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Stimulatory and inhibitory actions of excitatory amino acids on inositol phospholipid metabolism in rat cerebral cortex
Author(s) -
Godfrey Philip P.,
Wilkins C. Jason,
Tyler Wendy,
Watson Stephen P.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb16556.x
Subject(s) - kainate receptor , nmda receptor , inositol phosphate , excitatory postsynaptic potential , inhibitory postsynaptic potential , inositol , chemistry , agonist , quisqualic acid , kainic acid , medicine , glutamate receptor , biology , ampa receptor , endocrinology , biochemistry , receptor
1 The effects of excitatory amino acids on [ 3 H]‐inositol phosphate levels have been examined in rat cortical slices under basal conditions or following agonist stimulation. 2 Ibotenate and quisqualate provoked a substantial dose‐dependent (EC 50 , 30 μ M and 20 μ M respectively) increase in inositol phosphates; these responses were not additive suggesting a common site of action for the two amino acids. The responses to maximally effective concentrations of ibotenate and quisqualate were not blocked by verapamil, tetrodotoxin or Cd 2+ , indicating that these effects are not indirect. Small, but significant, increases in inositol phosphates were also seen with glutamate and N‐methyl‐DL‐aspartate (NMDLA); kainate and aspartate were ineffective. 3 Each excitatory amino acid tested reduced carbachol (1 mM) stimulated inositol phosphate formation. Kainate (IC 50 , 20 μ M ) and NMDLA (IC 50 , 20 μ M ) were the most effective inhibitors. Kainate also reduced the responses to noradrenaline, 5‐hydroxytryptamine and 20 mM K + . 4 The inhibitory action of NMDLA, but not kainate, could be reversed with the NMDA antagonists, DL‐2‐amino‐5‐phosphonovalerate (APV) and MK‐801; DL‐2‐amino‐4‐phosphonobutyrate (APB) was without effect. Since MK‐801 blocks the ion channels associated with the NMDA receptor, it appears that inhibition requires the entry of ions into the cell. 5 APV and MK‐801 potentiated the stimulatory response to ibotenate but had no effect on the response to quisqualate. Potentiation was presumably the result of blocking the inhibition by ibotenate mediated through NMDA receptors. 6 In conclusion, excitatory amino acids appear to reduce agonist‐mediated inositol phosphate formation in rat cerebral cortex by a non‐specific action, possibly including the influx of Na + ions. In addition ibotenate and quisqualate substantially enhance inositol phosphate production: the pharmacology of the response suggests that it is mediated by a receptor distinct from previously defined excitatory amino acid receptor subtypes.