Excitatory amino acid agonist-antagonist interactions at 2-amino-4-phosphonobutyric acid-sensitive quisqualate receptors coupled to phosphoinositide hydrolysis in slices of rat hippocampus.
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 greater than or equal to 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-hydroxy-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 approximately 135% of basal values.(ABSTRACT TRUNCATED AT 250 WORDS)
Schoepp
D D
DD
Central Nervous System Research Division, Eli Lilly and Company, Indianapolis, Indiana 46285.
Johnson
B G
BG
D000596:Amino Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004347:Drug Interactions; D006624:Hippocampus / Q000378:metabolism*; D006868:Hydrolysis; D007051:Ibotenic Acid / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism*
D000596:Amino Acids; D000613:Aminobutyrates; D010069:Oxadiazoles; D010716:Phosphatidylinositols; D018091:Receptors, AMPA; D011955:Receptors, Drug; D007051:Ibotenic Acid; D016318:Quisqualic Acid; D002217:Carbachol; C012729:2-amino-4-phosphonobutyric acid; D009638:Norepinephrine