Ibotenic acid mediates neurotoxicity and phosphoinositide hydrolysis by independent receptor mechanisms.
Ibotenic acid (Ibo) has been shown to have agonist activity at both the N-methyl-D-aspartate (NMDA) and trans-ACPD or metabolotropic quisqualate (Qm) receptor sites in several systems. Both of these receptor sites have been implicated in excitotoxicity. Like NMDA neurotoxicity, Ibo neurotoxicity can be enhanced by glycine and blocked by MK-801. Ibo induced stimulation of phosphoinositide (PI) hydrolysis, on the other hand, is unaffected by either of these treatments. We therefore conclude that Ibo is capable of acting at both NMDA and trans-ACPD receptors in the CNS, although only activation of NMDA receptors is involved in Ibo neurotoxicity. This conclusion leads us to postulate that stimulation of phosphoinositide hydrolysis is neither necessary nor sufficient for neurotoxicity.
Zinkand
W C
WC
Department of CNS Pharmacology, ICI Americas, Wilmington, DE 19897.
Moore
W C
WC
Thompson
C
C
Salama
A I
AI
Patel
J
J
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation; D005998:Glycine / Q000494:pharmacology / Q000633:toxicity; D006868:Hydrolysis; D007051:Ibotenic Acid / Q000494:pharmacology / Q000633:toxicity*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D018009:Receptors, Glycine; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects*; D010738:Type C Phospholipases / Q000378:metabolism
D010716:Phosphatidylinositols; D018009:Receptors, Glycine; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C073111:metabotropic quisqualate receptor; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D016318:Quisqualic Acid; D010738:Type C Phospholipases; D005998:Glycine