Magnesium‐Dependent Inhibition of Agonist‐Stimulated Phosphoinositide Breakdown in Rat Cortical Slices by Excitatory Amino Acids

Abstract

The excitatory amino acid agonists kainate, N-methyl-D-aspartate (NMDA), and quisqualate inhibited ligand-stimulated phosphoinositide hydrolysis in rat cortical slices. The NMDA channel blocker MK-801 antagonized the inhibition by NMDA but had no effect on the inhibition due to kainate or quisqualate. The antagonist 6-cyano-7-nitroquinoxaline-2,3-dione blocked the effects of quisqualate and kainate but not the effect of NMDA. These data indicate that activation of the NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainate types of ionotropic receptors has the same effect. In membranes prepared from cortical slices, there was no inhibition of carbachol-stimulated phosphoinositidase C activity by excitatory amino acids, suggesting that excitatory amino acids indirectly affect carbachol-stimulated phosphoinositide hydrolysis. The inhibition by excitatory amino acids of carbachol-stimulated phosphoinositide breakdown was dependent on extracellular Mg2+ and was abolished by procedures that increase intracellular Ca2+. Veratridine inhibition of carbachol-stimulated phosphoinositide hydrolysis was reversed by ouabain but not by other procedures that increase intracellular Ca2+. In contrast to excitatory amino acids, veratridine potentiated carbachol-stimulated phosphoinositide breakdown in the presence of 10 mM extracellular Mg2+. These data suggest that excitatory amino acids inhibit carbachol-stimulated phosphoinositide breakdown in rat cortex by lowering intracellular Ca2+ through a mechanism dependent on extracellular Mg2+.

Norepinephrine promotes long-term potentiation in the adult rat hippocampus in vitro

“…Similar to the findings presented here, the inhibition of LTP by NMDA is overcome by NE acting via ␣1-adrenoceptors (Izumi et al, 1992b). Additionally, NMDA inhibits PI turnover stimulated by mGluRs and cholinergic receptors (Palmer et al, 1988;Gonzales et al, 1991;Bohner et al, 1992;Lee and Fain, 1992;Myles et al, 1996) but not PI turnover mediated by ␣1-adrenoceptors (Jope and Li, 1989). The inhibition of LTP by NMDA is also blocked by administration of 10 µM APV and 100 µM L-NMMA, suggesting that NO release produced by untimely NMDA receptor activation has a negative influence on LTP induction in slices from younger animals (Izumi et al, 1992c).…”

Modulation by Ionotropic Excitatory Amino Acids and Potassium of (±)‐1‐Aminocyclopentane‐trans‐1,3‐Dicarboxylic Acid‐Stimulated Phosphoinositide Hydrolysis in Mouse Cerebellar Granule Cells

“…The involvement of a specific feedback mechanism is supported by several reports showing that NMDA inhibits phosphoinositide hydrolysis stimulated by metabotropic agonists (Palmer et al, 1988;Bohner et al, 1992 ;Lee and Fain, 1992;Ham and Scanlon, 1994 ;Morari et al ., 1994) . In this and other studies , higher concentrations of NMDA, rather than inhibiting phosphoinositide hydrolysis per se, appeared to have a reduced ability to potentiate trans-ACPD-stimulated responses .…”