6,7-Dinitroquinoxaline-2,3-dione and 6-nitro,7-cyanoquinoxaline-2,3-dione antagonize responses mediated by N-methyl-d-aspartate and NMDA-associated glycine recognition sites in vivo: Measurements of cerebellar cyclic-GMP
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AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors mediate excitatory responses to neurotransmitters in the brain and in other neurons of the central nervous system. Menuz et al . report that the presence or absence of auxiliary AMPA receptor subunits has a dramatic effect on the pharmacological properties of these receptors. The compound CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) generally acts as a competitive antagonist of AMPA receptors. However, in receptor complexes in which one of the auxiliary subunits known as TARPS (for transmembrane AMPA receptor regulatory proteins) is present, CNQX actually functions as a partial agonist of the receptor. The presence of the extra subunit may help couple conformational changes in the receptor ligand-binding domains to opening of the receptor ion channel. K. Menuz, R. M. Stroud, R. A. Nicoll, F. A. Hays, TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists. Science 318 , 815-817 (2007). [Abstract] [Full Text]
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AMPA receptors may play an important role in acute and chronic neurodegenerative diseases. An assay for the specific binding of [3H]-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) to receptors in membranes from post-mortem human brain is described, which can be used in screening for selective AMPA receptor antagonists. Membranes were prepared from frozen human adult hippocampus and whole fetal brain tissues. [3H]-AMPA binding to human hippocampus was saturable; Scatchard analysis of equilibrium binding data indicated high and low affinity sites with affinity binding constants (KD) of 3.4 +/- 0.5 nM and 65 +/- 9 nM (n = 7) respectively. Biphasic association and dissociation rate constants for [3H]-AMPA binding were consistent with the biphasic Scatchard analysis. Inhibition of [3H]-AMPA binding revealed a rank order of potency as quisqualate = AMPA > BOAA > L-glutamate = DNQX = CNQX > kainate > L-aspartate = NMDA. AMPA receptors in human fetal brain had a comparable pharmacology. AMPA/kainate receptors were expressed in frog oocytes following injection of RNA prepared from human fetal brain. Human brain tissues may therefore be utilized for screening and functional analysis of AMPA receptor antagonists.
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Four cloned cDNAs encoding 900-amino acid putative glutamate receptors with approximately 70 percent sequence identity were isolated from a rat brain cDNA library. In situ hybridization revealed differential expression patterns of the cognate mRNAs throughout the brain. Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate > glutamate > kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX).
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Abstract The mechanisms underlying the neurodegenerative effects of the glutamate receptor agonist, AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate), were studied using brain slice preparations of young rat (8–9 days old) cerebellum and hippocampus. Rapid AMPA toxicity (exerted on some cerebellar interneurons) was inhibited by including the appropriate receptor blocker, CNQX (6‐cyano‐7‐nitroquinoxaline‐2,3‐dione, 10 μM), in the exposing solution. The degeneration of other neurons, including Purkinje cells and hippocampal pyramidal neurons, persisted. It could, however, be largely prevented if CNQX was included for 1.5 h during the post‐incubation period, suggesting that an enduring ‘rebound’ AMPA receptor activation was responsible for this delayed type of degeneration, not the exposure itself. In cerebellar slices, independent evidence for the occurrence, postexposure, of persisting AMPA receptor stimulation was obtained electrophysiologically. Omission of Ca 2+ during the exposure period (and for 10 min beforehand) markedly reduced rapid AMPA toxicity but was ineffective in protecting most of the Purkinje cells. However, if the slices were previously starved of Ca 2+ for 1 h, then most of these neurons survived, even if the ion was reinstated during the recovery period. Slow AMPA toxicity, which takes place during long (2 h) exposures, could be inhibited either by CNQX or by omission of Ca 2+ (30 min preincubation). The results indicate that the rapid oedematous necrosis induced by AMPA, like that caused by N ‐methyl‐ d ‐aspartate and kainate, is likely to involve excessive influx of Ca 2+ . In contrast, the induction of the delayed mechanism, as well as its ‘expression’ during the postincubation period, probably depends on intracellular Ca 2+ , rather than Ca 2+ influx.
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