A phencyclidine recognition site is associated with N-methyl-D-aspartate inhibition of carbachol-stimulated phosphoinositide hydrolysis in rat cortical slices.
The effects of N-methyl-D-aspartate (NMDA) on muscarinic receptor-stimulated phosphoinositide (PI) hydrolysis in rat cortical slices were studied. NMDA inhibits carbachol-stimulated PI hydrolysis with an IC50 of 9.8 +/- 1.4 microM and a maximal inhibition of 70% at 100 microM. The inhibitory effect of NMDA is not due to increased metabolism of accumulated inositol phosphates. NMDA inhibition of carbachol-stimulated PI hydrolysis was significantly reduced in the absence of extracellular calcium. Although the inhibitory effect of NMDA is observed in the presence of 1.18 mM Mg2+, the concentration-response curve is slightly shifted to the left (5-fold) in the absence of extracellular Mg2+. Antagonists of NMDA-evoked excitations were effective inhibitors of the NMDA modulation of PI hydrolysis, including the competitive antagonist 2-amino-5-phosphonopentanoic acid and the noncompetitive antagonist MK-801. The rank order of potencies of the antagonists were MK-801 greater than phencyclidine = (-)-cyclazocine greater than ketamine = etoxadrol greater than N-allylnormetazocine greater than 2-amino-5-phosphonopentanoic acid. (+)-MK-801 and (-)-cyclazocine were more potent inhibitors, by 4-5-fold, of the NMDA response than their respective isomers, whereas N-allylnormetazocine isomers were approximately equipotent antagonists. The activity of dexoxadrol against NMDA inhibition of carbachol-stimulated PI hydrolysis could not be determined because of its antimuscarinic effects. The rank order of potencies of antagonists, the stereoselectivity of the isomers of MK-801, cyclazocine, and N-allylnormetazocine, and Mg2+ sensitivity of the NMDA inhibitory response suggest that a phencyclidine binding similar to the one located in the cation channel gated by NMDA receptors is associated with the NMDA receptor that modulates muscarinic-stimulated PI hydrolysis.
Gonzales
R A
RA
Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Moerschbaecher
J M
JM
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D016202:N-Methylaspartate; D010622:Phencyclidine / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D017478:Receptors, Phencyclidine
D010716:Phosphatidylinositols; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D001224:Aspartic Acid; D016202:N-Methylaspartate; D002217:Carbachol; D010622:Phencyclidine