Kainic Acid Inhibits the Synaptosomal Plasma Membrane Glutamate Carrier and Allows Glutamate Leakage from the Cytoplasm but Does Not Affect Glutamate Exocytosis

Pocock, Jennifer M.; Murphie, H; Nicholls, David G.

doi:10.1111/j.1471-4159.1988.tb02977.x

Cited by 65 publications

(32 citation statements)

References 18 publications

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“…However, there is also evidence that KAinduced blockade of Glu/Asp uptake can be a primary event in producing an increase in extracellular Glu and Asp (Lakshamanan et al, 1974;McGeer et al, 1978;Johnston et al, 1979;Krespan and Padmanaban, 1982;Pastuszko et al, 1984). Along these lines, one recent report in cerebrocortical synaptosomes presented evidence for a slow leak of Glu or Asp and showed that KA could potentiate this Caz+-independent net efflux of Glu and Asp apparently by inhibiting reuptake; in that system, KA did not affect Caz+-dependent synaptic release of endogenous Glu (Pocock et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro

1991

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Under defined culture conditions, exogenous glutamate (Glu), NMDA, or an endogenous Glu-related toxin is lethal to rat retinal ganglion cells; these detrimental effects are NMDA receptor mediated because specific NMDA antagonists can prevent cellular injury. In the presence of an endogenous Glu-like toxin, 125 microM kainate (KA) increases the proportion of retinal ganglion cells that die, but the toxicity (due to both KA and the endogenous toxin) is totally prevented by 2-amino-5- phosphonovalerate (APV), a specific NMDA receptor antagonist. These findings indicate that the KA-induced portion of retinal ganglion cell death also appears to be mediated via NMDA receptors. There are at least 2 possible mechanisms for this lethal effect. In addition to KA receptors, KA could directly stimulate NMDA receptors. Alternatively, KA might activate its own specific receptor, which in turn leads to a net increase in the release of an endogenous Glu-related toxin; this endogenous substance would then activate NMDA receptors. Patch-clamp electrophysiology experiments have helped to distinguish between these possibilities. Concentrations of APV that completely block the current elicited by maximal nondesensitizing doses of NMDA exert no detectable inhibition of KA-evoked currents. Hence, at the concentrations used, it appears unlikely that KA directly activates NMDA receptors in this preparation. Furthermore, the fraction of toxicity attributed to the addition of KA can be blocked by the relatively specific non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). This finding is consistent with the hypothesis that KA adds an increment of toxicity in this system by directly interacting with KA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro

1991

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“…This finding is supportive to our observations that the NMDA-induced glutamate accumulation in HI cells was 50% higher than in shamoperated cells. The augmentation of NMDA-induced glutamate accumulation in HI cells can be attributed to the increase in NO production, as indicated by the cGMP formation, although blockade of uptake mechanism may also cause increase in extracellular glutamate accumulation, as done by KA (38). In the current study, NMDA-and KA-induced glutamate accumulation seems to occur by different mechanisms, because HI insults only augmented NMDA-induced glutamate accumulation and L-NMMA could block NMDA-induced but not KAinduced glutamate increases.…”

Section: Resultsmentioning

confidence: 99%

Intrauterine Hypoxia-Ischemia Increases N-Methyl-D-Aspartate-Induced cGMP Formation and Glutamate Accumulation in Cultured Rat Cerebellar Granule Cells

et al. 1995

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Effects of intrauterine hypoxia-ischemia (HI) on brain func-thase inhibitor, NMDA-induced cGMP formation was blocked, tional development in the term rat were examined in cerebellar and the blockade of cGMP formation by L-NMMA (10 pM) granule cell cultures obtained from an in utero HI model. On could be reversed by simultaneous application of 1 mM arginine gestation d 17, HI conditions were achieved by complete clamp-in both control and HI cells. Antenatal HI insult (20-35 min) also ing of the uterine vasculature for designated durations followed augmented NMDA-, but not KA-, stimulated accumulation of by removal of the clamps to permit reperfusion. Sham operation extracellular glutamate. The hypersensitive response in NMDA-(surgery without vasculature clamping) was performed as the induced glutamate accumulation could be suppressed by 150 p M control. After surgery, the uterine horns were returned to dam's L-NMMA. The overall results suggest that antenatal HI occurring abdomen to let the pups deliver naturally. Severe HI insult from in the last half of gestation may result chronically in adverse the surgical manipulation was evident in that the lactate levels of effects on NMDA receptor-mediated neurotransmission and that fetal Gain increased, and fetal blood pH decreased with the nitric oxide is possibly involved in these effects. In utero HI is a major contributor to long-term neurologic humans, and brain injury is determined immediately after the abnormalities. The severe sequelae include learning disabili-insult. It is not fully understood whether and how HI occurring ties, motor disturbances, behavioral alterations, and mental retardation (1, 2). The establishment of many perinatal HI animal models (3, 4), including several rat models (5-8), has greatly expanded our knowledge of the critical events and biochemical alterations occurring during or after the initial HI insult. However, in most of these experimental models the HI insult is given acutely near term or during the first a few days of postnatal life (in case of the rat model), which is thought to be a developmental stage equivalent to the third trimester in Received November 18, 1994; accepted March 7, 1995 at a relatively early gestational stage results in chronic adverse effects on CNS development. Recent animal studies have provided evidence that intermittent antenatal hypoxia has longterm effects on rat brain ornithine decarboxylase activity and causes several behavioral changes, although with maturation those abnormal behaviors are not evident (9). Clinical evidence also indicates that neurologic damage in newborn infants due to antenatal insults is demonstrable (10-12) and that the observed neonatal encephalopathy, after the exclusion of infants with major malformations or infections, is not always due to birth asphyxia and is sometimes due to preexisting abnormalities (13). It is thus desirable to have an animal model for

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“…A number of inhibitors of the acidic amino acid transporter have been described, including cis-1 -aminocyclobutane-1,3-dicarboxylic acid (Fletcher et al, 1991), homocysteic acid (Griffiths et al, 1989) kainate and dihydrokainate (Ferkany and Coyle, 1986;Pocock et al, 1988). Some diversity of the presynaptic transporter is indicated by the failure of dihydrokainate to inhibit uptake into cerebellar synaptosomes (Ferkany and Coyle, 1986).…”

Section: The Plasma Membrane Acidic Amino Acid Transportermentioning

confidence: 99%

The glutamatergic nerve terminal

Nicholls

1993

European Journal of Biochemistry

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207

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Glutamate as a neurotransmitterThe human brain has about lolo neurones, each of which, on average, makes about 1000 synaptic contacts with other neurones. Of these l O I 3 synapses perhaps up to 90% utilize amino acids as their neurotransmitter. Glutamate is the major excitatory amino acid (acting predominantly on depolarizing post-synaptic receptors) while 4-aminobutyrate (GABA) and glycine are the major inhibitory transmitters (acting on hyper-polarizing receptors). As well as playing the dominant role in fast information transfer, glutamate is of particular interest in view of its involvement in current models of memory and learning (Bliss and Dolphin, 1982;Cotman et al., 1988;Collingridge and Singer, 1990) and because a pathological release of glutamate in brain ischaemia is neurotoxic and a major contributor to the damage caused under these conditions (Rothman and Olney, 1986;Choi, 1988 ;Meldrum and Garthwaite, 1990).A synapse has a pre-synaptic element responsible for the storage and release of transmitter and a post-synaptic element containing one or more classes of receptor for the transmitter. The potent combination of electrophysiology and molecular cloning has allowed a dramatic advance in our understanding of post-synaptic events. Three classes of post-synaptic ionotropic (possessing an integral ion channel) glutamate receptors have been identified and cloned: the 2-amino-3-hydroxy-5-methyl-4-isoxazole propionatekainate (AMPA/ KA) receptor Nakanishi et al., 1990;Sakmann, 1992), the high-affinity KA receptor (Egebjerg et al., 1991) and the N-methyl D-aSpartate (NMDA) receptor (Moriyoshi et al., 1991 ; Kumar et al., 1991 ;Barnard, 1992). Each can exist in many isoforms by combining subunits formed from distinct genes, by alternative splicing or by post-transcriptional modification (Monyer et al., 1991 ;Burnashev et al., 1992).The AMPNKA receptor is responsible for fast information transfer while the NMDA receptor is only operative when the post-synaptic membrane is independently depolarized by another receptor. This 'associative' behaviour of the latter is believed to underlie aspects of the learning process.

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Kainic Acid Inhibits the Synaptosomal Plasma Membrane Glutamate Carrier and Allows Glutamate Leakage from the Cytoplasm but Does Not Affect Glutamate Exocytosis

Cited by 65 publications

References 18 publications

N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro

N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro

Intrauterine Hypoxia-Ischemia Increases N-Methyl-D-Aspartate-Induced cGMP Formation and Glutamate Accumulation in Cultured Rat Cerebellar Granule Cells

The glutamatergic nerve terminal

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