Signal transduction pathways involved in the acute potentiation of NMDA responses by 1S,3R‐ACPD in rat hippocampal slices

Abstract

1 A grease-gap recording technique has been used to investigate the mechanisms underlying the acute potentiation of N-methyl-D-aspartate (NMDA) responses by aminocyclopentane-1S,3R-dicarboxylic acid (IS,3R-ACPD) in area CAI of rat hippocampal slices.2 1S,3R-ACPD (1OM), but not IR,3S-ACPD (1OEM), potentiated submaximal responses to NMDA (dose-ratio of 0.81 ± 0.02 (mean ± s.e.mean); n = 55), but not to a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), in a readily reversible manner. Potentiation also occurred in slices treated with 0.2 tLM tetrodotoxin, and in slices perfused with Mg2"-free medium.3 IS,3R-ACPD-induced potentiation was unaffected by the protein kinase inhibitors K-252b (0.1 tLM) and staurosporine (1 gM) and the intracellular Ca2+ store depletor, thapsigargin (10 gM). Coapplication of staurosporine and thapsigargin was also without effect. 4 IS,3R-ACPD-induced potentiation was unaffected by inhibitors of arachidonic acid formation, bromophenacyl bromide (50 tM) and RG80267 (100 gM). Arachidonic acid (10-50 gM) depressed reversibly NMDA-induced responses. The potentiation was unaffected by 8-bromo cyclic AMP (500 jAM) or the PKA inhibitor Rp-adenosine 3,5-cyclic monophosphothioate triethylamine (Rp-cAMPS; 50 jAM). 5 IS,3R-ACPD-induced potentiation was abolished in slices perfused with Ca2+-free medium. The potentiation was also blocked by phorbol-12,13-diacetate (1 gM), in a staurosporine-sensitive manner.6 It is concluded that the potentiation of NMDA responses by IS,3R-ACPD is not mediated by protein kinase A or C, by release of Ca2+ from intracellular stores or by arachidonic acid. It involves a Ca2+-sensitive process and is negatively regulated by protein kinase C.

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

“…At low concentrations, NMDA potentiates lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation, probably by increasing intracellular Ca2" concentration and facilitation of agonist-stimulated PI-PLC activity. These observations suggest that as well as NMDA-receptor/ion channel activity being affected by metabotropic receptor activation (Bleakman et al, 1992;Courtney & Nicholls, 1992;Chen & Huang, 1992;Kelso et al, 1992;Harvey & Collingridge, 1993), reciprocal modulations can also occur, providing additional evidence for the complexities of ionotropic/ metabotropic 'cross-talk' between glutamate receptors which are considered to underlie phenomena such as synaptic plasticity (Madison et al, 1991;Bashir et al, 1993;Behnisch & Reymann, 1993;Bliss & Collingridge, 1993). In contrast, exposure of neonatal cerebral cortex slices to higher concentrations of NMDA causes a rapidly developing inhibition of agonist-stimulated phosphoinositide responses which are most likely to be due to an acute, Ca2"-dependent neurotoxic action of NMDA in this brain preparation.…”

“…With respect to ionotropic/metabotropic interactions, activation of metabotropic glutamate receptors using a selective agonist (e.g. l-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD)) can potentiate NMDA receptor-mediated responses (Bleakman et al, 1992;Harvey & Collingridge, 1993), and co-activation of metabotropic and NMDA receptors has been implicated as a necessary requirement for induction and maintenance of long-term potentiation (Zheng & Gallagher, 1992;Bashir et al, 1993;Behnisch & Reymann, 1993).…”

Expression of Functional Metabotropic Glutamate Receptors in Primary Cultured Rat Osteoblasts

“…The majority of previous studies have demonstrated enhancement of NMDA responses upon activation of mGluRs (31)(32)(33)(34), but inhibitory effects mediated through group 1 (PLClinked) mGluRs have also been reported (35)(36)(37)(38). The inhibitory pathway varies, being via generation of diacylglycerol and protein kinase C activation (mimicked by 4␤-phorbol 12,13-dibutyrate; Ref.…”

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

“…One prominent effect of mGluR activation in many neuronal populations is an enhancement of agonist-evoked currents through NMDA receptor channels (Aniksztejn et al, 1991;Jones and Headley, 1995;Bleakman et al, 1992;Harvey and Collingridge, 1993;Fitzjohn et al, 1996;Pisani et al, 1997;Awad et al, 2000). In each of these cases, mGluR-induced potentiation of NMDA receptor currents is mediated by a group I mGluR.…”