levels in ipsilateral interneurons threefold, indicating the activation of phospholipase D coupled receptors. Non-neurodegenerative doses of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.3 nmol) caused modest increases in NPY mRNA levels in ipsilateral interneurons, whereas neurodegenerative doses (1-10 nmol) induced markedly increased NPY mRNA levels in granule cells (up to 11-fold) and interneurons (up to threefold). It is suggested that activation of metabotropic glutamate receptors stimulates NPY mRNA expression in granule cells and interneurons in the rat dentate gyrus. Whereas in granule cells NPY mRNA upregulation is preferentially mediated by group I metabotropic glutamate receptors, it may involve ionotropic and metabotropic glutamate receptors in interneurons.

Animals↗
PubMed2003

Glutamate and the glutamate receptor system: a target for drug action.

Glutamate is the most important excitatory neurotransmitter in the central nervous system. In the process, glutamate fulfills numerous physiological functions, but also plays an important role in the pathophysiology of different neurological and psychiatric diseases, especially when an imbalance in glutamatergic neurotransmission occurs. Under certain conditions, glutamate has a toxic action resulting from an activation of specific glutamate receptors, which leads to acute or chronic death of nerve cells. Such mechanisms are currently under discussion in acute neuronal death within the context of hypoxia, ischaemia and traumas, as well as in chronic neurodegenerative or neurometabolic diseases, idiopathic parkinsonian syndrome, Alzheimer's dementia and Huntington's disease. It is hoped that glutamate antagonists will lead to novel therapies for these diseases, whereby the further development of glutamate antagonists for blocking disease-specific subtypes of glutamate receptors may be of major importance in the future.

Alzheimer Disease↗
PubMed2001

Regulation of human glutamate dehydrogenases: implications for glutamate, ammonia and energy metabolism in brain.

Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate using NAD or NADP as cofactors. In mammalian brain, GDH is located predominantly in astrocytes, where it is probably involved in the metabolism of transmitter glutamate. The exact mechanisms that regulate glutamate fluxes through this pathway, however, have not been fully understood. In the human, GDH exists in heat-resistant and heat-labile isoforms, encoded by the GLUD1 (housekeeping) and GLUD2 (nerve tissue-specific) genes, respectively. These forms differ in their catalytic and allosteric properties. Kinetic studies showed that the K(m) value for glutamate for the nerve tissue GDH is within the range of glutamate levels in astrocytes (2.43 mM), whereas for the housekeeping enzyme, this value is significantly higher (7.64 mM; P < 0.01). The allosteric activators ADP (0.1-1.0 mM) and L-leucine (1.0-10.0 mM) induce a concentration-dependent enzyme stimulation that is proportionally greater for the nerve tissue-specific GDH (up to 1,600%) than for the housekeeping enzyme (up to 150%). When used together at lower concentrations, ADP (10-50 mM) and L-leucine (75-200 microM) act synergistically in stimulating GDH activity. GTP exerts a powerful inhibitory effect (IC(50) = 0.20 mM) on the housekeeping GDH; in contrast, the nerve tissue isoenzyme is resistant to GTP inhibition. Thus, although the housekeeping GDH is regulated primarily by GTP, the nerve tissue GDH activity depends largely on available ADP or L-leucine levels. Conditions associated with enhanced hydrolysis of ATP to ADP (e.g., intense glutamatergic transmission) are likely to activate nerve tissue-specific GDH leading to an increased glutamate flux through this pathway.

Adenosine Diphosphate↗
PubMed1991

Displacement of endogenous glutamate with D-aspartate: an effective strategy for reducing the calcium-independent component of glutamate release from synaptosomes.

D-aspartate was used in the present study to partially deplete the cytosolic pool of glutamate, which is released independent of extracellular Ca2+, prior to measuring the K(+)-evoked release of this endogenous acidic amino acid from rat hippocampal mossy fiber synaptosomes. This pretreatment is known to be an effective method for substantially reducing the Ca(2+)-independent component of glutamate release. The rate of glutamate efflux is dependent on the concentration of sodium ions in the external medium and can be stimulated by exposure of hippocampal mossy fiber synaptosomes to external D-aspartate (50 microM). Following the partial displacement of this cytosolic pool of glutamate with D-aspartate, the K(+)-evoked release of the residual, presumably vesicular, pool of endogenous glutamate has a strict requirement for external calcium and is highly dependent on the extent to which depolarization elevates the level of free cytosolic calcium. It is concluded that the protocol described in this study for the displacement of cytosolic glutamate with D-aspartate provides a useful alternative method of controlling for the Ca(2+)-independent component of glutamate release in synaptosomal preparations.

Animals↗
PubMed1996

Consumption of a high dietary dose of monosodium glutamate fails to affect extracellular glutamate levels in the hypothalamic arcuate nucleus of adult rats.

We examined the effects of systemic or oral ad libitum monosodium glutamate (MSG) administration on glutamate levels in plasma, and on glutamate release from the arcuate nucleus of the hypothalamus (estimated using brain microdialysis). Systemic MSG administration (0.25, 0.5, 1 or 2 g/kg, i.p.) to adult rats caused dose-dependent increases in glutamate levels within arcuate nucleus dialysates. These levels increased during the initial 20 min after systemic MSG administration, and peaked during the second 20-min interval (maximally to 116 +/- 7%, 146 +/- 15%, 790 +/- 191% and 1230 +/- 676% of basal values, respectively). Plasma glutamate levels, measured simultaneously, were increased maximally during the initial 20 min after MSG administration. These increases were 10-, 13-, 76- and 163-fold after doses of 0.25, 0.5, 1 and 2 g/kg, i.p., respectively. In feeding experiments, consumption of 2.3 g/kg of MSG by previously-trained rats during an 1-h period increased plasma glutamate levels to 352 +/- 61% of basal values 140 min after the start of the feeding period. No changes were observed in glutamate levels of arcuate nucleus dialysates. These findings may explain why ad libitum dietary consumption of MSG apparently lacks neurotoxic potential.

Animals↗
PubMed1991

Inhibition of high affinity L-glutamic acid uptake into rat cortical synaptosomes by the conformationally restricted analogue of glutamic acid, cis-1-aminocyclobutane-1,3-dicarboxylic acid.

The action of two cyclobutane derivatives of L-glutamic acid on the high affinity uptake of L-glutamic acid was investigated using a preparation of synaptosomes from rat cerebral cortex. cis-1-Aminocyclobutane-1,3-dicarboxylic acid (also known as trans-2,4-methanoglutamic acid) potently inhibited L-glutamic acid uptake (IC50 30 microM), whereas trans-1-aminocyclobutane-1,3-dicarboxylic acid (also known as cis-2,4-methanoglutamic acid), a potent N-methyl-D-aspartate (NMDA) agonist, was inactive. Analysis of the kinetics of L-glutamic acid uptake in the presence and absence of cis-1-aminocyclobutane-1,3-dicarboxylic acid (CACB) suggests that it may act as a competitive inhibitor (Ki 8 microM). CACB may be substrate for the L-glutamic acid high-affinity uptake carrier since preincubation of CACB with the synaptosomal preparation increased its potency in inhibiting L-glutamic acid uptake. The conformationally restricted structure of CACB may be indicative of the conformations of L-glutamic acid that interact with the high affinity uptake carrier.

Amino Acids, Dicarboxylic↗
PubMed1995

Developmental change from inhibition to facilitation in the presynaptic control of glutamate exocytosis by metabotropic glutamate receptors.

We have addressed the role of presynaptic metabotropic glutamate receptors in the control of glutamate release from cerebrocortical nerve terminals. The metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid enhances the release evoked by a submaximal depolarization in the presence of low concentrations of arachidonic acid and in a staurosporine-sensitive manner. In contrast, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid and L(+)-2-amino-4-phosphonobutyrate inhibit the release evoked by a maximal depolarization, in the absence of arachidonic acid and by a staurosporine-insensitive mechanism. Interestingly, the effects of the metabotropic glutamate receptors that inhibit glutamate release are only observed in the nerve terminals from young rats (one to three weeks), while the facilitatory effects are better seen in latter developmental stages (three to four weeks) and adult (two to three months) rats, coinciding with the development of the maximal capacity of glutamate uptake. These results indicate the existence of important developmental changes in the presynaptic control of glutamate release.

Animals↗