Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S,3R‐ACPD in neonatal rat cerebral cortex

Abstract

1 The effect of NMDA-receptor stimulation on phosphoinositide signalling in response to the metabotropic glutamate receptor agonist I-aminocyclopentane-1S,3R-dicarboxylic acid (lS,3R-ACPD) has been examined in neonatal rat cerebral cortex slices. 7 Both basal and 1S,3R-ACPD-stimulated Ins(1,4,5)P3 accumulations were reduced when slices were incubated in nominally Ca2"-free medium. Under these conditions only a concentration-dependent enhancement of the response was observed (EC50 for NMDA facilitation of lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation of 32 AM). 8 These experiments have revealed that at low concentrations, NMDA can dramatically potentiate 1S,3R-ACPD-stimulated phosphoinositide hydrolysis, probably by a Ca2"-dependent facilitation of agonist-stimulated phosphoinositide-specific phospholipase C activity. Higher concentrations of NMDA result in time-dependent inhibition of the metabotropic agonist-stimulated response. We believe the former effect could be fundamental in glutamate receptor 'cross-talk', whereas the latter may reflect a Ca2+-dependent neurotoxic effect of NMDA on the neonatal cerebral cortex slices.

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

“…Previous studies have shown that NMDA potentiates mGluR5 responses (Challiss et al, 1994;Luthi et al, 1994). We have previously shown that a likely mechanism for this effect is via reversal of PKC-mediated desensitization of mGluR5 (Alagarsamy et al, 1999a).…”

“…For instance, low concentrations of NMDA can enhance mGluR-mediated increases in phosphoinositide hydrolysis in rat cortex (Challiss et al, 1994;Alagarsamy et al, 1999b). Furthermore, NMDA receptor activation potentiates an inward current induced by 1S,3R-ACPD in hippocampal pyramidal cells (Luthi et al, 1994;Alagarsamy et al, 1999a).…”

Differences in agonist and antagonist activities for two indices of metabotropic glutamate receptor‐stimulated phosphoinositide turnover

“…Thus, in studies investigating the interactions between ionotropic and metabotropic glutamate receptor signalling mechanisms we demonstrated that modest concentrations of NMDA could not only enhance the maximal [3H]-InsPx response to IS, 3R-ACPD, but also significantly leftward-shift the EC50 value (from 16.6 to 4.9 gM; Challiss et al, 1994b). [3H]-InsPx responses would be that the Ca2+-mediated component is less susceptible (or is insensitive) to (±)-MCPG.…”

“…Although heterologous expression of specific mGluR subtypes can in theory provide almost unlimited supplies of material for pharmacological characterization of putative mGluR agonists/antagonists using radioligand binding methods, few studies have adopted this approach (Thomsen et al, 1993;Laurie et al, 1995) (Schoepp et al, 1991;Manzoni et al, 1992;Jones & Roberts, 1993;Challiss et al, 1994b). In contrast, IR, 3S-ACPD was essentially without effect at concentrations up to 300 gM.…”

“…That IR, 3R-ACPD exerts its predominant action via NMDAreceptor activation provides a possible explanation for the decreasing ability of this agent to stimulate [3H]-InsPx accumulation at higher concentrations (see Figure la). We have previously shown that substantial activation of NMDA-receptors in this tissue can cause a rapid Ca2 +-dependent neurotoxic effect which compromises subsequent or on-going phosphoinositide cycle activation (Challiss et al, 1994b). Indeed, preliminary experiments have shown that, in contrast to the time-course of [3H]-InsPx accumulation stimulated by IS, 3R-ACPD (see Figure 5), 300 gM IR, 3R-ACPD causes a linear [3H]-InsPx for only the first 1-2 min after agonist addition with the rate decreasing progressively with increasing exposure time, reminiscent of the response seen previously following NMDA challenge (Challiss et al, 1994b evident that in the presence of (± )-MCPG the inhibitory effect of this agent was more pronounced during the initial 1-2 min following IS, 3R-ACPD addition (see Figure 5).…”