Inhibition of excitatory amino acid-stimulated phosphoinositide hydrolysis in the neonatal rat hippocampus by 2-amino-3-phosphonopropionate.
The effects of excitatory amino acid agonists and alpha-amino-omega-phosphonocarboxylic acid antagonists on phosphoinositide hydrolysis in hippocampal slices of the 7-day neonatal rat were examined. Significant stimulation of [3H]inositol monophosphate formation was observed with ibotenate, quisqualate, L-glutamate, L-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, L-homocysteate, and kainate. N-Methyl-D-aspartate had no effect. Of these agonists, ibotenate and quisqualate were the most potent and efficacious. Stimulations by ibotenate and quisqualate were partially inhibited by L-2-amino-4-phosphonobutyrate (10(-3) M), but this antagonist had no effect on L-glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, or kainate. At 10(-3) M, D,L-2-amino-3-phosphonopropionate completely inhibited ibotenate and quisqualate stimulations, partially inhibited L-glutamate stimulation, and had no effect on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-, kainate-, or carbachol-induced [3H]inositol monophosphate formation. Concentration-effect experiments showed D,L-2-amino-3-phosphonopropionate to be five times more potent as an antagonist of ibotenate-stimulated phosphoinositide hydrolysis than L-2-amino-4-phosphonobutyrate. Thus in the neonatal rat hippocampus, like in the adult rat brain, D,L-2-amino-3-phosphonopropionate is a selective and relatively potent inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis. Because this glutamate receptor is uniquely sensitive to D,L-2-amino-3-phosphonopropionate, these studies provide further pharmacological evidence for the existence of a novel excitatory amino acid receptor subtype that is coupled to phosphoinositide hydrolysis in brain.
Schoepp
D D
DD
Central Nervous System Research, Eli Lilly and Company, Indianapolis, Indiana 46285.
Johnson
B G
BG
D000409:Alanine / Q000494:pharmacology / Q000031:analogs & derivatives; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006868:Hydrolysis; D007051:Ibotenic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology; D018021:Lithium Chloride; D016202:N-Methylaspartate; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D002712:Chlorides; D018377:Neurotransmitter Agents; D010069:Oxadiazoles; D010716:Phosphatidylinositols; C000211:2-amino-3-phosphonopropionic acid; D007051:Ibotenic Acid; D001224:Aspartic Acid; D007294:Inositol; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D002217:Carbachol; D008094:Lithium; D018021:Lithium Chloride; D000409:Alanine; D007608:Kainic Acid