Agonists selective for phosphoinositide-coupled receptors sensitize neurons to depolarization by L-2-amino-4-phosphonobutanoic acid (L-AP4).
Exposure of hippocampal and cortical slices to quisqualate induces a 30- to 100-fold decrease in the half-maximal concentration of L-2-amino-4-phosphonobutanoic acid (L-AP4) required to depolarize neurons. This sensitization persists for hours and has previously been shown to be induced only by quisqualate, via the interaction of quisqualate with a 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-insensitive site. Here we tested the hypothesis that quisqualate may act on phosphoinositide (PI) metabolism to enhance the response to L-AP4, and found that sensitization to L-AP4 was induced by trans-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD), an agonist selective for PI-coupled excitatory amino acid receptors, and by carbachol and norepinephrine, agonists at other PI-coupled receptors. However, these compounds produced only a 2- to 5-fold sensitization to L-AP4, that was of shorter duration than that induced by quisqualate. These results suggest that sensitization to L-AP4 may be induced, at least in part, via PI-coupled receptors, and that the sensitivity of neurons to an excitatory amino acid agonist may be modified by heteroreceptor activation of the PI second messenger system.
Whittemore
E R
ER
Department of Psychobiology, University of California, Irvine 92717.
Cotman
C W
CW
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007051:Ibotenic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear
D000613:Aminobutyrates; D009467:Neuromuscular Depolarizing Agents; D011810:Quinoxalines; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; C040985:phosphatidylinositol receptors; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D007051:Ibotenic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016318:Quisqualic Acid; D002217:Carbachol; C012729:2-amino-4-phosphonobutyric acid; D009638:Norepinephrine