Excitatory Amino Acid Agonist‐Antagonist Interactions at 2‐Amino‐4‐Phosphonobutyric Acid‐Sensitive Quisqualate Receptors Coupled to Phosphoinositide Hydrolysis in Slices of Rat Hippocampus
- 30 April 1988
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 50 (5), 1605-1613
- https://doi.org/10.1111/j.1471-4159.1988.tb03050.x
Abstract
Studies were carried out to define the relative affinities and intrinsic activities of excitatory amino acid agonists that activate receptor sites coupled to phosphoinositide hydrolysis in brain. Slices of rat hippocampus were prelabeled with myo-[3H]inositol, and agonist stimulation was indexed by measuring the accumulation of [3H]inositol monophosphate ([3H]IP) in the presence of Li+. It was observed that ibotenic (IBO) and quisqualic (QUIS) acids both elicit highly significant, concentration-dependent stimulation of phosphoinositide hydrolysis. Whereas maximal stimulation by IBO (10-3 M) was four- to fivefold over basal values, the maximal effect of QUIS (10-4 M) was less (about twofold). Based on the relative concentrations required for 50% maximal stimulation. QUIS was 20 times more potent than IBO. Stimulation of phosphoinositide hydrolysis by either IBO or QUIS was additive to the effects of nonexcitatory amino acid agonists (carbachol and norepinephrine) in this tissue. However, the stimulatory effects of IBO plus QUIS were not additive. At .gtoreq. 10-4 M. QUIS significantly inhibited phosphoinositide hydrolysis by a maximal stimulatory concentration of IBO (10-3 M) to a level observed with QUIS alone. Other excitatory amino acid agonists, including kainate, N-methyl-D-aspartate, and .alpha.-amino-3-hyroxy-5-methyl-4-isoxazolepropionic acid (AMPA), had no stimulatory effects at concentrations as high as 10-3 M. The D,L or L forms of 2-amino-4-phosphonobutyric acid (AP4), but not D-AP4, significantly enhanced [3H]IP levels to .apprx. 135% of basal vaalues. D,L-AP4 and L-AP4 also inhibited stimulation by either IBO or QUIS, but relative inhibition of QUIS effects was quantitatively less than that of IBO effects. These studies indicate that IBO represents a full agonist at these "AP4-sensitive QUIS receptors" coupled to phosphoinositide hydrolysis in brain. QUIS is a partial agonist with the highest affinity for the receptor, and L-AP4 represents a partial agonist with relatively weak intrinsic activity. Furthermore, this receptor effect is not mediatged at "QUIS" receptor sites that are activated by AMPA.Keywords
This publication has 34 references indexed in Scilit:
- Multiple mechanisms of serotonergic signal transductionLife Sciences, 1987
- Magnesium Ions Inhibit the Stimulation of Inositol Phospholipid Hydrolysis by Endogenous Excitatory Amino Acids in Primary Cultures of Cerebellar Granule CellsJournal of Neurochemistry, 1987
- Differences between substrate specificities of l-glutamate uptake by neurons and glia, studied in cell lines and primary culturesNeurochemistry International, 1987
- Excitatory amino acids inhibit stimulation of phosphatidylinositol metabolism by aminergic agonists in hippocampusNature, 1986
- Neurotensin stimulates inositol phospholipid hydrolysis in rat brain slicesBrain Research, 1984
- Characterization of neurotransmitter receptor-mediated phosphatidylinositol hydrolysis in the rat hippocampusLife Sciences, 1984
- Turnover of Inositol Phospholipids and Signal TransductionScience, 1984
- The Ca2+/Cl− dependent L‐[3H]glutamate binding: a new receptor or a particular transport process?FEBS Letters, 1984
- Correlation between inositol phospholipid hydrolysis and substance P receptors in rat CNSNature, 1984
- Inositol Phospholipid Hydrolysis in Rat Cerebral Cortical Slices: I. Receptor CharacterisationJournal of Neurochemistry, 1984