NMDA receptors, 50-51

In addition to being expressed in neurons, NMDA receptors are expressed as well in growth cones of oligodendrocytes, and play a critical role both in development and in ischemia-induced damage (Karadottir et al., 2005 Salter and Fern, 2005). 

Molecular composition NMDA receptors are composed of multiple subunits including at least one NR1 subunit and one or more modulatory subunits from the NR2 (NR2A-NR2D) and/or NR3 (NR3A, NR3B) families. Further eight splice variants have been identified for the NR1 subunits. Each functional NMDA receptor is a heteromultimer, consisting of combinations of NR1, NR2 and/or NR3 subunits. 

Levels of both glycine and D-serine are reported to be reduced in schizophrenia, although findings remain controversial. In the case of glycine, reduced plasma levels in schizophrenia correlate with the severity of negative symptoms (Sumiyoshi et al., 2004 Neeman et al., 2005) and response to clozapine (Sumiyoshi et al., 2005). In the case of D-serine, reduced serum (Hashimoto et al., 2003) and CSF (Hashimoto et al., 2005 Bendikov et al., 2007) levels have been reported, although contrary results have also been obtained (Fuchs et al., 2008). 

Moreover, if AMPA density falls below a critical threshold, levels of depolarization are insufficient to unblock NMDA channels, preventing postsynaptic depolarization or Ca2+ influx. The lack of Ca2+ influx prevents subsequent AMPA receptor insertion into the postsynaptic membrane. Thus, such synapses, despite containing intact NMDA receptors, are functionally silent and cannot be recovered by electrical stimulation alone (Isaac et al., 1999). This silencing of synapses could limit the degree of recovery to be expected even if normal glutamatergic functioning could be restored. 

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In addition to halopeiidol, the putative neuroleptics, limcazole (311), lemoxipiide (312), and gevotioline (313) bind to (7-ieceptois as does the dopamine uptake blocker, GBR 12909 (314) and two ligands active at the NMDA receptor, ifenprodil (315) and CNS 1102 (316). NPC 16377, (317) is a selective (7-teceptor ligand. MAO inhibitors and antidepressants also bind to (7-teceptors. Some evidence indicates that (7-teceptors in the brain are in fact a form of cytochrome which may account for the diversity of ligands interacting with (7-sites. 

Grb-2 facilitates the transduction of an extracellular stimulus to an intracellular signaling pathway, (b) The adaptor protein PSD-95 associates through one of its three PDZ domains with the N-methyl-D-aspartic acid (NMDA) receptor. Another PDZ domain associates with a PDZ domain from neuronal nitric oxide synthase (nNOS). Through its interaction with PSD-95, nNOS is localized to the NMDA receptor. Stimulation by glutamate induces an influx of calcium, which activates nNOS, resulting in the production of nitric oxide. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Lovinger DM (2000) Examination of ethanol spermine and acamprosate actions on native and recombinant NMDA receptors. Alcohol Clin Exp Res 24 183A... 

Whereas the role of AMPA and NMDA receptors in fast synaptic transmission is well characterized, only few examples demonstrating synaptic responses due to kainate receptor activation are known so far. 

Both AMPA and NMDA receptors are multimeric, probably tetrameric, assemblies of various molecularly distinct subunits, giving rise to large receptor diversity. For AMPA receptors this is achieved by assembling the... 

In contrast to AMPA receptors, NMDA receptor channels display a prominent Ca2+ permeability, which is largely independent ofthe subunit composition. It has been shown by mutational analysis that the Ca2+ permeability of recombinant NMDA receptors is dependent on a residue at a position equivalent to the Q/R site of AMPA subunits. Both NR1 and NR2 subunits contain an asparagine (N) residue at this position. Replacing this N with an R within the NR1 subunit led to the formation of NMDA receptors with a strongly reduced Ca2+ permeability, whereas exchanging N for Q in the NR2 subunit had only a small effect,... 

Antagonists selective for kainate receptors are not available yet. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocks AMPA as well as kainate receptors. Nevertheless, compounds like GYKI53655, which acts as a noncompetitive antagonist of AMPA receptors and completely blocks AMPA receptor function at certain concentrations at which no antagonistic effect on kainate receptors is discernible, has been used to demonstrate the kainate receptor-mediated currents in neurons. 

Kemp JA, Kew JNC, Gill R (1999) NMDA receptor antagonists and their potential as neuroprotective agents, chapter 16 Ionotropic glutamate receptors in the CNS. Springer Verlag... 

Lipton SA (2006) Paradigm shift in neuroprotection by NMDA receptor blockade memantine and beyond. Nat Rev Drug Discov 5 160-170... 

NMDA (iV-methyl-D-aspartic acid) is a synthetic derivative of aspartic acid and represents the prototypical agonist at the NMDA receptors for which the latter were named. 

NMDA receptors are subtypes of ionotropic glutamate receptors activated by NMDA forming heteromers... 

On the pathophysiological side, hyperactive nNOS has been implicated in A/-methyl-D-aspartate (NMDA)-receptor-mediated neuronal death in cerebrovascular-stroke. Some disturbances of smooth muscle tone within the gastrointestinal tract (e.g., gastroesophageal reflux disease) may also be related to an overproduction of NO by nNOS in peripheral nitrergic nerves. 

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