Potent Glutamate Research Articles

Postoperative psychosis in homocystinuria

Young homocystinuria patients suffering from lens dislocation frequently have to undergo eye surgery. We describe a 16-year-old girl with mild mental retardation who became psychotic-delirant immediately after the last of three lentectomia operations performed under general thiopental anaesthesia. Because methionine, homocysteine, its oxidation product homocysteate and cysteine are potent glutamate agonists, the disturbance of the sulphur containing amino acid (SCAA) metabolism in homocystinuria patients may alter the function of cerebral glutamatergic transmission. The chronic and acute neurological and psychiatric symptoms of homocystinuria patients offer a clue to studies of the neurotoxic but also antipsychotic potency of glutamate agonists like the SCAAs in humans.

Failure of glycine site NMDA receptor antagonists to protect against l-2-chloropropionic acid-induced neurotoxicity highlights the uniqueness of cerebellar NMDA receptors

Cultured cerebellar granule cells and cerebellar slices from neonatal rats have been widely used to examine the biochemistry of excitatory amino acid-induced cell death mediated in part by the activation of NMDA receptors. However, the NMDA subunit stoichiometry, producing functional NMDA receptors is different in cultured granule cells, neonatal and adult rat cerebellum as compared to the NMDA receptors in forebrain regions. We have used the l-2-chloropropionic acid ( l-CPA) (750 mg/kg) model of NMDA-medialed selective cerebellar granule cell necrosis in vivo to examine the role of the glycine binding site and possible effect of the NR2C subunit (which is largely expressed only in the cerebellum) on granule cell necrosis. The abilities of various NMDA receptor antagonists were examined in vivo to determine the relative contribution of both glutamate and glycine sites involved in the l-CPA-induced neurotoxicity. The potent neuroprotective, non-competitive NMDA receptor antagonist dizocilpine (MK-801) was compared with glutamate and glycine site NMDA antagonists. We have examined a number of markers for the l-CPA-induced granule cell necrosis. The l-CPA-induced reduction in cerebellar aspartate and glutamate concentrations were used as markers of granule cell necrosis. We also measured the cerebellar water content and sodium concentrations as measures of the l-CPA-induced cerebellar edema that accompanies the granule cell necrosis. Finally the ability of the NMDA antagonists to attenuate the l-CPA-induced reductions in body weight gain and the prevention of the loss in hindlimb function using a behavioral measure of hindlimb retraction were examined. The potent glutamate antagonists, CPP and CGP40116 and dizocilpine prevented the l-CPA-induced locomotor dysfunction and granule cell necrosis as measured by their ability to prevent l-CPA-induced reductions in aspartate and glutamate concentrations. CPR CGP40116 and dizocilpine also prevented the appearance of cerebellar edema following l-CPA administration. In addition, dizocilpine, CPP and CGP40116 were able to partially prevent the l-CPA-induced loss in body weight over the 48 h experimental period. In contrast, none of the glycine partial agonists or antagonists, namely (±)HA-966, d-cycloserine, MDL-29951, DPCQ, MNQX or L-701 252 were able to prevent the l-CPA-induced loss in body weight, l-CPA-induced granule cell necrosis and behavioral disturbances when administered to rats. None of the NMDA antagonists had any effect on the cerebellar neurochemistry when injected alone or had any effect on animal behavior except for dizocilpine, CPP, CGP401 l6 and (±)HA-966 which resulted in a transient sedation for between three and five hours immediately following their administration. In conclusion, we demonstrate that NMDA open channel blockade and glutamate antagonists can provide full neuroprotection against the l-CPA-induced granule cell necrosis. The failure of the glycine partial agonists and antagonists to provide any neuroprotection against l-CPA-induced neurotoxicity in the cerebellum contrasts with their neuroprotective efficacy in other animal models of excitatory amino acid-induced cell death in forebrain regions in vivo. We therefore suggest that the glycine site plays a lesser role in modulating NMDA receptor function in the cerebellum and may explain why cells expressing NMDA receptors composed of NR1/NR2C subunits are particularly resistant to excitatory amino acid-induced neurotoxicity.

The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures.

Because of the well-documented importance of glutamate uptake in protecting neurons against glutamate toxicity, we were interested in testing the effects of L-trans-pyrrolidine-2,4-dicarboxylate (PDC) on rat cortical cultures. This compound is a substrate for glutamate transporters and is a potent glutamate transport inhibitor that does not interact significantly with glutamate receptors. Using a 30 min exposure, and assessing neuronal survival after 20-24 h, PDC was neurotoxic in conventional astrocyte-rich cortical cultures, with an EC50 in these cultures of 320 +/- 157 microM. In astrocyte-poor cultures, an EC50 for PDC of 50 +/- 5 microM was determined. The neurotoxicity of PDC in both astrocyte-rich and astrocyte-poor cultures was blocked by the NMDA antagonist MK-801, but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). We tested the possibility that the neurotoxicity of PDC might be due to release of excitatory amino acids using several approaches. After pre-loading cells with the non-metabolizable analogue of glutamate, [3H]-D-aspartate, first we demonstrated that PDC caused significant efflux of [3H]-D-aspartate. This effect of PDC was dependent upon extracellular sodium. In contrast with glutamate neurotoxicity, PDC neurotoxicity was inhibited by removal of extracellular sodium. In the presence of 1 mM PDC, sodium caused neurotoxicity with an EC50 of 18 +/- 7.6 mM. Tetrodotoxin had no effect on either PDC neurotoxicity or on PDC-evoked [3H]-D-aspartate release. PDC-evoked release of [3H]-D-aspartate was demonstrable in astrocyte cultures with no neurons present. PDC also evoked release of endogenous glutamate. Finally, the neurotoxicity of PDC was blocked by coincubation with glutamate-pyruvate transaminase plus pyruvate to degrade extracellular glutamate. These results demonstrate the neurotoxicity of PDC, and suggest that the mechanism of this toxicity is the glutamate transporter-dependent accumulation of glutamate in the extracellular space.

Real-time imaging of intrinsic optical signals during early excitotoxicity evoked by domoic acid in the rat hippocampal slice

Excitotoxicity involves neuronal depolarization and eventual cell death primarily through excess activation of glutamate receptors. Neuronal cell swelling is considered an early excitotoxic event mediated by ionic influx (mainly Na+ and Cl-) followed by water. Changes in the intrinsic optical signals of nerve tissue correlate with neuronal activity such that light transmittance (LT) increases across the brain slice as cells swell. The present study examined the effects of domoic acid, a potent excitotoxic food contaminant and glutamate analogue, on intrinsic optical signals in the rat hippocampal slice. A brief 1-min exposure to 10 microM domoate at 22 degrees C elevated LT by 58% in the apical dendritic region of CA1 and to a lesser extent in the molecular layer of the upper dentate gyrus. The responses peaked by 5 min and slowly reversed during a 30-min wash. The same responses were evoked by a 1-min application of 10 microM alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) at 22 degrees C. Minor changes were observed in the CA3 region and the lower blade of the dentate gyrus. At 37 degrees C, exposure to 10 microM domoate for 10 min resulted in apparent irreversible neuronal damage in the CA1 and upper dentate regions. The Na+ channel blocker tetrodotoxin (1 microM) eliminated the evoked CA1 population spike but not the LT increase, indicating that the domoate signal is not associated with action potential discharge pre- or post-synaptically. However, the response to domoate at 22 degrees C was reversibly blocked by the nonspecific glutamate receptor antagonist kynurenate and the non-N-methyl-D-aspartate (non-NMDA) receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). The response was not blocked by the NMDA receptor antagonist 2-amino-5-phosphonovaleate (AP-5) nor the kainate receptor blocker gamma-D-glutamylaminomethyl sulfonate (GAMS). Relative tissue resistance (RREL) measured across the CA1 dendritic region increased rapidly in response to domoate and fell slowly over 30 min, which paralleled the LT response described above. The increase in RREL was blocked by kynurenate. We propose that domoate binding to AMPA receptors opens channels mediating ionic influx, presumably Na+ followed passively by Cl-. Water follows, producing prolonged postsynaptic swelling in the CA1 and dentate regions where AMPA receptors are most abundant. At higher temperature this swelling can progress to permanent neuronal injury. Imaging intrinsic optical signals allows a real-time view of early excitotoxic events and may prove useful in assessing potentially therapeutic agents that reduce damage induced by excitotoxic agents or ischemia.

Contributing mechanisms for cysteine excitotoxicity in cultured cerebellar granule cells.

Several possible mechanisms for cysteine toxicity on rat cerebellar granule cells were studied and compared with the excitotoxic effect of glutamate. It was shown that the excitotoxic potency of both cysteine and glutamate increased in the presence of elevated concentrations of bicarbonate or increased pH. Pharmacological studies showed that the cysteine toxicity was specifically coupled to the NMDA receptor, whereas the glutamate toxicity was mediated to a smaller extent also by non-NMDA receptors. Treatment of cerebellar granule cells with cysteine led to an increased extracellular level of glutamate. In addition, cysteine sensitized NMDA receptors by reducing disulfide bonds in the receptor to sulfhydryl groups. A mechanism for cysteine excitotoxicity may therefore be formation of cysteine-sensitized NMDA receptors that are stimulated either by cysteine and/or by endogenous glutamate. This mechanism may also be important for the effects observed during regulated physiological release of cysteine.

Characterization of glutamate toxicity in cultured rat cerebellar granule neurons at reduced temperature.

We have defined conditions whereby glutamate becomes toxic to isolated cerebellar granule neurons in a physiologic salt solution (pH 7.4). In the presence of a physiologic Mg++ concentration, acute glutamate excitotoxicity manifests only when the temperature was reduced from 37 degrees C to 22 degrees C. In contrast to glutamate, N-methyl-D-aspartate (NMDA) was nontoxic at either temperature at concentrations as high as 1 mM. Glycine strongly potentiated both the potency and efficacy of glutamate but revealed only a modest NMDA response. The non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxalinedione (CNQX), potently protected against glutamate challenge, although the contribution of antagonism at strychnine-insensitive glycine sites could not be excluded. To further characterize the non-NMDA receptor contribution to the excitotoxic response, the promiscuity of glutamate interaction with ionotropic receptors was simulated by exposing neurons to NMDA in the presence of non-NMDA receptor agonists. NMDA toxicity was potentiated four- to sevenfold when non-NMDA receptors were coactivated by a subtoxic concentration of AMPA, kainate, or domoate. These results suggest that non-NMDA receptor activation participates in the mechanism of acute glutamate toxicity by producing neuronal depolarization (via sodium influx), which in turn promotes the release of the voltage-dependent magnesium blockade of NMDA receptor ion channels.

Practical, convergent total synthesis of polyamine amide spider toxin NSTX-3

A practical, total synthesis of polyamine amide spider toxin NSTX-3, a potent glutamate receptor antagonist with potential as a neuroprotective agent, is reported. The unsymmetrical polyamine motiety was built by a conjugate addition to afford putreamine and regioselective acylation of L-asparaginyl-cadaverine.

Toxic NMDA‐Receptor Activation Occurs During Recovery in a Tissue Culture Model of Ischemia

In some animal models of reversible ischemia, there is a therapeutic window during early recovery when glutamate receptor antagonists can rescue neurons from injury. We have previously reported that organotypic cultures of the hippocampus can be protected by NMDA-receptor antagonists during recovery from a brief period of simulated ischemia. To model ischemia, we have used potassium cyanide to inhibit oxidative metabolism and 2-deoxyglucose to inhibit glycolysis. To study the time course and mechanisms of delayed NMDA-receptor toxicity in more detail, we have extended these studies to dissociated cortical cultures. Injury was assessed by release of lactate dehydrogenase into the culture medium. Metabolic inhibition for 15 min caused dose-dependent injury. Morphologic signs of neuronal toxicity were delayed until the recovery period. MK-801 reduced injury significantly when present throughout the experiment. Surprisingly, MK-801 provided the same protection when administration was delayed until after the end of the metabolic inhibition, blocking NMDA receptors only during recovery. To examine NMDA toxicity during metabolic inhibition, the competitive NMDA-receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid was added during exposure. The protective effect of NMDA-receptor blockade was completely lost if the antagonist was removed during 1 min of continuing selective inhibition of oxidative metabolism. The toxic potency and effectiveness of glutamate were enhanced during metabolic inhibition, showing that receptors were not inactivated by simulated ischemia. These results are consistent with the specific hypothesis that return of oxidative metabolism triggers a critical period of toxic NMDA-receptor activation.

Transient functional connections between the developing corticospinal tract and cervical spinal interneurons as demonstrated by c- fos immunohistochemistry

Previous research on the rat corticospinal tract (CST) which develops mainly postnatally revealed that some CST axons grow transiently into the spinal gray matter and are subsequently eliminated. In the present study the question was addressed whether these fibres also form transient functional connections. Rats aged 14 and 60 days postnatally received unilateral injections of the potent glutamate agonist kainate into the cerebral motor cortex. After a survival period of 90 min. the rats were perfused and their brains and spinal cords processed for the immediate early gene c- fos by immunobistochemistry. Increased levels of c- fos as opposed to sham-operated animals was observed in several brain nuclei as well as in the cervical spinal cord. In the spinal gray one population of labelled interneurons in particular appeared to correlate well with the CST projection field. A decrease was noted in the number of c- fos positive neurons from postnatal day 14 to 60, suggesting that during development transient functional connections are formed between the CST and its target.

Intracerebral microdialysis combined with recording of extracellular field potential: a novel method for investigation of depolarizing drugs in vivo.

1. The purpose of this study was to examine whether depolarizations evoked by excitatory amino acids can be recorded quantitatively, in vivo, with a microelectrode incorporated within a microdialysis probe. 2. Microdialysis probes incorporating a chlorided silver wire were implanted in the striatum of anaesthetized rats and perfused with artificial cerebrospinal fluid (ACSF). Increasing concentrations of excitatory amino acids were applied for 2 min via the microdialysis probe, and the extracellular direct current (d.c.) potential was recorded between the microdialysis electrode and a reference electrode placed under the scalp. 3. N-methyl-D-aspartate (NMDA, 25-500 microM), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, 5-1000 microM), kainate (5-500 microM), and glutamate (0.25-100 mM) evoked concentration-dependent depolarizations with maxima ranging from 7 to 10 mV, i.e. 3 to 10 times larger than those recorded from brain slices in vitro. Depolarizations evoked by glutamate receptor agonists applied by microdialysis shared several features with those recorded from brain slices. The most characteristic were: steep onset and recovery of NMDA and glutamate responses; marked post-depolarization hyperpolarization with NMDA; and very slow recovery after kainate application. At high concentrations (500 microM), NMDA occasionally initiated spreading depression. The relative potency of glutamate and NMDA was of the same order of magnitude to that obtained with the cortical wedge and hippocampal slices, glutamate being 100 to 400 times less potent than NMDA. 4. Two consecutive series of NMDA-stimuli within the same procedure evoked comparable depolarizations, indicating that reliable quantitative analysis of drug action can be performed, with each animal serving as its own control. This is relevant to the study of drugs acting on glutamate receptors especially antagonists. The remarkable inter-animal reproducibility is also a valuable feature.5. Pretreatment with dizocilpine maleate (MK-801, 2mgkg'1, i.p.) reduced by 65% the responses evoked by NMDA (500 fM). The non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX,100 1M) applied via the microdialysis probe reduced by around 78% the responses to AMPA and kainate (250 micro M). The fact that drugs, especially antagonists, can be administered either systemically, or directly through the dialysis probe to by-pass the blood-brain barrier or avoid peripheral effects, is especially relevant for neuropharmacological studies.6. Intracerebral microdialysis combined with in vivo recording of extracellular field potential is a novel and valuable method for the quantitative analysis of the action of drugs acting on glutamate receptors.This method should prove especially useful for comparing the sensitivity of specific brain structures to selective glutamate receptor agonists under normal conditions and when the neuronal micro environment is altered. It should also be useful for investigating the action of other depolarizing agents, such as veratridine, and their antagonists.

Electrophysiologically potent non-competitive glutamate antagonists at crayfish neuromuscular junctions are also potent inhibitors of [ 3H]MK801 binding to synaptic membranes from rat central nervous system

This paper describes effects of non-competitive glutamate antagonists, also known as “glutamate open channel blockers”, at crayfish neuromuscular junctions, on the binding of [ 3H]glutamate, [ 3H]CPP, [ 3H]AMPA, [ 3H]kainate and [ 3H]MK-801 to Triton-treated rat hippocampal synaptic membranes, and [ 3H]MK-801 to Triton-treated synaptic membranes from young rat spinal cord. The compounds tested were oxymatrine, theanine, diltiazem, chlorisondamine, tuberostemonine, trimethaphan, N 2- dansyl- L-arginine -4-t-butylpiperidi amide (TI 233), (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperid-inopropyl amino) hexane-1-ol (MLV-5860) and (4S,5R)-4-(2-methylpropyl)-3-[3-(perhydroazepin-1-yl)propyl]-5-phenyl-1, 3-oxazoline-2-one (MLV-6976). Among compounds tested, MLV-5860, MLV-6976 and TI 233 potently inhibited the binding of [ 3H]MK-801 to Triton-treated rat hippocampal synaptic membranes, but not that of other 3H-labelled ligands. The inhibitory potency of MLV-6976 and MLV-5860 on the binding of [ 3H]MK-801 was similar to that of MK-801. MLV-6976 could also inhibit the inhibitory potency was similar to MK-801. These results suggest that potent glutamate antagonists, acting as open channel blockers at crayfish neuromuscular junction, may have similar pharmacological properties to MK-801 at the mammalian central nervous system, but the reverse may not always be true.

Active accumulation of glutamate and aspartate by insect epidermal cells

Similar and high concentrations of most amino acids are present in the blood plasma and tissues of insects. Plasma levels of the dicarboxylated amino acids glutamate and aspartate, however, are much lower than tissue levels. Plasma concentrations may be regulated by tissues such as the epidermis which is able to accumulate and retain glutamate and aspartate against strong concentration gradients. When larval epidermis from the mealworm Tenebrio molitor was exposed to 250 μM concentrations of these two amino acids in saline, tissue concentrations climbed within 3 h from 7.3 to 45 mM for glutamate and from 0.9 to 31 mM for aspartate. At this concentration the uptakes for glutamate and aspartate were estimated to be 5.5 and 4.7 pmol amino acid/mm 2 tissue/min. Tissue swelling occurs during amino acid accumulation, implying that the epidermis is osmotically stressed by the treatment. Other protein amino acids tested at micromolar concentrations were not concentrated by the epidermis. Glutamate and aspartate taken up by the epidermis were converted into other amino acids, the dominant transamination products being aspartate on tissue exposure to glutamate, and glutamate and alanine on exposure to aspartate. The synthesis of small amounts of β-alanine, but not of glutamine, asparagine or proline, was also detected. Glutamate is an important neurotransmitter, and aspartate a potent glutamate agonist, at the neuromuscular synapse in insects. The primary role of the transport system for glutamate and aspartate may be to keep their plasma levels below the synaptic threshold, rather than to supply the epidermis with its metabolic requirements for these amino acids.

346 Neurotoxicity of a novel and potent metabotropic glutamate receptor agonist, DCG-IV

346 Neurotoxicity of a novel and potent metabotropic glutamate receptor agonist, DCG-IV

Glutamate Toxicity: An Experimental and Theoretical Analysis.

In slices of 8-day-old rat cerebellum, the lowest concentration of glutamate that induced toxicity (30 min exposure; 90 min recovery) was 100 microM, but the damage only occurred in the outermost regions. As the concentration was raised, the band of necrosis became progressively deeper until, at 3 mM, it was uniform across the slice thickness. At a test concentration of 300 microM, the width of the necrotic band did not change when either the exposure time or the recovery period was varied between 30 min and 3 h. These results are predicted by a theoretical model in which the diffusion of glutamate into brain tissue is countered by cellular uptake of the amino acid, and they argue against the idea that glutamate toxicity is inherently self-propagating. When slices were examined immediately after exposure (300 microM), a prominent swelling of glial cells was present at the slice surface. Swelling per se did not appear to compromise their uptake function, and the model predicts that cellular swelling, by reducing the rate of diffusion of glutamate, protects against glutamate toxicity. The damage produced by 3 mM glutamate, which was primarily exerted against granule cells, was prevented by N-methyl-d-aspartate (NMDA) receptor blockade, whereas antagonists acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors were ineffective. Under conditions of energy deprivation, the neurotoxic potency of glutamate was markedly enhanced and a normally non-toxic concentration (30 microM) became maximally toxic towards granule cells. Dark vacuolar degeneration of Purkinje cells was also present, and this could be inhibited by blocking AMPA receptors. The results and theoretical analysis suggest that intact brain tissue is remarkably resistant to glutamate toxicity, chiefly because of the formidable properties of the uptake system. However, under special circumstances, glutamate can become a potent neurotoxin and its toxicity can then involve both NMDA and AMPA receptors.

Reduced NMDA receptor-ion channel function in the vitamin B-6 restricted neonatal rat brain

We have measured the binding of [ 3H]-MK-801 to cortical and hippocampal membrane preparations from the vitamin B-6 restricted neonatal rat. The results indicate a reduced potency and efficacy of glutamate and glycine in enhancing [ 3H]-MK-801 binding to the N-methyl- D-aspartate (NMDA) receptor-ion channel. Scatchard analysis of [ 3H]-MK-801 binding isotherms showed a significantly lower number of [ 3H]-MK-801 binding sites in the cortex and hippocampus of vitamin B-6 restricted rats. These results indicate a reduced function of the NMDA receptor-ion channel in the brain of these animals.

Patterns of glutamate immunoreactivity in the goldfish retina

Postembedding silver-intensified immunogold procedures reveal high levels of glutamate immunoreactivity in "vertical" elements of the goldfish retina: (1) Red-sensitive and green-sensitive cones display strong glutamate immunoreactivity, especially in their synaptic terminals, but blue-sensitive cones are poorly immunoreactive. (2) All type Mb (on-center) and Ma (off-center) mixed rod-cone bipolar cells and all identifiable cone bipolar cells are highly glutamate immunoreactive. We find no evidence for bipolar cells that lack glutamate immunoreactivity. (3) The majority of the somas in the ganglion cell layer and certain large cells of the amacrine cell layer resembling displaced ganglion cells are strongly glutamate immunoreactive. (4) Despite their high affinity symport of acidic amino acids, the endogenous levels of glutamate in Müller's cells are among the lowest in the retina. (5) GABAergic neurons possess intermediate levels of glutamate immunoreactivity. Quantitative immunocytochemistry coupled with digital image analysis allows estimates of intracellular glutamate levels. Photoreceptors and bipolar and ganglion cells contain from 1 to 10 mM glutamate. The bipolar and ganglion cell populations maintain high intracellular glutamate concentrations, averaging about 5 mM, whereas red-sensitive and green-sensitive cones apparently maintain lower levels. Importantly, photoreceptor glutamate levels are extremely volatile, and in vitro maintenance is required to preserve cone glutamate immunoreactivity in the goldfish. GABAergic horizontal and amacrine cells contain about 0.3-0.7 mM glutamate, which matches the values predicted from the Km of glutamic acid decarboxylase. Müller's cells and non-GABAergic amacrine cells contain less than 0.1 mM glutamate. Though Müller's cells are known to possess potent glutamate symport, they clearly possess equally potent mechanisms for maintaining low intracellular glutamate concentrations.

Invertebrate Pharmacological Assay of Novel, Potent Glutamate Antagonists: Acylated Spermines

Invertebrate Pharmacological Assay of Novel, Potent Glutamate Antagonists: Acylated Spermines

Generation of inositol phosphates, cytosolic Ca 2+ and secretion of noradrenaline in PC12 cells treated with glutamate

Glutamate transiently stimulated rat pheochromocytoma PC12 cells and caused an inositol trisphosphate formation and an increase in levels of Ca + in the cytosol. The rank order of potency of glutamate > N-methyl-D-aspartate (NMDA) > kainate = quisqualate is characteristic of an interaction with NMDA receptors. The effect of glutamate on inositol trisphosphate formation disappeared in a low Mg 2+ buffer and was not blocked by DL-2-amino-5-phosphonovalerate, an antagonist for NMDA receptors coupled to ion channels. Although glutamate failed to stimulate noradrenaline secretion, glutamate enhanced the effect of bradykinin, but not of Ca ionophore A23187, or KC1. These results suggest the existence of metabotropic glutamate receptors, different from previously reported receptors, in PC12 cells.

Invertebrate pharmacological assay of novel, potent glutamate antagonists: acylated spermines

Invertebrate pharmacological assay of novel, potent glutamate antagonists: acylated spermines

Invertebrate pharmacological assay of novel, potent glutamate receptor antagonists: Acylated spermines

AbstractSynthetic analogues of arthropod polyamine‐containing toxins have been investigated for antagonism of the quisqualate‐sensitive L‐glutamate receptor (quis‐GluR) of locust muscle. Block of the cation‐selective channel gated by quis‐GluR was demonstrated for N‐(4‐hydroxyphenylpropanoyl)‐and N‐(4‐hydroxyphenylacetyl)‐spermine at significantly lower concentrations than that for spermine.