Multiple subtypes of excitatory amino acid receptors coupled to the hydrolysis of phosphoinositides in rat brain.
The excitatory amino acid (EAA) analogues quisqualate, ibotenate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate (trans-ACPD) activate the metabotropic EAA receptors that are coupled to the hydrolysis of phosphoinositides (PI). Previous studies of hippocampal cross sections demonstrated that PI hydrolysis stimulated by these agonists can be inhibited by either L-aspartate-beta-hydroxamate (L-A beta HA) or DL-2-amino-3-phosphonopropionate (DL-AP3). The goal of the present studies was to determine if all metabotropic EAA receptors are sensitive to L-A beta HA and DL-AP3. Two approaches were used. In the first, using cerebellar cross sections, the effects of these agonists and inhibitors were examined. The EC50 values (the concentrations required to evoke half-maximal stimulation) of quisqualate, ibotenate, and trans-ACPD in cerebellum were similar to the EC50 values that we observed previously in hippocampus, but neither L-A beta HA nor DL-AP3 blocked PI hydrolysis. The EC50 values were 0.65 +/- 0.17 microM for quisqualate, 12.8 +/- 2.5 microM for ibotenate, and 18.1 +/- 3.1 microM for trans-ACPD. All data were best fit to theoretical curves that had Hill slopes of 1. In the second approach, another EAA analogue, D-aspartate, was identified as an agonist that stimulates PI hydrolysis. The EC50 for PI hydrolysis stimulated by D-aspartate was 470 +/- 90 microM in hippocampus. Neither L-A beta HA nor DL-AP3 blocked PI hydrolysis stimulated by D-aspartate in hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)
Littman
L
L
Children's Hospital of Philadelphia, PA 19104.
Glatt
B S
BS
Robinson
M B
MB
D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D007051:Ibotenic Acid / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017459:Receptors, Amino Acid / Q000187:drug effects / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*
D005971:Glutamates; D010716:Phosphatidylinositols; D017459:Receptors, Amino Acid; D017470:Receptors, Glutamate; C031959:aspartic acid receptor; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D007051:Ibotenic Acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D016318:Quisqualic Acid