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PubMed1990

Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake.

Glutamate uptake into nerve and glial cells usually functions to keep the extracellular glutamate concentration low in the central nervous system. But one component of glutamate release from neurons is calcium-independent, suggesting a non-vesicular release that may be due to a reversal of glutamate uptake. The activity of the electrogenic glutamate uptake carrier can be monitored by measuring the membrane current it produces, and uptake is activated by intracellular potassium ions. Here we report that raising the potassium concentration around glial cells evokes an outward current component produced by reversed glutamate uptake. This current is activated by intracellular glutamate and sodium, inhibited by extracellular glutamate and sodium, and increased by membrane depolarization. These results demonstrate a non-vesicular mechanism for the release of glutamate from glial cells and neurons. This mechanism may contribute to the neurotoxic rise in extracellular glutamate concentration during brain anoxia.

Animals↗
PubMed2002

Neuronal-induced and glutamate-dependent activation of glial glutamate transporter function.

The activity of high-affinity glutamate transporters is essential for the normal function of the mammalian central nervous system. Using a combined pharmacological, confocal immunocytochemical, enzyme-based microsensor and fluorescence imaging approach, we examined glutamate uptake and transporter protein localization in single astrocytes of neuron-containing and neuron-free microislands prior to pre-synaptic transmitter secretion and during functional neuronal activity. Here, we report that the presence or absence of neurons strikingly affects the uptake capacity of the astroglial glutamate transporters GLT1 and GLAST1. Induction of transporter function is activated by neurons and this effect is mimicked by pre-incubation of astrocytes with micromolar concentrations of glutamate. Moreover, increased glutamate transporter activation is reproduced by endogenous release of glutamate via activation of neuronal nicotinic receptors. The increase in transport activity is dependent on neuronal release of glutamate, is associated with the local redistribution (clustering) of GLT1 and GLAST1 but is independent of transporter synthesis and of glutamate receptor activation. Together, these results suggest an activity-dependent neuronal feedback system for rapid astroglial glutamate transporter regulation where neuron-derived glutamate is the physiological signal that triggers transporter function.

Animals↗
PubMed1997

Glutamate transporter currents in bergmann glial cells follow the time course of extrasynaptic glutamate.

Glutamate transporters in the central nervous system are expressed in both neurons and glia, they mediate high affinity, electrogenic uptake of glutamate, and they are associated with an anion conductance that is stoichiometrically uncoupled from glutamate flux. Although a complete cycle of transport may require 50-100 ms, previous studies suggest that transporters can alter synaptic currents on a much faster time scale. We find that application of L-glutamate to outside-out patches from cerebellar Bergmann glia activates anion-potentiated glutamate transporter currents that activate in <1 ms, suggesting an efficient mechanism for the capture of extrasynaptic glutamate. Stimulation in the granule cell layer in cerebellar slices elicits all or none alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor and glutamate transporter currents in Bergmann glia that have a rapid onset, suggesting that glutamate released from climbing fiber terminals escapes synaptic clefts and reaches glial membranes shortly after release. Comparison of the concentration dependence of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor and glutamate transporter kinetics in patches with the time course of climbing fiber-evoked responses indicates that the glutamate transient at Bergmann glial membranes reaches a lower concentration than attained in the synaptic cleft and remains elevated in the extrasynaptic space for many milliseconds.

Animals↗
PubMed2002

Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation.

The pathogenesis of Huntington's disease is still not completely understood. Several lines of evidence from toxic/non-transgenic animal models of Huntington's disease suggest that excitotoxic mechanisms may contribute to the pathological phenotype. Evidence from transgenic animal models of Huntington's disease, however, is sparse. To explore potential alterations in brain glutamate handling we studied transgenic mice expressing an N-terminal fragment of mutant huntingtin (R6/2). Intracerebral microdialysis in freely moving mice showed similar extracellular glutamate levels in R6/2 and littermate controls. However, partial inhibition of glutamate transport by L-trans-pyrrolidine-2,4-dicarboxylate (4 mM) disclosed an age-dependent increase in extracellular glutamate levels in R6/2 mice compared with controls, consistent with a reduction of functional glutamate transport capacity. Biochemical studies demonstrated an age-dependent downregulation of the glial glutamate transporter GLT-1 mRNA and protein, resulting in a progressive reduction of transporter function. Glutamate transporters other than GLT-1 were unchanged. In addition, increased extracellular glutamine levels and alterations to glutamine synthetase immunoreactivity suggested a perturbation of the glutamate-glutamine cycle. These findings demonstrate that the Huntington's disease mutation results in a progressively deranged glutamate handling in the brain, beginning before the onset of symptoms in mice. They also provide evidence for a contribution of excitotoxicity to the pathophysiology of Huntington's disease, and thus Huntington's disease may be added to the growing list of neurodegenerative disorders associated with compromised glutamate transport capacity.

Aging↗
PubMed2003

Methylmercury increases glutamate release from brain synaptosomes and glutamate uptake by cortical slices from suckling rat pups: modulatory effect of ebselen.

During the early postnatal period the brain is extremely sensitive to external agents. Here, we examined the effect of subcutaneous injections of methylmercury (MeHg; 2 mg/kg) during the suckling period (postnatal days [PND] 3-10, 3-17, or 3-24) on glutamate release from brain synaptosomal preparations and on glutamate uptake by brain cortical slices of rat pups. The possible antagonist effect of ebselen against MeHg effect was also examined at PND 24. MeHg increased the basal (but not K+-stimulated) glutamate release and glutamate uptake at PND 24. A strong tendency of increase in the basal glutamate release from synaptosomes (p= 0.088) was observed at PND 17. Ebselen, which did not affect glutamate release and uptake per se, prevented both effects of MeHg. This study indicates that (1) the effect of MeHg on glutamate release could be involved in its toxicity; (2) the increase in the glutamate uptake could represent a pathophysiological response to MeHg-induced glutamate release; (3) the inhibitory effect of ebselen on MeHg-induced glutamate release could be related to its reported neuroprotective effects.

Aging↗
PubMed1999

The effects of hypothermia on a cloned human brain glutamate transporter (hGLT-1) expressed in Chinese hamster ovary cells: -[3H]L-glutamate uptake study.

UNLABELLED: Hypothermia provides neuroprotection that inhibits increases in extracellular glutamate concentration during ischemia; however, the effect of hypothermia on the glutamate transporter is uncertain. A human glial glutamate transporter (hGLT-1) cDNA, isolated by screening a cDNA, library was cloned and stably transfected into Chinese hamster ovary cells. We assessed the effects of temperature on transporter activity in [3H]L-glutamate flux experiments at 23, 32, and 37 degrees C. Hypothermia of 23 degrees C and 32 degrees C decreased [3H]L-glutamate uptake at 60 min, to 76.7%+/-7.3% (P < 0.05, n = 5) and 70.7%+/-7.5% (P < 0.05, n = 5) of uptake at 37 degrees C, respectively. Reversed uptake of preloaded [3H]L-glutamate via hGLT-1 was not observed at any temperature. The specific uptakes (Q10 values) for 37 degrees C to 32 degrees C and 32 degrees C to 23 degrees C at 30 min were 3.48 and 2.37, whereas they were 2.17 and 0.91, respectively, for 60 min. These changes suggest that hypothermia attenuates uptake of extracellular glutamate via hGLT-1 in a temperature- and time-dependent manner. IMPLICATIONS: Under certain pathologic conditions, including cerebral ischemia and traumatic brain injury, glutamate neurotoxicity may initially be propagated by hypothermia due to relative failure of glutamate uptake via Human Glial Glutamate Transporter before a subsequent recovery of uptake.

ATP-Binding Cassette Transporters↗
PubMed2006

Immunohistochemical localization of glutamate in the gerbil main olfactory bulb using an antiserum directed against glutamate.

Information on the localization and the roles of glutamate in the nervous system is becoming valuable because the axon terminals of the olfactory sensory neurons and the synapses of the mitral and tufted output cells appear to be glutamatergic. In this study, we have analysed the distribution of glutamate immunoreactivity in the main olfactory bulb (MOB) of the Mongolian gerbil using an antiserum directed against glutamate. Glutamate immunoreactivity in the MOB was present in the olfactory nerve layer (Onl), glomerular layer (GL), external plexiform layer (EPL) and mitral cell layer (ML), but not in the granule cell layer (GCL). Glutamate immunoreactivity detected in the Onl was thought to be terminal ramifications of glomeruli. Some neurons in the periglomerular region showed glutamate immunoreactivity. In the EPL, glutamate immunoreactivity was found in some neuronal somata (tufted cells) and processes. In addition, mitral cells in the ML were labelled by the glutamate antibody. The pattern of glutamate immunoreactivity in the mitral cells was similar to that in the tufted cells. In brief, glutamate in the gerbil MOB is the neurotransmitter used by primary afferents and output neurons.

Animals↗
PubMed2004

Nicergoline enhances glutamate uptake via glutamate transporters in rat cortical synaptosomes.

To elucidate the mechanisms of neuroprotective action of nicergoline, we examined its effect on glutamate transport in rat cortical synaptosomes and cloned glutamate transporters. In synaptosomes, nicergoline enhanced the glutamate uptake at 1-10 microM in standard medium and suppressed the increase of extracellular glutamate by reversed transport in low Na(+) medium. Apparent increase of extracellular glutamate concentration by dihydrokinate, an inhibitor of glial glutamate transporter GLT-1, was antagonized by nicergoline. In Xenopus oocytes expressing mouse neuronal glutamate transporter (mEAAC1), the glutamate-induced inward current was enhanced by nicergoline. These results suggest that nicergoline reduces the extracellular glutamate concentration through its effect on glutamate transporters.

Amino Acid Transport System X-AG↗
PubMed1975

Interactions of a glutamate-aspartate binding protein with the glutamate transport system of Escherichia coli.

Escherichia coli cells cultured with succinate as the carbon source display apparent K-m values for the uptake of L-glutamate of 10 muM in the absence of added sodium ion and 0.7 muM in the presence of an optimal level of sodium ion (15 to 50 mM). The glutamate transport system of the succinate cultured cells is noncompetitively inhibited by L-aspartate. A protein which binds glutamate and aspartate with K-D values of 0.7 and 1.2 muM, respectively, is released from the succinate cultured cells by osmotic shock or with the formation of spheroplasts during the preparation of membrane vesicles. The membrane vesicles of succinate cultured cells do not retain the whole cell capacity for L-glutamate uptake, but do retain much of the whole cell capacity for L-aspartate uptake. Culture of E. coli cells with glucose as carbon source causes a 2- to 3-fold repression of glutamate-aspartate binding protein but does not affect the velocity component of glutamate transport. As shown by other workers, the glutamate transport system of glucose cultured cells displays a sodium affected K-m value (FRANK, L., AND HOPKINS, I. (1969) J. Bacteriol. 100, 329-336) and is noncompetitively inhibited by L-aspartate (HALPERN, Y. S., AND EVEN-SHOSHAN, A. (1967) J. Bacteriol. 93, 1009-1016). Membrane vesicles prepared from glucose cultured cells retain the whole cell capacity for the uptake of glutamate (LOMBARDI, J. F., AND KABACK, H. R. (1972) J. Biol. Chem. 247, 7844-7857). The glutamate transport system of E. coli strain W appears to be conditionally dependent on the presence of the osmotic shock-releasable glutamate-aspartate binding protein. The results are interpreted to suggest that the binding protein-ligand complex acts as a substrate which is competitive with unbound substrate(s) for a sodium affected translocation process; the organization and specificity of which are dependent on the carbon source of the culture.

Aspartic Acid↗
PubMed1988

L-glutamate evoked release of GABA from cultured avian retina cells does not require glutamate receptor activation.

gamma-Aminobutyric acid (GABA) and L-glutamate are the major inhibitory and excitatory transmitters in the central nervous system. Recent evidence has indicated that L-glutamate may stimulate GABA release by a novel exchange mechanism (Nascimento and De Mello, J. Neurochem., 1985, 45: 1820-1827). Here we provide strong support for this hypothesis by showing that the L-glutamate-evoked release of [3H]GABA from cultured avian retina cells is not dependent on the activation of excitatory amino acid receptors. Retina cells were found to incorporate [3H]GABA into a pool that was released when cultures were treated with L-glutamate (100 microM). This release was unaffected when calcium ions were removed, but was prevented when NaCl was replaced by LiCl. D-Aspartate, which in tracer experiments was shown to be taken into cells by the same carrier as L-glutamate, was also able to evoke release of [3H]GABA, with the same requirement for NaCl. In addition, L-glutamate and D-aspartate uptake by retina cells was inhibited in more then 80% when the uptake was measured in the presence of LiCl. As opposed to GABA, the release of acetylcholine (ACh) promoted by L-glutamate showed characteristics of classical mechanisms of neurotransmitter release. Glutamate-induced efflux of ACh was Ca2+-dependent and was not affected when NaCl was replaced by LiCl. Also, D-aspartate was ineffective in eliciting the release of ACh. Even at high concentrations, antagonists of excitatory amino acid receptors were unable to diminish the glutamate-evoked release of [3H]GABA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1984

Effect of meal components on peripheral and portal plasma glutamate levels in young pigs administered large doses of monosodium-L-glutamate.

Mean peak plasma glutamate concentrations and area under the plasma glutamate concentration-time curve are much lower in adult humans ingesting monosodium L-glutamate (MSG) in formula than in water. The present study investigated the effects of individual meal components on portal and vena caval plasma glutamate concentration in young pigs administered MSG. Portal vein catheters and gastrojejunal tubes were placed in four young male pigs, and the animals were allowed to recover. Each animal was then administered four water solutions providing 500 mg/kg body weight MSG in a Latin square design. One solution provided only MSG; the second provided MSG and 1 g/kg body weight metabolizable carbohydrate (partially hydrolyzed corn starch); the third provided MSG and 1 g/kg body weight nonmetabolizable carbohydrate (beta-cellobiose); and the fourth provided MSG and 0.4 g/kg body weight of an amino acid mixture (Aminosyn, Abbott Laboratories, North Chicago, Ill). Mean peak plasma glutamate concentration and area under the plasma glutamate concentration-time curve were significantly lower (P less than 0.05) in both portal and vena caval blood when MSG was administered with metabolizable carbohydrate than when administered in water. Simultaneous ingestion of MSG with nonmetabolizable carbohydrate (beta-cellobiose) or amino acids had no significant effect on either mean peak portal or vena caval plasma glutamate concentration or area under the plasma glutamate concentration-time curves when compared to values observed when MSG was administered alone. The data suggest that metabolizable carbohydrate is the meal component affecting plasma glutamate concentration.

Alanine↗
PubMed1984

Glutamate dehydrogenase and a proposed glutamate-aspartate pathway for citrate synthesis in rat ventral prostate.

Glutamate dehydrogenase activity was determined in mitochondrial preparations from rat ventral prostate and rat kidney. Kinetic parameters of the ventral prostate enzyme were comparable to those for the kidney enzyme. Glutamate dehydrogenase activity in the direction of glutamate oxidative deamination was inhibited by alpha-ketoglutarate. However, the characteristics of alpha-ketoglutarate inhibition indicated that glutamate oxidation via glutamate dehydrogenase can occur at in vivo prostatic alpha-ketoglutarate levels. These results suggest that glutamate dehydrogenase activity in prostate may provide a continuous source of alpha-ketoglutarate for aspartate transamination to oxalacetate and ultimate citrate synthesis. In addition prostate mitochondria are able to couple the glutamic dehydrogenase reaction to aspartate aminotransferase. Under these conditions aspartate in the presence of glutamate and acetyl coenzyme A will result in a net synthesis of citrate. Consequently we propose an aspartate-glutamate pathway for citrate synthesis in prostate.

Acetyl Coenzyme A↗
PubMed2000

Glutamate-mediated neuroprotection against N-methyl-D-aspartate toxicity: a role for metabotropic glutamate receptors.

We studied N-methyl-D-aspartate-induced cell death in organotypic hippocampal slices from seven-day-old Wistar rat pups cultured for 12-14 days in a medium containing no added glutamate. Propidium iodide fluorescence intensity was used as an indicator of cell death measured with the help of confocal microscopy. Exposure of slices for 2h to L-glutamate (1-500 microM) prior to the N-methyl-D-aspartate challenge significantly reduced N-methyl-D-aspartate-induced cell death. Glutamate at 10 and 500 microM concentrations was highly protective against N-methyl-D-aspartate-induced cell death, but was less protective at the 1 microM concentration. The protection was not blocked by the Na(+) channel blocker tetrodotoxin (1 microM), the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoic acid (20 microM) or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM). 1S, 3R-1-Aminocyclopentane-trans-1,3-dicarboxylic acid, an agonist at metabotropic glutamate receptor types 1, 2/3 and 5, was protective at 100 microM but not at 50 microM. In contrast, the ionotropic glutamate receptor agonist aspartate (250 microM) facilitated N-methyl-D-aspartate toxicity. Treatment of slices with the protein kinase C inhibitor staurosporine (0.2 microM) or antisense oligonucleotide (10nM, 72 h) that selectively inhibits metabotropic glutamate receptor type 5 synthesis significantly reduced glutamate protection. These results suggest that ambient glutamate may reduce nerve cell susceptibility to injury caused by excessive N-methyl-D-aspartate receptor activation by acting at metabotropic glutamate receptors linked to protein kinase C.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

L-glutamate uptake inhibitors may stimulate phosphoinositide hydrolysis in baby hamster kidney cells expressing mGluR1a via heteroexchange with L-glutamate without direct activation of mGluR1a.

The functional efficacies of inhibitors of L-glutamate uptake for altering second messenger formation in baby hamster kidney cells expressing subtypes mGluR1a, mGluR2, and mGluR4 of the metabotropic glutamate receptor family were examined. L-Serine-O-sulfate was an agonist at mGluR1a (EC50 = 70 microM), mGluR2 (EC50 = 25 microM), and mGluR4 (EC50 = 324 microM). L-Cysteine sulfinate, 1-aminocyclobutane-trans-1,3-dicarboxylate, L-cysteine, and DL-threo-3-methylaspartate stimulated phosphoinositide hydrolysis in mGluR1a cells with EC50 values of 43, 64, 463, and 488 microM, respectively, and displaced L-[3H]glutamate binding from membranes prepared from these cells with respective IC50 values of 48, 44, 79, and 139 microM. However, D-aspartate, L-trans-pyrrolidine-2,4-dicarboxylate, L-threo-3-hydroxyaspartate, and L-aspartate-beta-hydroxamate stimulated phosphoinositide hydrolysis in mGluR1a cells (respective EC50 values of 73, 54, 57, and 430 microM) but did not displace L-[3H]glutamate binding. These compounds inhibited Na(+)-dependent L-glutamate uptake into baby hamster kidney cells with IC50 values similar to those for stimulation of phosphoinositide hydrolysis in mGluR1a cells. Phosphoinositide hydrolysis in mGluR1a cells, as stimulated by inhibitors of (or substrates for) this L-glutamate transporter, was significantly attenuated in the presence of L-glutamate decarboxylase (EC 4.1.1.15) or L-alanine aminotransferase (EC 2.6.1.2). Furthermore, incubation with 1 mM L-trans-pyrrolidine-2,4-dicarboxylate for 30 min increased the basal levels of free glutamate (1.5 +/- 0.2 microM) in the assay buffer four- to fivefold as measured by HPLC analysis. Thus, heteroexchange with endogenous L-glutamate may lead to erroneous estimations of the functional efficacies at mGluR1a.

Alanine Transaminase↗
PubMed1989

Activation of glutamate by gamma-glutamate kinase: formation of gamma-cis-cycloglutamyl phosphate, an analog of gamma-glutamyl phosphate.

gamma-Glutamate kinase, the enzyme that catalyzes the first step in the pathway from glutamate to proline, has been postulated to convert glutamate to a gamma-activated form (possibly gamma-glutamyl phosphate), which is reduced by a NADPH-linked reductase to yield glutamate gamma-semialdehyde (in equilibrium with delta 1-pyrroline-5-carboxylate). In the present work we found that the kinase, in the absence or presence of the reductase (and in the absence of NADPH), catalyzes stoichiometric formation of 5-oxo-L-proline and Pi from L-glutamate and ATP, but catalyzes hydroxamate formation at only about 10% of the rate of ATP-cleavage. A new substrate of the kinase was found; thus, cis-cycloglutamate (cis-1-amino-1,3-dicarboxycyclohexane), a glutamate analog which cannot cyclize to form an analog of 5-oxoproline, interacts effectively with the kinase. The trans form of cycloglutamate does not interact with the kinase; only the cis form can assume a diequatorial conformation equivalent to the extended conformation of glutamate. cis-Cycloglutamyl phosphate formation was shown and evidence was obtained for formation of an enzyme-ADP-cycloglutamyl phosphate complex. Although cis-cycloglutamyl phosphate is not a reducible substrate of the NADPH-dependent reductase, the findings indicate that it interacts with the reductase. These studies, which elucidate several aspects of the mechanism of the utilization of glutamate for formation of delta 1-pyrroline-5-carboxylate, support the hypothesis that the kinase and reductase function as an enzyme complex. A model is suggested in which gamma-glutamyl phosphate formed on the kinase interacts with the reductase to form a gamma-glutamyl-reductase complex, which is reduced by NADPH to yield glutamate gamma-semialdehyde.

Adenosine Diphosphate↗
PubMed2000

N-methyl-D-aspartate but not glutamate induces the release of hydroxyl radicals in the neonatal rat: modulation by group I metabotropic glutamate receptors.

Although they likely involve activation of N-methyl-D-aspartate (NMDA) receptors, the mechanisms giving rise to perinatal hypoxic-ischemic-induced damages remained unclear. The purpose of the present study was to investigate in vivo the mechanisms regulating the glutamate-induced release of toxic hydroxyl radicals (.OH) in neonatal rat. Anesthetized 7-day-old Wistar rat pups bearing a microdialysis cannula implanted in the striatum were perfused with a solution containing salicylate as an.OH trap. Hydroxyl radicals formation was evaluated, after a 3 hr postoperative delay, by measuring the 2,3-DHBA levels by HPLC/EC before, during and over 3 hr after the administration of glutamatergic agonists or antagonists. Administration of NMDA and of ibotenate dramatically increased the efflux of.OH, 17-fold and sixfold, respectively. Glutamate, used at the same concentration did not produce any significant increase in the.OH release and may even decrease this efflux when given at larger concentrations. The NMDA-induced.OH response was partially but progressively reduced by glutamate coinjection and completely blunted by DHPG [(RS)-3, 5-dihydroxyphenylglycine], a group I metabotropic glutamate receptor agonist. Conversely, AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid], an antagonist of the same receptors, unmasked an.OH response to glutamate. These results are evidence that the glutamate-induced activation of a group I metabotropic glutamate receptor normally protected the neonatal brain from any glutamate activation of NMDA receptor, which otherwise would produce the release of toxic hydroxyl radicals. Targeting group I metabotropic glutamate receptors and/or.OH might contribute to protecting the neonatal brain against perinatal hypoxic-ischemic induced lesions.

Animals↗
PubMed1999

Circadian variations in plasma and erythrocyte concentrations of glutamate, glutamine, and alanine in men on a diet without and with added monosodium glutamate.

Variations in plasma and erythrocyte concentrations of glutamate, glutamine, and alanine during the day were studied in 10 healthy men fed ordinary Taiwanese meals, first without and, 1 week later, with monosodium glutamate (MSG) added. MSG at a level of 15, 40, and 45 mg/kg (total, 100 mg/kg/d) was added, respectively, to the breakfast, lunch, and dinner meals. Heparinized blood samples were collected over 24 hours with 1- to 3-hour intervals. In both trials, plasma glutamate concentrations increased significantly after lunch and dinner. Although the circadian variations of plasma glutamate were small (between 32 and 53 micromol/L), the levels nevertheless varied significantly as a function of the time of day in both trials. Considering that the dietary intake of glutamate was high when MSG was added, the low plasma glutamate concentration over 24 hours indicates that glutamate is actively metabolized. On the other hand, the concentrations of erythrocyte glutamate (507 to 631 micromol/L) and glutamine (427 to 613 micromol/L) did not show a significant postprandial increase or circadian variation. Nevertheless, the concentration of plasma glutamine (539 to 657 micromol/L) varied significantly as a function of time in both trials. The plasma concentration of alanine (274 to 494 micromol/L) increased significantly after each meal and decreased significantly from 2:00 to 5:00 AM in both trials. Both plasma and erythrocyte alanine concentrations varied significantly as a function of time. These results show that the substantial amount of MSG intake had no apparent effect on the circadian variation profiles of blood glutamate, glutamine, and alanine.

Adult↗
PubMed2002

Intraplantar injection of glutamate evokes peripheral adenosine release in the rat hind paw: involvement of peripheral ionotropic glutamate receptors and capsaicin-sensitive sensory afferents.

Glutamate receptors have been identified on the peripheral terminals of both primary sensory afferents and sympathetic post-ganglionic neurons, and activation of these receptors produces peripheral sensitization and enhances nociception. Adenosine is an endogenous agent that has a regulatory effect on pain. In brain and spinal cord, adenosine release can be promoted by excitatory amino acids. In the present study, we used in vivo microdialysis to determine whether glutamate also can release adenosine in peripheral tissues. Rats were anesthetized with pentobarbital and microdialysis probes were implanted into the subcutaneous tissue of the plantar aspect of the rat hind paw. Subcutaneous injection of glutamate (50 microL, 0.3-100 micromol) evoked a short-lasting adenosine release immediately following drug injection. Co-administration of either the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocipine maleate (MK-801, 1 nmol) or the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline (CNQX, 10 nmol) with glutamate blocked such release, suggesting an involvement of peripheral ionotropic glutamate receptors in this response. Systemic pre-treatment with capsaicin, a neurotoxin selective for unmyelinated sensory afferents, significantly reduced glutamate-evoked peripheral adenosine release, but release was not affected by systemic pre-treatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic nerve efferents. Neither MK-801 nor CNQX blocked 5% formalin-evoked adenosine release, suggesting adenosine release by formalin is not secondary to ionotropic glutamate receptor activation. We conclude that administration of glutamate evokes peripheral adenosine release, and that peripheral ionotropic glutamate receptors on unmyelinated sensory afferents are involved in such release. The released adenosine may provide a negative feedback control on nociception.

Adenosine↗