NMDA receptors are typically excited by a combination of glutamate and glycine. Here we describe excitatory responses in CNS myelin that are gated by a glycine agonist alone and mediated by NR1/NR3 "NMDA" receptor subunits. Response properties include activation by d-serine, inhibition by the glycine-site antagonist CNQX, and insensitivity to the glutamate-site antagonist d-APV. d-Serine respon...

Multiple lines of evidence indicate that hypofunction of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia, suggesting that increasing NMDA receptor function via pharmacological manipulation could provide a new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptor...

Acutely isolated rat hippocampal neurons were voltage-clamped in the whole-cell configuration. The currents through N-methyl-D-aspartate (NMDA) channels were elicited by fast application of aspartate in a Mg(2+)-free 3 microM glycine-containing solution. Eosine, known as a potent reversible inhibitor of the plasma membrane Ca(2+) pump, proved to be able to induce a blockade of NMDA channels. Th...

Provocative emerging evidence suggests that the N-methyl-d-aspartate (NMDA) receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depre...

The interactions between N-methyl-D-aspartate (NMDA) and D(1) dopamine receptors in the rat prefrontal cortex were examined using whole-cell recordings from pyramidal neurons. The effects of NMDA, the D(1) agonist SKF38393, or both compounds combined were tested on measures of cell excitability. Both NMDA (10-100 microM) and SKF38393 (5-10 microM) independently increased the number of spikes an...

Interactions between dopaminergic and glutamatergic systems in the striatum are thought to underlie both the symptoms and adverse effects of treatment of Parkinson's disease. We have previously reported that activation of the dopamine D1 receptor triggers a rapid redistribution of striatal N-methyl-d-aspartate (NMDA) receptors between intracellular and postsynaptic sub-cellular compartments. To...

Activation of N-methyl-D-aspartate (NMDA) receptors is known to produce arachidonic acid release, which has been implicated in excitotoxicity. Antagonists and partial agonists at the glycine site of the NMDA receptor, despite exhibiting functional differences in electrophysiological studies, inhibit glutamate-induced neurotoxicity and ischemia-induced neurodegeneration. The objective of this st...

The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic ...

NMDA receptors are tetrameric ligand-gated ion channels. In the continuous presence of saturating agonists, NMDA receptors undergo stationary gating, in which the channel stochastically switches between an open state that permits ion conductance and a closed state that prevents permeation. The ligand-binding domains (LBDs) of the four subunits are expected to have closed clefts in the channel-o...

Glutamate-gated channels mediate fundamental brain processes, yet the mechanisms by which the neurotransmitter controls channel activation are incompletely understood. Structural studies revealed that the agonist has the critical role of bridging the divide between two flexible extracellular lobes and solidified the view that agonist-induced cleft-closure drives further isomerizations, which ev...