Hippocampal slices do not appear to accumulate low micromolar concentrations of quisqualate by an active uptake mechanism

Harrison, Peter S.; Kilpatrick, Ian C.

doi:10.1016/0304-3940(91)90788-u

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…However, the proposed sequestration of Quis via these sites (Zaczek et al, 1987b) is supported in the present study by the fact that responses to Quis rather than AMPA are relatively selectively enhanced by anion transport blockers, consistent with the >60 fold greater potency of Quis over AMPA to displace binding (Butcher et al, 1983;Werling et al, 1983). This is circumstantial evidence indicating that the exchange hypothesis is possible, but there is no direct evidence that Quis has indeed been sequestrated by the cortical tissue, although this has been demonstrated in the hippocampus (Harrison & Kilpatrick, 1991). However, the marked difference in the suppression of induction by DL-AP4 and L-*-AA points away from the exchange hypothesis, and the evidence that these amino acids are also potential antagonists of the metabotropic L-glutamate receptor (Schoepp & Johnson, 1989) suggests that PI turnover may also be involved in the induction process, supporting the sensitization hypothesis.…”

Section: Discussionsupporting

confidence: 63%

“…Therefore, with 40 gM Quis, there may well be sufficient sequestration by Na+-dependent transport to provide an anion transport blocker-resistant source of Quis for heterogeneous exchange with AP4. A study of uptake of Quis by hippocampal tissue reveals that negligible amounts of Quis are sequestered via a Na'-dependent mechanism at a concentration of 16 iM (Harrison & Kilpatrick, 1991). Therefore, the experiments with SITS were repeated using 1 !LM Quis applied for 60 min as the sensitiz- Table 2 The influence of amino acid analogues and anion transport blockers on the induction of DL-2-amino-4-phosphonobutyrate (DL-AP4, 500 tM) responses, by their application prior to and during the first quisqualate (Quis) exposure ing pulse, and 60 min allowed for the re-equilibration in control Krebs medium.…”

Section: The Effect Of Dl-ap4 and L-c-aa On Induction By Quismentioning

confidence: 99%

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Anion transport blockers inhibit dl‐2‐amino‐4‐phosphonobutyrate responses induced by quisqualate in the rat cerebral cortex

Turner

1993

British J Pharmacology

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1 Depolarizing responses to DL-2-amino-4-phosphonobutyrate (AP4) and related amino acids have been studied in the rat cerebral cortex slice following the application of quisqualate (Quis). 2 Before exposure to Quis, 500 AM DL-AP4 had little or no effect. However, following a single application of 40 jAM Quis for 2 min, DL-AP4 produced depolarizing responses. With repeated applications of DL-AP4, there was a decline in response amplitude. A second application of Quis restored the depolarizing potency of DL-AP4 to a level above that for the first DL-AP4 response after the first Quis application. With a sequence of alternate applications of Quis and DL-AP4, the amplitude of DL-AP4 responses became maximal after the second Quis application. Responses to DL-AP4 could also be induced by the application of 1 gM Quis for 60 min, but were smaller in amplitude.3 Responses to the normally inactive amino acids L-cysteine (Cys), L-cystathionine (CTN) and L-aaminoadipate (AA) were also induced once Quis was applied. These responses were also maximized after a second application of Quis, except those to L-Cys, which failed to reach a plateau after three Quis applications. 4 The co-application of DL-AP4 with the first Quis application depressed the subsequent mean DL-AP4 response by 47%. Re-application of Quis restored the amplitude of DL-AP4 responses to levels comparable to control. L-a-AA also suppressed the induction of DL-AP4 responses, when co-applied with the first Quis exposure, reducing mean response amplitude by 98%. Unlike DL-AP4, however, the effect with L-x-AA persisted so that DL-AP4 responses were significantly suppressed compared to control, even after further applications of Quis. 5 The effects of the anion transport blockers, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 4-acetoamido-4'-isothiocyanatostilbene-2,2'-disulphonic acid (SITS) on the induction process and the DL-AP4 responses themselves were examined. DIDS (100 jLM) significantly inhibited the DL-AP4 responses, and to a lesser extent the induction of the responses by 40 AM Quis (2 min), while SITS (300 AM) only inhibited the DL-AP4 responses. However, the induction of responses by 1 gM Quis (60 min) was significantly affected by this concentration of SITS.6 DIDS (100 jAM) had no effect on responses to x-amino-3-hydroxy-5-methyl4-isoxazoleproprionate (AMPA), but selectively potentiated those to Quis. Examination of the full concentration-response curve for Quis revealed that, while the Rmax remained constant, the Hill slope was increased and the EC50 was decreased in the presence of DIDS. SITS (300 jAM), however, antagonized responses to AMPA, and had little effect on responses to Quis except at the highest concentration of Quis tested (20 jAM), where a potentiation was observed, suggesting that it is a non-NMDA receptor antagonist. 7 These observations indicate that the production of depolarizing responses to a number of amino acids, including DL-AP4, in the cerebral cortex is mediated via an anion transport mechanism sensitive to...

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Section: Discussionsupporting

confidence: 63%

Section: The Effect Of Dl-ap4 and L-c-aa On Induction By Quismentioning

confidence: 99%

Anion transport blockers inhibit dl‐2‐amino‐4‐phosphonobutyrate responses induced by quisqualate in the rat cerebral cortex

Turner

1993

British J Pharmacology

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“…Moreover, this heteroexchange system would have to be very potent, since sensitization lasts > 1 h with repetitive applications of L -A P~, and can be induced by concentrations of quisqualate which cause virtually no detectable effect themselves. Furthermore, a recent study by Harrison and Kilpatrick (1991) using hippocampal slices has shown that, while glutamate and aspartate are actively taken up and concentrated by an ouabain-sensitive process, quisqualate is not (but cf. Koh et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Characterization of L‐2‐Amino‐4‐Phosphonobutanoate Action Following Sensitization by Quisqualate in Rat Hippocampal Slice Cultures

Charpak

Thompson

Gähwiler

et al. 1992

Eur J of Neuroscience

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An excitatory action of l-2-amino-4-phosphonobutanoate (l-AP4), a glutamate analogue, is observed following pre-exposure of tissue to quisqualate. We have studied the mechanism of sensitization of l-AP4 responses by quisqualate in voltage-clamped CA3 pyramidal cells in rat hippocampal slice cultures in the presence of tetrodotoxin. Prior to quisqualate addition, CA3 cells did not respond to l-AP4 (50 - 1000 microM). Following brief application of quisqualate (500 nM for 30 s), l-AP4 (50 - 200 microM) induced a complex excitatory response which could be obtained for >1 h. l-AP4 caused an ionotropic inward current associated with a conductance increase. This response was in part sensitive to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and in part sensitive to d-2-amino-5-phosphonovalerate (d-AP5) and Mg2+ ions. At depolarizing potentials, in the presence of CNQX and d-AP5, l-AP4 caused excitation by depressing K+ currents, mimicking the metabotropic action of glutamate. This indicates that the action of l-AP4 is mediated by three different receptor types: N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors, and glutamatergic metabotropic receptors. The l-AP4 response persisted in solutions containing low Ca2+ and high Mg2+ concentrations or 100 - 200 microM Cd2+, suggesting that it is independent of extracellular Ca2+. We were unable to identify any substance other than quisqualate capable of sensitizing the l-AP4 action. This effect also occurred when quisqualate was applied in Ca2+-free solution or in solutions containing low concentrations of Na+ or Cl-. Sensitization of l-AP4 responses by quisqualate was not observed in acutely dissociated pyramidal cells recorded by means of the whole-cell recording mode, although ionotropic quisqualate responses were present. Sensitization was readily reversed by short applications of the endogenous excitatory amino acids glutamate, aspartate and homocysteate at concentrations of 10 - 100 microM. Our data are consistent with the hypothesis that the excitatory action of l-AP4 results from a Ca2+-independent release of endogenous excitatory amino acids from some presynaptic neuronal or glial site.

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Quisqualic acid induced sensitization and the active uptake ofl-quisqualic acid by hippocampal slices

1993

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Hippocampal slices do not appear to accumulate low micromolar concentrations of quisqualate by an active uptake mechanism

Cited by 7 publications

References 21 publications

Anion transport blockers inhibit dl‐2‐amino‐4‐phosphonobutyrate responses induced by quisqualate in the rat cerebral cortex

Anion transport blockers inhibit dl‐2‐amino‐4‐phosphonobutyrate responses induced by quisqualate in the rat cerebral cortex

Characterization of L‐2‐Amino‐4‐Phosphonobutanoate Action Following Sensitization by Quisqualate in Rat Hippocampal Slice Cultures

Quisqualic acid induced sensitization and the active uptake ofl-quisqualic acid by hippocampal slices

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