Protein kinase C‐mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes.

Abstract

SUMMARY1. N-Methyl-D-aspartate (NMDA) receptors were expressed in Xenopus oocytes injected with rat brain RNA. The modulation of NMDA-induced currents was examined by activating protein kinase C (PKC) either directly (using phorbol esters) or indirectly (via metabotropic glutamate agonists).2. Bath application of the PKC activator, 4-,f-phorbol-12,13-dibutyrate (PDBu) resulted in a two-fold increase in the NMDA-evoked current at all holding potentials examined (-80 to 0 mV). The inactive (a) stereoisomer of phorbol ester was ineffective.3. The increase was observed under conditions that eliminate the oocyte's endogenous calcium-dependent chloride current, which often contributes to the NMDA response in oocytes. 4. The PDBu effect was specific to the NMDA subclass of glutamate receptors in that no increase was observed in the responses to two other glutamate agonists, kainate and AMPA (ac-amino-3-hydroxy-5-methylisoxazole-4-propionic acid).5. Stimulation of PKC by activation of metabotropic receptors via either quisqualate or trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) also led to an increase in NMDA currents.6. Both methods of enhancement induced transient effects. PDBu effects lasted 10-45 min, depending upon both dose and length of application. Quisqualate and trans-ACPD effects were shorter, lasting less than 10 min under these conditions of application. 7. Both methods of enhancement were blocked by the PKC inhibitor, staurosporine. In addition, the phorbol ester-induced enhancement of NMDA responses occluded further enhancement by quisqualate.8. The results suggest a role for metabotropic glutamate receptors in modulation of NMDA-mediated processes.

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

“…Consistent with this hypothesis, mGluR5 knockout (KO) mice are deficient in NMDA receptor-dependent LTP and spatial learning (Lu et al, 1997;Jia et al, 1998). These effects may be mediated by PKC-mediated potentiation of NMDA receptor function by group I mGluRs (Kelso et al, 1992;Aniksztejn et al, 1991;Skeberdis et al, 2001). …”

Ethanol inhibits kainate responses of glutamate receptors expressed in Xenopus oocytes: role of calcium and protein kinase C

“…Of the many Ca*'-mediated processes that might be responsible for the enhanced ethanol sensitivity, we focused on the role of PKC based on the existence of PKC consensus sites among the GluRs (Keinanen et al, 1990) and PKC-dependent receptor phosphorylation (McGlade-McCulloh et al, 1993) together with our work showing that activation of PKC inhibited kainate-induced currents in oocytes expressing different GluR subunits . However, there are reports that failed to show modulation of AMPA/kainate receptors by PKC (Sigel and Baur, 1988;Chen and Huang, 1992;Kelso et al, 1992), indicating that PKC modulation may not be a common mechanism for all of the GluRs or that the conditions required for PKC-dependent phosphorylation may be slightly different for different GluRs. We found that the PKC inhibitor peptide or the PKC inhibitor calphostin C prevented the enhanced ethanol inhibition in high-Ca'+ buffer but had no effect in normal buffer.…”

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.…”