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Stimulatory and Inhibitory Effects of N ‐Methyl‐D‐Aspartate on 3 H‐Inositol Polyphosphate Accumulation in Rat Cortical Slices
Author(s) -
Baird John G.,
Nahorski Stefan R.
Publication year - 1991
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1991.tb03794.x
Subject(s) - inositol , nmda receptor , carbachol , inositol phosphate , inhibitory postsynaptic potential , chemistry , excitatory postsynaptic potential , polyphosphate , agonist , glutamate receptor , biochemistry , endocrinology , medicine , biology , receptor , phosphate
The actions of the excitatory amino acid N ‐methyl‐D‐aspartate (NMDA) on the accumulation of 3 H‐inositol polyphosphate isomers in rat cerebral cortex slices have been examined over short (less than 5 min) incubation periods. NMDA caused the dose‐dependent accumulation of only [ 3 HJinositol monophosphate and [ 3 H]inositol bisphosphate (maximal effect between 0.3 and 1 m M ), with no increase in [ 3 H]inositol trisphosphate ([ 3 H]InsP 3 ) and ( 3 H]inositol tetrakisphosphate ([ 3 H]InsP 4 ). HPLC analysis confirmed this, showing no increases in the breakdown products of [ 3 H]Ins(1, 3, 4, 5)P4. When present with the muscarinic agonist carbachol (1 m M ), high concentrations of NMDA (1 m M ) could almost totally inhibit carbachol‐induced accumulation of 3 H‐inositol polyphosphates. In contrast, at lower concentrations of NMDA (10 γM ), the inhibitory effect was replaced with a synergistic accumulation of inositol polyphosphates, especially [ 3 H]InsP 4 and [ 3 H]InsP 3 . The inhibitory effects of NMDA were only apparent when extracellular Ca 2+ was present, although incubation in media with no added Ca 2+ resulted in somewhat reduced stimulatory responses to NMDA alone, but suppressed totally the inhibitory effects of 1 m M NMDA and reduced the synergistic effects of 10 γM NMDA on carbachol responses. These studies, therefore, reveal Ca 2+ ‐dependent effects of NMDA indicative of indirect mechanisms of action and show that care must be made in interpreting the effects of NMDA on phosphoinositide metabolism unless the inositol polyphosphate composition has been fully characterised.