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PubMed2004

Glutamate taste: Discrimination between the tastes of glutamate agonists and monosodium glutamate in rats.

Taste aversion studies have demonstrated that rats conditioned to avoid monosodium glutamate (MSG) with amiloride added to reduce the intensity of the sodium component of MSG taste, generalize this aversion to aspartic acid and to L-AP4, but not to ionotropic glutamate receptor agonists. That is, MSG, L-AP4 and aspartate have similar tastes to rats. However, conditioned taste aversion methods are unable to show to what extent the tastes of two substances are different. If two substances activate the same afferent processes (e.g. taste receptors), they are likely to produce the same tastes, but if they activate different afferent processes, the subject may detect differences between the tastes of the substances. In this study, rats were tested to determine if they could discriminate between the tastes of these agonists and MSG. We also established the detection thresholds for NMDA, aspartic acid and L-AP4, with and without amiloride (a sodium channel antagonist). Taste threshold values were 1-4 mM for NMDA and aspartic acid and 0.5-2.5 microM for L-AP4. None were affected by 30 micro M amiloride. Rats could readily distinguish between the tastes of MSG and NMDA but they had difficulty discriminating between the tastes of aspartic acid and MSG. Rats could also easily distinguish between 10-100 mM MSG and 0.01-5 mM L-AP4. However, in two separate experiments error rates increased significantly when L-AP4 concentrations were between 10-100 mM, indicating that the tastes of L-AP4 and MSG were similar at these concentrations.

Amiloride↗
PubMed1983

Cerebral glutamate, neuroleptic drugs and schizophrenia: increase of cerebrospinal fluid glutamate levels and decrease of striate body glutamate levels following sulpiride treatment in rats.

Chronic (12 days) administration of sulpiride (50 mg/kg, i.p.) in rats resulted in a significant (12%) increase in the glutamate contents of cerebrospinal fluid. Sulpiride had no effect on the GABA content of the brain areas investigated (frontal cortex, striatum, hippocampus and substantia nigra). Sulpiride is a neuroleptic drug which is believed to block especially the non-adenylate cyclase dopaminergic receptors which are supposed to be inhibitory axoaxonic receptors on glutamatergic corticostriatal terminals. The results are compatible with the hypothesis that glutamatergic hypofunction might be the primary defect in schizophrenia rather than hyperactivity of the dopamine synapses.

Animals↗
PubMedDate not supplied

Astroglia and glutamate in physiology and pathology: aspects on glutamate transport, glutamate-induced cell swelling and gap-junction communication.

Astroglia have the capacity to monitor extracellular glutamate (Glu) and maintain it at low levels, metabolize Glu, or release it back into the extracellular space. Glu can induce an increase in astroglial cell volume with a resulting decrease of the extracellular space, and thereby alter the concentration of extracellular substances. Many lines of evidence show that K(+) can be buffered within the astroglial gap-junction-coupled network, and recent results show that gap junctions are permeable for Glu. All these events occur dynamically: the astroglial network has the capacity to interfere actively with neurotransmission, thereby contributing to a high signal-to-noise ratio for the Glu transmission. High-quality neuronal messages during normal physiology can then be maintained. With the same mechanisms, astroglia might exert a neuroprotective function in situations of moderately increased extracellular Glu concentrations, i.e., corresponding to conditions of pathological hyper-excitability, or corresponding to early stages of an acute brain injury. If the astroglial functions are failing, neuronal dysfunction can be reinforced.

Animals↗
PubMed1976

Analysis of the cross-reactive immune suppression induced by the random copolymers L-glutamic acid50-L-tyrosine50 (GT), L-glutamic acid60-L-alanine40 and L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT).

Cross-reactivity in the induction of immune suppression by the structurally related polymers of L-glutamic acid, L-alanine, and/or L-tyrosine (GAT, GA, GT) was studied. SJL (H-2S) and DBA/1 (H-2q) mice are nonresponders to GAT and GT, whereas SJL, but not DBA/1 responds to GA. Both strains respond to these polymers when complexed to the immunogenic carrier methylated bovine serum albumin (MBSA). Preimmunization with GA suppresses GA-MBSA as well as GAT-MBSA and GT-MBSA plaque-forming cell (PFC) responses in DBA/1 mice. Likewise, GAT suppresses GAT-MBSA and GA (SJL) and GA-MBSA (DBA/1) PFC responses in both strains while being totally ineffective on GT-MBSA responses. GT preimmunization suppressed GA, GAT-MBSA, and GT-MBSA PFC responses in SJL but not DBA/1 responses. This study demonstrates that cross-reactive immune suppression does not follow predictable patterns based upon cross-reactivity of specific antibodies and that cross-suppression is not reciprocal.

Alanine↗
PubMed1978

Glutamate transport in pig heart mitochondria. Binding and structural properties of high-glutamate affinity proteolipid: reconstitution studies.

Previously, a proteolipid that can bind glutamate with high affinity has been isolated from pig heart mitochondrial membranes. A final affinity chromatography on gamma-methylglutamate-albumin coreticulated on glass fiber was necessary. This procedure includes long dialysis steps which tend to denature the high-glutamate affinity proteolipid. Here is described a new method of isolation which avoids long dialysis steps and yields greater amounts of the high-glutamate affinity proteolipid. The binding of glutamate or aspartate on high-glutamate affinity proteolipid has been studied by gel filtration, by equilibrium dialysis or by a new procedure of rapid centrifugation based on the insolubility of high-glutamate affinity proteolipid in water. The latter method permits the detection of low and high affinity sites for glutamate with a Kd 60 mM and 55 muM, respectively. Among a series of analogues, aspartate appeared to be the best competitor: Kd = 30 muM and two Ki values, 0.37 mM (at high glutamate concentration) and 3.8 muM (at low glutamate concentration). High-glutamate affinity proteolipid binds 0.4 nmol of glutamate but only 0.1 nmol of aspartate per mg protein. The sites for glutamate and aspartate appear to be different but interdependent. In the presence of high-glutamate affinity proteolipid, externally added glutamate stimulated the efflux of aspartate from preloaded liposomes. High-glutamate affinity proteolipid contains cardiolipin, phosphatidyl choline and phosphatidyl ethanolamine the distribution of which is different from that of the inner membrane. The effects of various phospholipases, trypsin, and thiol reagents were studied on the binding of glutamate. High-glutamate affinity proteolipid binds 9 nmol N-ethylmaleimide per mg protein but only 6.1 nmol in the presence of glutamate. The dissociation of high-glutamate affinity proteolipid caused by thiol reagents yielded a soluble protein fraction with higher affinity for glutamate. Electrophoresis and an immunological approach allowed the detection and titration of the glutamate dehydrogenase and aspartate aminotransferase present in high-glutamate affinity proteolipid in inhibited forms, the latter being 26-fold more concentrated than the former.

Animals↗
PubMed1999

Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST.

Glutamate transporters clear glutamate from the extracellular space by high-affinity binding and uptake. Factors that regulate glutamate transporter expression and activity can thereby influence excitatory neurotransmission. Transporter function in GABAergic and other systems has been shown to be regulated by transporter substrates. Here, glutamate regulation of glutamate transport was studied using primary murine astrocyte cultures that express the GLAST (EAAT1) and GLT-1 (EAAT2) transporter subtypes. Glutamate was found to stimulate glutamate transport capacity (V(max)) in a dose- and time-dependent manner. The maximal increase was 100%, with an ED(50) of 40 microM glutamate and with onset beginning approximately 15 min after onset of glutamate exposure. The uptake stimulation was reproduced by D-aspartate, which is also a transporter substrate, but not by nontransported glutamate receptor agonists. Moreover, glutamate incubation did not stimulate transport when performed in a sodium-free medium, suggesting that the stimulatory effect of glutamate is triggered by increased transporter activity rather than receptor activation. Treatment with the actin-disrupting agents cytochalasin B or cytochalasin D prevented the glutamate-induced increase in glutamate uptake. Biotinylation labeling of membrane surface proteins showed that glutamate incubation produced an increase in GLAST expression at the astrocyte cell surface. These results suggest that cell-surface expression of GLAST can be rapidly regulated by glutamate through a process triggered by GLAST activity and involving the actin cytoskeleton. This feedback loop provides a mechanism by which changes in extracellular glutamate concentrations could rapidly modulate astrocyte glutamate transport capacity.

ATP-Binding Cassette Transporters↗
PubMed1967

Inducible glutamate transport in Mycobacteria and its relation to glutamate oxidation.

Washed-cell preparations of Mycobacterium tuberculosis strain H37Ra and M. smegmatis 607 grown in Sauton's medium demonstrated a lag in glutamate oxidation. Washed-cell preparations of M. fortuitum and M. phlei oxidized glutamate immediately and in a linear fashion. Glutamate was oxidized without a lag by washed cells of M. tuberculosis H37Ra and M. smegmatis 607 harvested from a modified medium containing glutamate. Chloramphenicol inhibited the oxidation of glutamate by washed cells grown in the absence of glutamate. These findings suggested the induction of either an enzyme system for glutamate oxidation or a glutamate transport system. The activity of glutamic dehydrogenase was not significantly greater in extracts prepared from cells grown with glutamate. However, the initial rate of glutamate uptake by induced cells was three to four times higher than in noninduced cells. The induction of the glutamate transport system in M. tuberculosis H37Ra and M. smegmatis 607 was shown to parallel the induction of glutamate oxidation. After a 60-min lag, the inducible glutamate transport system appeared. Chloramphenicol prevented the induction of glutamate uptake, although the antibiotic had no effect on glutamate uptake by previously induced cells. Some of the properties of this glutamate uptake system are described.

Biological Transport↗
PubMed1997

Differential distribution of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 messenger RNAs in the entopeduncular nucleus of the rat.

The entopeduncular nucleus is one of the major output nuclei of the basal ganglia, with topographically organized projections to both motor and limbic structures. Neurons of the entopeduncular nucleus use GABA as the principal transmitter, and glutamic acid decarboxylase (the GABA synthetic enzyme) is widely distributed throughout the region. Previous studies have shown that glutamate decarboxylase exists in two forms (glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67), and that the messenger RNAs for these different enzymes are widely distributed in rat brain. The purpose of the present experiment was to describe the distribution of glutamic acid decarboxylase-65 and glutamic decarboxylase-67 messenger RNAs throughout the entopeduncular nucleus using recently developed oligodeoxynucleotide probes and in situ hybridization histochemical methods. In agreement with previous studies, northern analysis of rat brain poly(A)+ messenger RNA preparations showed that the glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 probes used in the present study hybridized to messenger RNAs of approximately 5.7 and 3.7 kb, respectively. Film autoradiographic analysis revealed large region-dependent, isoform-specific differences in the levels of expression of the two messenger RNAs, with glutamic acid decarboxylase-65 messenger RNA predominating in rostral and medial regions of the entopeduncular nucleus and glutamic acid decarboxylase-67 messenger RNA most abundant in the caudal region. Cellular analysis showed that these region-dependent differences in labelling were due to differences in the relative amounts of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 messenger RNAs expressed per cell rather than the number of cells expressing each form of glutamic acid decarboxylase messenger RNA. The differences in the distribution of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 messenger RNAs are closely related to the organization of limbic and motor circuits of the entopeduncular nucleus, suggesting that GABAergic transmission through the limbic pathway is regulated predominantly by glutamic acid decarboxylase-65, whereas glutamic acid decarboxylase-67 is of principal importance in the motor pathway. These data provide additional evidence that the neurons of the limbic and motor subregions of the entopeduncular nucleus are neurochemically distinct.

Animals↗
PubMed2004

Changes in properties of glutamate transport in Trichoderma viride vegetative mycelia upon adaptation to glutamate as carbon source.

The U-(14)C-labelled glutamate uptake was measured in both sucrose- and glutamate-grown mycelia of Trichoderma viride. The biomass yield was five-fold lower with glutamate as a sole carbon source. The rate of glutamate transport measured at a glutamate concentration of 1 mM remained unchanged in glutamate-grown mycelia whereas the properties of the glutamate transport were substantially changed compared to sucrose-grown mycelia. The glutamate uptake in both sucrose- and glutamate-grown mycelia was inhibited by an uncoupler (3,3',4',5-tetrachlorosalicylanilide) but the inhibitory efficiency was higher in the latter. The affinity of the permease to glutamate increased approximately five-fold in the glutamate-grown mycelia (about 76 microM compared to about 16 microM). The pH optimum for glutamate uptake was 4 in sucrose-grown mycelia but the glutamate-grown mycelia had two pH optima, one at pH 4 and the second between pH 6 and 7. The inhibition of glutamate uptake by other amino acids yielded different inhibitory patterns in the two mycelia under study. The glutamate uptake in mycelia of different ages also showed differences in both transport rate and temporal pattern. The results show that the growth of mycelia on glutamate led to the appearance of an additional permease with different properties and suggest that only this permease is operating in mycelia grown on glutamate.

Adaptation, Physiological↗
PubMed2002

Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens.

The regulation of extracellular glutamate in the nucleus accumbens by group II metabotropic glutamate receptors (mGluR2/3) was examined in vivo. Stimulation of mGluR2/3 with 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or N-acetylaspartylglutamate reduced extracellular glutamate levels. Conversely, blockade of mGluR2/3 by LY143495 or (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate, an effect antagonized by the coadministration of APDC. These effects likely involve both vesicular and nonvesicular glutamate, because the increase in glutamate by APICA or the decrease by APDC was prevented by blocking N-type calcium channels and the release of glutamate after potassium-induced membrane depolarization was antagonized by APDC. In addition, blockade of the cystine-glutamate exchange, a major nonvesicular source of extracellular glutamate, by (S)-4-carboxyphenylglycine blocked the effects induced by either APDC or APICA. However, blockade of Na(+) channels by tetrodotoxin or Na(+)-dependent glutamate transporters by DL-threo-beta-benzyloxyaspartate failed to affect the alterations in extracellular glutamate by APICA or APDC, respectively. Group II mGluRs are G(i)-coupled and coperfusion with the cAMP-dependent protein kinase (PKA) activator Sp-cAMPS blocked the reduction in glutamate by APDC and the PKA inhibitor Rp-cAMPS prevented the elevation in glutamate by APICA. Taken together, these data support three conclusions: 1) group II mGluRs regulate both vesicular and nonvesicular release of glutamate in the nucleus accumbens, 2) there is tonic in vivo stimulation of mGluR2/3 by endogenous glutamate, and 3) modulation of group II mGluRs of extracellular glutamate is Ca(2+)- and PKA-dependent.

Amino Acid Transport System X-AG↗
PubMed2004

Glutaric acid stimulates glutamate binding and astrocytic uptake and inhibits vesicular glutamate uptake in forebrain from young rats.

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by glutaryl-CoA dehydrogenase deficiency, which leads to accumulation in body fluids and in brain of predominantly glutaric acid (GA), and to a lesser extent of 3-hydroxyglutaric and glutaconic acids. Neurological presentation is common in patients with GA I. Although the mechanisms underlying brain damage in this disorder are not yet well established, there is growing evidence that excitotoxicity may play a central role in the neuropathogenesis of this disease. In the present study, preparations of synaptosomes, synaptic plasma membranes and synaptic vesicles, as well as cultured astrocytes from rat forebrain were exposed to various concentrations of GA for the determination of the basal and potassium-induced release of [(3)H]glutamate by synaptosomes, Na(+)-independent glutamate binding to synaptic membranes and vesicular glutamate uptake and Na(+)-dependent glutamate uptake into astrocytes, respectively. GA (1-100 nM) significantly stimulated [(3)H]glutamate binding to brain plasma membranes (40-70%) in the absence of extracellular Na(+) concentrations, reflecting glutamate binding to receptors. Furthermore, this stimulatory effect was totally abolished by the metabotropic glutamate ligands DHPG, DCG-IV and l-AP4, attenuated by the ionotropic non-NMDA glutamate receptor agonist AMPA and had no interference of the NMDA receptor antagonist MK-801. Moreover, [(3)H]glutamate uptake into synaptic vesicles was inhibited by approximately 50% by 10 and 100 nM GA and Na(+)-dependent [(3)H]glutamate uptake by astrocytes was significantly increased (up to 50%) in a dose-dependent manner (maximal stimulation at 100 microM GA). In contrast, synaptosomal glutamate release was not affected by the acid at concentrations as high as 1 mM. These results indicate that the inhibition of glutamate uptake into synaptic vesicles by low concentrations GA may result in elevated concentrations of the excitatory neurotransmitter in the cytosol and the stimulatory effect of this organic acid on glutamate binding may potentially cause excitotoxicity to neural cells. Finally, taken together these results and previous findings showing that GA markedly decreases synaptosomal glutamate uptake, it is possible that the stimulatory effect of GA on astrocyte glutamate uptake might indicate that astrocytes may protect neurons from excitotoxic damage caused by GA by increasing glutamate uptake and therefore reducing the concentration of this excitatory neurotransmitter in the synaptic cleft.

Animals↗
PubMed1996

Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes.

The metabolic fate of glutamate in astrocytes has been controversial since several studies reported > 80% of glutamate was metabolized to glutamine; however, other studies have shown that half of the glutamate was metabolized via the tricarboxylic acid (TCA) cycle and half converted to glutamine. Studies were initiated to determine the metabolic fate of increasing concentrations of [U-13C] glutamate in primary cultures of cerebral cortical astrocytes from rat brain. When astrocytes from rat brain were incubated with 0.1 mM [U-13C] glutamate 85% of the 13C metabolized was converted to glutamine. The formation of [1,2,3-13C3] glutamate demonstrated metabolism of the labeled glutamate via the TCA cycle. When astrocytes were incubated with 0.2-0.5 mM glutamate, 13C from glutamate was also incorporated into intracellular aspartate and into lactate that was released into the media. The amount of [13C] lactate was essentially unchanged within the range of 0.2-0.5 mM glutamate, whereas the amount of [13C] aspartate continued to increase in parallel with the increase in glutamate concentration. The amount of glutamate metabolized via the TCA cycle progressively increased from 15.3 to 42.7% as the extracellular glutamate concentration increased from 0.1 to 0.5 mM, suggesting that the concentration of glutamate is a major factor determining the metabolic fate of glutamate in astrocytes. Previous studies using glutamate concentrations from 0.01 to 0.5 mM and astrocytes from both rat and mouse brain are consistent with these findings.

Alanine↗
PubMed1997

L-trans-pyrrolidine-2,4-dicarboxylic acid-evoked striatal glutamate levels are attenuated by calcium reduction, tetrodotoxin, and glutamate receptor blockade.

L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) reverses plasma membrane glutamate transporters and elevates extracellular glutamate levels in vivo. We investigated the possibility that L-trans-PDC-stimulated glutamate levels are mediated partially by increases in transsynaptic activity. Therefore, the degree to which L-trans-PDC-evoked glutamate levels depend on calcium, sodium-channel activation, and glutamate-receptor activation was investigated by infusing via reverse microdialysis (a) 0.1 mM calcium, (b) 1 microM tetrodotoxin, a selective blocker of voltage-dependent sodium channels, (c) R(-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a selective NMDA-receptor antagonist, or (d) LY293558, a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonist. In separate experimental groups, L-trans-PDC-evoked glutamate levels were reduced significantly by 55% in the presence of 0.1 mM calcium and by 46% in the presence of tetrodotoxin. Additionally, CPP and LY293558 significantly attenuated L-trans-PDC-evoked glutamate levels without altering basal glutamate levels. These data suggest that glutamate transporter reversal by L-trans-PDC initially elevates extracellular glutamate levels enough to stimulate postsynaptic glutamate receptors within the striatum. It is proposed that glutamate-receptor stimulation activates a positive feedback loop within the basal ganglia, leading to further glutamate release from corticostriatal and thalamostriatal afferents. Therefore, either extracellular striatal calcium reduction or tetrodotoxin perfusion leads to decreased action potential-dependent glutamate release from these terminals. In addition, blocking glutamate receptors directly reduces medium spiny neuronal firing and indirectly attenuates corticostriatal and thalamostriatal activity, resulting in an overall depression of L-trans-PDC-stimulated glutamate levels.

Animals↗
PubMed1999

Glutamate-containing parenteral nutrition doubles plasma glutamate: a risk factor in neurosurgical patients with blood-brain barrier damage?

OBJECTIVES: Animal studies have shown that the elevation of plasma glutamate levels increase cerebral edema formation whenever the blood-brain barrier is disturbed. Therefore, changes in plasma glutamate levels as influenced by the administration of a glutamate-containing amino acid solution were investigated in neurosurgical patients. DESIGN: Prospective, descriptive study. SETTING: Eight-bed neurosurgical intensive care unit in a university hospital. PATIENTS: Twenty-three neurosurgical patients requiring parenteral nutrition. INTERVENTIONS: Parenteral nutrition was begun 24 hrs after craniotomy. Patients receiving a glutamate-containing amino acid solution (3.75 g/L glutamate) were compared with patients infused with a glutamate-free solution. MEASUREMENTS AND MAIN RESULTS: Arterial plasma and urine amino acids were analyzed using high-performance liquid chromatography. Administration of a glutamate-containing solution doubled plasma glutamate levels in neurosurgical patients (from 53.3 +/- 9.8 microM [preinfusion] to 98.5 +/- 18.7 microM [after 4 hrs of infusion]; p < 0.001), whereas no elevation was seen when infusing a glutamate-free solution (from 52.3 +/- 7.3 [1 hr of infusion] to 53.6 +/- 6.4 microM [4 hrs of infusion]). Upon terminating the glutamate-containing infusion, arterial plasma glutamate levels decreased immediately (from 120 +/- 13.2 microM to 81.2 +/- 19.5 microM). Glutamate as infused in excess appears to exceed a renal threshold and is eliminated renally. CONCLUSIONS: As shown in animal models, administration of a glutamate-containing amino acid solution significantly increased plasma glutamate levels. Because such an increase in plasma glutamate levels could aggravate cerebral edema formation, glutamate-containing amino acid solutions cannot be recommended for patients with a disturbed blood-brain barrier.

Asparagine↗
PubMed1994

Glutamate blocks astroglial stellation: effect of glutamate uptake and volume changes.

Neurotransmitters which increase intracellular cAMP levels can cause cultured astroglia to change from a flat, polygonal shape to a stellate morphology. Little is known about how glial stellation can be regulated by other transmitters. In the present study, we demonstrated that L-glutamate blocked isoproterenol (ISO) or dibutyryl-cAMP induced stellation in astroglia. The glutamate inhibition was concentration dependent, with its maximal effect on > 90% of cells at 500 microM. Glutamate also reversed glial stellation within a short period (< 30 min). Glutamate uptake analogues, D-glutamate and D-aspartate, rather than receptor agonists, kainate and quisqualate, mimicked the glutamate effect. Likewise, the glutamate uptake blocker, D-thero-beta-hydroxyaspartate, blocked the glutamate effect. The glutamate inhibition was not a result of inhibition of cAMP formation, since norepinephrine, which inhibited 80% of ISO-stimulated cAMP, also caused glial stellation. Increases in extracellular K+ to 50 mM also reduced glial stellation, whereas 25 mM K+ had little effect. Since 25 mM K+ caused much greater depolarization than 400 microM glutamate, it was unlikely that the effects of both glutamate and high [K+] on glial stellation were due to membrane depolarization. Hypotonic treatment (120 mOsm) enhanced, whereas hypertonic treatment (520 mOsm) prevented, the glutamate reversal of glial stellation. Thus, glial swelling appeared to be a primary mechanism for the inhibitory effect of glutamate and high [K+] on glial stellation. This mechanism could also explain the observation that glutamate inhibited stellation induced by PMA, a PKC activator. Our data suggest that glutamate released from neurons during neuronal activity or pathology can be taken up by astrocytes and alter their morphology. Changes in glial morphology may in turn affect the volume and composition of the extracellular space and, as a result, neuronal activity.

Animals↗
PubMed1984

Regulation of hepatic glutamate metabolism. Role of 2-oxoacids in glutamate release from isolated perfused rat liver.

In isolated perfused rat liver, addition of the oxoanalogues of leucine, isoleucine, methionine and phenylalanine is followed by a rapid and reversible stimulation of glutamate release. This is not observed with the corresponding amino acids or 2-oxoisovalerate, 2-oxoglutarate or oxaloacetate. The increased glutamate release by the liver is accompanied by a decrease in the tissue contents of 2-oxoglutarate and glutamate by about 25% and 50%, respectively. During the metabolism of glutamine, i.e. conditions with elevated tissue glutamate concentrations, 2-oxoacid-induced glutamate release is stimulated. In the presence of glutamine (5 mM), 2-oxoisocaproate, 2-oxo-4-methylvalerate and 2-oxo-4-methylthiobutyrate were found to be most effective and glutamate release by the liver increased linearly from about 80 nmol g-1 min-1 to 600 nmol g-1 min-1 at increasing 2-oxoacid concentrations up to 1 mM. When glutamate tissue levels were decreased by phenylephrine, stimulation of glutamate release by 2-oxoisocaproate was markedly diminished. 2-Oxoacid-stimulated glutamate release is independent of oxoacid metabolism, indicating that the effect is probably not explained by a 2-oxoacid/glutamate exchange across the liver plasma membrane. 2-Oxoacid-induced glutamate export predominantly occurs in a sodium-independent way. At low concentrations of 2-oxoisocaproate (below 0.2 mM), the increased glutamate release was accompanied by a slight inhibition of 14CO2 production from added [14C]glutamate, indicating a simultaneous glutamate uptake and release also under these conditions. Stimulation of glutamate release by 2-oxoisocaproate is followed by a decreased rate of urea and glutamine synthesis from portal ammonia, as a consequence of an increased glutamate release.

Animals↗
PubMed2004

Interactions between glutamate transporters and metabotropic glutamate receptors at excitatory synapses in the cerebellar cortex.

Five glutamate transporter genes have been identified; two of these (EAAT3 and EAAT4) are expressed in neurons and are predominantly confined to the membranes of cell bodies and dendrites. At an ultrastructural level, glutamate transporters have been shown to surround excitatory synapses in hippocampus and cerebellum [J. Neurosci. 18 (1998) 3606; J. Comp. Neurol. 418 (2000) 255]. This pattern of localization overlaps the well-described perisynaptic distribution of Group I metabotropic glutamate receptors or mGluRs [Neuron 11 (1993) 771; J. Chem. Neuroanat. 13 (1997) 77]. Both of the principal excitatory synaptic inputs to cerebellar Purkinje neurons, the parallel fiber (PF) and climbing fiber (CF) synapses, express mGluR-dependent forms of synaptic plasticity [Nat. Neurosci. 4 (2001) 467]. Prompted by the colocalization of postsynaptic glutamate transporters and mGluRs, we have examined whether glutamate uptake limits mGluR-mediated signals and mGluR-dependent forms of plasticity at PF and CF synapses in cerebellar slices. We find that, at PF and, surprisingly also at CF synapses, mGluR activation generates a slow synaptic current and triggers intracellular calcium release. At both PF and CF synapses, mGluR responses are strongly limited by glutamate transporters under resting conditions and are facilitated by short trains of stimuli. Nearly every Purkinje neuron expresses an mGluR-mediated synaptic current upon inhibition of glutamate transport. Global applications of glutamate achieved by photolysis of chemically caged glutamate yield similar results and argue that the colocalized transporters can effectively limit glutamate access to the mGluRs even in the face of such a large amount of transmitter. We hypothesize that neuronal glutamate transporters and Group I mGluRs located in the perisynaptic space interact to sense and then regulate the amount of glutamate escaping excitatory synapses. This hypothesis is currently being tested using electrophysiological methods and the introduction of optically tagged glutamate transporter proteins. In the brain, synaptic signals are terminated mainly by neurotransmitter transporters. Families of genes encoding transporters for the major neurotransmitters (dopamine, GABA, glutamate, glycine, norepinephrine and 5-HT) have been identified. Although transporters serve as targets for important classes of therapeutic drugs (e.g. selective serotonin reuptake inhibitors) and drugs of abuse (amphetamine, cocaine), little is known about how they operate at a molecular level or contribute to synaptic transmission.

Amino Acid Transport System X-AG↗
PubMed1998

Glutamate in the nucleus of the solitary tract activates both ionotropic and metabotropic glutamate receptors.

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus of the solitary tract (NTS). Blockade of ionotropic glutamate receptors with kynurenic acid blocks the arterial baroreflex but, paradoxically, does not abolish the response to exogenous glutamate. This study tested the hypothesis that exogenous glutamate in the NTS activates both ionotropic and metabotropic glutamate receptors (mGluRs). In urethan-anesthetized rats, unilateral microinjections of glutamate into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The cardiovascular response to injection of glutamate was not altered by NTS blockade of mGluRs with alpha-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid attenuated the response to glutamate injection. After combined NTS injection of MCPG and kynurenic acid, the response to glutamate was blocked. These data suggest that exogenous glutamate microinjected into the NTS acts at both ionotropic glutamate receptors and mGluRs. In addition, blockade of both classes of glutamate receptors is required to block the cardiovascular response to microinjection of glutamate in the NTS.

Animals↗