Abstract
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.
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|