Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NMDA receptors are composed of multiple receptor subunit proteins, of which NMDAR1 appears to be a critical component for normal receptor function (Nakanishi, 1992). In this study, quantitative immunocytochemical methods were used at the light and electron microscopic levels to localize NMDAR1 subunits in the primary motor (M1) and somatic sensory (S1) cortex of monkeys, and in the primary visual cortices (V1) of monkey and human. Three principal features of NMDAR1 subunit organization were examined in detail in the monkey cortex: (1) the laminar and cellular distribution patterns, relying in part on double-labeling paradigms with the calcium-binding proteins parvalbumin (PV) and calretinin (CR) as markers for discrete subpopulations of GABAergic interneurons; (2) the codistribution of NMDAR1 subunits with non-NMDA ionotropic receptor subunits; (3) a quantitative assessment of the percentages of asymmetrical synapses in layers II/III, IV, and V/VI that were NMDAR1 immunoreactive. In monkey M1, S1, and V1, NMDAR 1 immunoreactivity was present in all layers, localized primarily to large numbers of pyramidal cell somata and proximal apical dendrites, to presumptive spiny stellate cells in layer IV of V1, and to the vast majority (approximately 80-90%) of PV-immunoreactive cells. By contrast, NMDAR1 immunoreactivity was present in only a very small percentage of the CR-immunoreactive cells (approximately 6-9%). Colocalization with non-NMDA receptor subunits showed that all cells (100%) that contained GluR2/3 subunits were also NMDAR1 immunoreactive. In addition, the complete codistribution of GluR5/6/7 subunits with GluR2/3 subunits suggests, indirectly, that all GluR5/6/7-immunoreactive cells are also NMDAR1 immunoreactive. The laminar and cellular distribution patterns of immunostaining in human V1 were very similar to those in monkey V1. Electron microscopy of monkey sections confirmed an extensive dendritic and synaptic localization of NMDAR1 subunits. Labeling of synapses was present on asymmetrical postsynaptic densities associated with both dendritic shafts and spines. In supragranular layers of V1, a greater percentage of asymmetrical synapses were NMDAR1 immunopositive (44%) in comparison to layer IVC beta (34%) or deep layers (19%). In contrast, in area 3b of S1, the percentage of labeled synapses was greatest in layer IV (45%) in comparison to superficial (26%) and deep (37%) layers, while in M1, the percentages of labeled synapses were similar between superficial (46%) and deep (40%) layers. Taken together, these data indicate that NMDAR1-immunoreactive cells in neocortex represent a morphologically, functionally, and neurochemically heterogeneous population.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Distribution and synaptic localization of immunocytochemically identified NMDA receptor subunit proteins in sensory-motor and visual cortices of monkey and human. 820 75

1. We have identified a new type of NMDA channel in rat central neurones that express mRNA for the NR2D subunit. We have examined single NMDA channels in cerebellar Purkinje cells (which possess NR1 and 2D), deep cerebellar nuclei (NR1, 2A, 2B and 2D) and spinal cord dorsal horn neurones (NR1, 2B and 2D). 2. In Purkinje cells, NMDA opened channels with a main conductance of 37.9 +/- 1.1 pS and a subconductance of 17.8 +/- 0.7 pS, with frequent transitions between the two levels. 3. NMDA activated low-conductance ('38/18 pS') events (along with high-conductance--'50/40 pS'--openings) in some patches from deep cerebellar nuclei and dorsal horn neurones. Our evidence suggests that 38/18 pS and 50/40 pS events arose from distinct types of NMDA receptors. 4. The transitions for 38/18 pS events were asymmetrical: steps from 38 to 18 pS were more frequent (72.2%) than steps from 18 to 38 pS. This feature appeared common to the 38/18 pS events in all three cell types, suggesting similarity in the low-conductance channels. 5. The 38/18 pS channels in Purkinje cells exhibited characteristic NMDA receptor properties, including requirement for glycine, antagonism by D-2-amino-5-phosphonopentanoic acid (D-AP5) and 7-chlorokynurenic acid, and voltage-dependent block by extracellular Mg2+. 6. The mean open time for the 38 pS state (0.74 +/- 0.07 ms) was significantly briefer than that for the 18 pS state (1.27 +/- 0.18 ms). 7. Mg2+ block of low-conductance NMDA channels in Purkinje cells was less marked than block of 50/40 pS channels in cerebellar granule cells. 8. The time course of appearance of 38/18 pS NMDA channels matched the expression of mRNA for the NR2D subunit. Thus 38/18 pS events were present in > 70% of Purkinje cell patches in 0- to 8-day-old animals, and absent by postnatal day 12. 9. We propose that the 38/18 pS NMDA channels identified here (associated with the NR2D subunit), and the other low-conductance NMDA channel associated with the NR2C subunit, may together constitute a functionally distinct subclass of native NMDA receptors.
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PMID:Identification of a native low-conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones. 884 6

We used electron microscopic immunocytochemistry with antibodies against NR1 and NR2A and B subunits to study the distribution of N-methyl-D-aspartate (NMDA) receptors in presynaptic axon terminals in the rat cerebral cortex. In all sections examined, NR1 and NR2A/B immunoreactivities were observed in axon terminals: NR1- and NR2A/B-positive axon terminals made both symmetrical and asymmetrical synapses on unlabelled dendritic profiles. Combined pre- and postembedding studies showed that all NR1 and NR2A/B-positive axon terminals making symmetrical synapses were gamma-aminobutyric acid (GABA)-positive. These observations show that both auto- and hetero- NMDA receptors do exist in the cerebral cortex, and indicate that part of the effects of NMDA receptor activation might be determined by modulating glutamate and GABA release.
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PMID:Presynaptic NMDA receptors in the neocortex are both auto- and heteroreceptors. 898 65

We have investigated the membrane properties and excitatory synaptic transmission of mitral cells in a slice preparation of rat olfactory bulb. In response to intracellular injection of depolarizing current, most mitral cells showed several distinct membrane properties: (1) delayed onset of firing (suggesting the presence of a type of potassium A current); (2) subthreshold oscillation of the membrane potential; and (3) repetitive firing of clustered action potentials during prolonged threshold stimulation. Olfactory nerve (ON) stimulation evoked a long-lasting EPSP in most of the mitral cells. This long EPSP was completely blocked by combined application of NMDA and non-NMDA receptor antagonists (20 microM CNQX and 100 microM APV), confirming that glutamate is the neurotransmitter at the synapses from ON to mitral cells. The ON-evoked EPSP was preceded by a prespike, which was resistant to membrane potential hyperpolarization at the soma. This fast prepotential may be indicative of an active response in the primary dendritic tufts of the mitral cells. Stimulation of the lateral olfactory tract evoked an antidromic pulse followed by a short EPSP, which could also be elicited independently of an antidromic spike in the recorded cell. Since the asymmetrical synapses so far observed on the mitral cells are all form the ON, this antidromically evoked EPSP may reflect self-excitation of a mitral cell by glutamate released from its own dendrites by antidromic impulse invasion, or/and lateral excitation by neighboring invaded dendrites.
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PMID:Membrane and synaptic properties of mitral cells in slices of rat olfactory bulb. 903 9

The cellular and synaptic localization of immunoreactivity for the N-methyl-D-aspartate (NMDA) receptor subunit, NMDAR1, was investigated in inferotemporal and prefrontal association neocortices of monkeys and humans. In all monkey association areas examined, the laminar distribution patterns of NMDAR1 immunoreactivity were similar, and characterized by predominant pyramidal-like neuronal labeling in layers II, III, V and VI and a dense neuropil labeling consisting of intensely stained puncta and fine-caliber processes present throughout layers I-III, and V-VI. Layer IV, in contrast, contained only very lightly immunostained neurons which mostly lacked extensive dendritic staining. The laminar distribution of NMDAR1 immunolabeling in human association cortex was similar to that observed in monkeys. Electron microscopy of monkey areas 46 and TE1 confirmed that intensely immunoreactive asymmetrical postsynaptic densities were present throughout all cell-dense layers of prefrontal and inferotemporal association cortex. Quantitative analyses of the laminar proportions of immunoreactive synapses demonstrated that in both areas examined, the percentages of immunolabeled synapses were mostly similar across superficial layers, layer IV and infragranular layers. Finally, quantitative double-labeling immunofluorescence for non-NMDA receptor subunits or calcium-binding proteins demonstrated that virtually all GluR2/3 or GluR5/6/7-immunoreactive neurons were also labeled for NMDAR1, while regionally-specific subsets of parvalbumin-, calbindin- and calretinin-immunoreactive neurons were co-labeled. These data indicate that in primate association cortex, NMDA receptors are heterogeneously distributed to subsets of functionally distinct types of neurons and subsets of excitatory synapses, suggesting a critical and highly specific role in mediating the activity of excitatory connectivity which converges on cortical association areas.
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PMID:Quantitative localization of NMDAR1 receptor subunit immunoreactivity in inferotemporal and prefrontal association cortices of monkey and human. 913 25

1. Two classes of amphiphilic compounds, lysophospholipids and arachidonic acid, have been suggested to produce opposite deformations of the lipid bilayer. We have found that their effects on N-methyl-D-aspartate (NMDA) responses are opposite, and resemble those of mechanical deformations of the plasma membrane. 2. Lysophospholipids inhibited NMDA responses both in nucleated patches taken from cultured neurons and in cells expressing recombinant NMDA receptors. This inhibition was reversible, voltage independent and stronger at non-saturating doses of agonist. It was not linked to the charge of the polar head, and was not mimicked by lysophosphatidic acid or phosphatidylcholine. In outside-out patches, lysophospholipids reduced the open probability of NMDA-activated channels without changing their single-channel conductance. 3. The inhibition produced by lysophospholipids occluded that produced by a mechanical compression induced by changes in osmotic or hydrostatic pressure. 4. The potentiation of NMDA responses by arachidonic acid was observed both in native and recombinant receptors, including those in which the putative 'fatty acid binding domain' had been deleted. This suggests that, like lysophospholipids, arachidonic acid alters the NMDA receptor by insertion into the lipid bilayer. 5. Recombinant receptors in which the cytoplasmic tails had been modified or deleted were still sensitive to mechanical deformation. A linkage to the cytoskeleton is therefore not required for NMDA receptor mechanosensitivity. 6. The fact that the NMDA responses are depressed similarly by compression and lysophospholipids, and potentiated similarly by stretch and arachidonic acid supports the notion that the modulation of NMDA receptor activity by asymmetrical amphiphilic compounds involves pressure changes transmitted through the lipid bilayer. Compounds with a large hydrophilic head mimic the effects of a compression, and compounds with a small hydrophilic head mimic the effects of stretch.
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PMID:Opposite modulation of NMDA receptors by lysophospholipids and arachidonic acid: common features with mechanosensitivity. 980 85

A unilateral injury to the forelimb area of the sensorimotor cortex results in an increase in dendritic arborization in the contralateral homotopic cortex which is followed by a pruning back of these dendritic arbors. The increase in arborization is due to an increase in the use of the unimpaired forelimb for postural-motor support; whereas, the dendritic pruning is related, in time, to the return to more symmetrical limb use, but is not prevented by the maintenance of asymmetrical limb use. Dendritic pruning can be prevented by administering an NMDA receptor antagonist (such as MK801 or ethanol) during the pruning phase. This manipulation also coincides with the chronic reinstatement of behavioral deficits. The purpose of this study was to see whether removing the antagonism of the NMDA receptor results in the eventual return of dendritic pruning and behavioral recovery. Therefore, MK801 was administered to lesioned animals starting at post-lesion day 18. One group received MK801 injections until day 60 (Lesion + MK60) and another lesioned group received MK801 until day 30 after which the injections were changed to saline until day 60 (Lesion + MK30). Lesion + MK60 animals showed a prevention of dendritic pruning as well as a chronic reinstatement of forelimb deficits. Lesion + MK30 animals also showed a prevention of dendritic pruning, however, they showed behavioral recovery. These findings suggest that pruning of dendritic arbors may not be directly related to behavioral recovery.
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PMID:Relationship between dendritic pruning and behavioral recovery following sensorimotor cortex lesions. 986 34

Glutamatergic neurotransmission in the neostriatum and the globus pallidus is mediated through NMDA-type as well as other glutamate receptors and is critical in the expression of basal ganglia function. In order to characterize the cellular, subcellular and subsynaptic localization of NMDA receptors in the neostriatum and globus pallidus, multiple immunocytochemical techniques were applied using antibodies that recognize the NR1 subunit of the NMDA receptor. In order to determine the spatial relationship between NMDA receptors and AMPA receptors, double labelling was performed with the NR1 antibodies and an antibody that recognizes the GluR2 and 3 subunits of the AMPA receptor. In the neostriatum all neurons with characteristics of spiny projection neurons, some interneurons and many dendrites and spines were immunoreactive for NR1. In the globus pallidus most perikarya and many dendritic processes were immunopositive. Immunogold methods revealed that most NR1 labelling is associated with asymmetrical synapses and, like the labelling for GluR2/3, is evenly spread across the synapse. Double immunolabelling revealed that in neostriatum, over 80% of NR1-positive axospinous synapses are also positive for GluR2/3. In the globus pallidus most NR1-positive synapses are positive for GluR2/3. In both regions many synapses labelled only for GluR2/3 were also detected. These results, together with previous data, suggest that NMDA and AMPA receptor subunits are expressed by the same neurons in the neostriatum and globus pallidus and that NMDA and AMPA receptors are, at least in part, colocalized at individual asymmetrical synapses. The synaptic responses to glutamate in these regions are thus likely be mediated by both AMPA and NMDA receptors at the level of individual synapses.
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PMID:Subcellular and subsynaptic distribution of the NR1 subunit of the NMDA receptor in the neostriatum and globus pallidus of the rat: co-localization at synapses with the GluR2/3 subunit of the AMPA receptor. 987 51

Generally, compounds discriminated by animals possess psychotropic effects in animals and humans. As with many other drugs of abuse, strength of the ethanol discriminative stimulus is dose related. The majority of studies show that doses close to 1.0 g/kg are close to the minimum at which the discrimination can be learned easily. Substitution studies suggest that anxiolytic, sedative, atactic, and myorelaxant effects of ethanol all play an important role in the formation of its intercoeptive stimulus. Low doses of ethanol produce more excitatory cues, similar to amphetamine-like subjective stimuli, whereas higher doses produce rather sedative/hypnotic stimuli similar to those elicited by barbiturates. Substitution studies have shown that the complete substitution for ethanol may be exerted by certain GABA-mimetic drugs acting through different sites within the GABA(A)-benzodiazepine receptor complex (e.g., diazepam, pentobarbital, certain neurosteroids), gamma-hydroxybutyrate, and antagonists of the glutamate NMDA receptor. Among the NMDA receptor antagonists both noncompetitive (e.g., dizocilpine) and competitive antagonists (e.g., CGP 40116) are capable of substituting for ethanol. Further, some antagonists of strychnine-insensitive glycine modulatory sites among the NMDA receptor complex (e.g., L-701,324) dose-dependently substitute for the ethanol discriminative stimulus. On the other hand, neither GABA-benzodiazepine antagonists nor NMDA receptor agonists produce contradictory effects (i.e., reduce the ethanol discriminative stimulus). There is influence of a particular training dose of ethanol on the substitution pattern of different compounds. For example, 5-HT(1B/2C) agonists substitute for intermediate (1.0 g/kg) but not higher (2.0 g/kg) ethanol training doses. Discrimination studies with ethanol and drugs acting on NMDA and GABA receptors consistently indicate asymmetrical generalization. For example, ethanol is able to generalize to barbiturates and benzodiazepines, but neither the benzodiazepine nor barbiturate response generalizes to ethanol. Only a few drugs are able to antagonize, at least to some extent, the discriminative stimulus of ethanol (e.g., partial inverse GABA-benzodiazepine receptor antagonist Ro 15-4513 and the opioid antagonist naloxone). The ethanol stimulus effect may be increased (i.e., stronger recognition) by N-cholinergic drugs (nicotine), dopaminergic drugs (apomorphine), and 5-HT3 receptor agonists (m-chlorophenylbiguanide). Thus, the ethanol stimulus is composed of the several components, with the NMDA receptor and GABA(A) receptor complex being of particular importance. This suggests that a drug mixture may be more capable of substituting for ethanol (or block its stimulus) than a single compound. The ability of drugs to substitute for the ethanol discriminative stimulus is frequently, although not preclusively, associated with the reduction of voluntary ethanol consumption. The examples of positive correlation are gamma-hydroxybutyrate, possibly memantine and certain serotonergic drugs such as fluoxetine. However, it remains uncertain to what extent the discriminative stimulus of ethanol can be seen as relevant in the understanding of the complex mechanisms of dependence.
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PMID:Discriminative stimulus effects of ethanol: neuropharmacological characterization. 989 39

1. Dual whole-cell recordings were made from pairs of synaptically coupled excitatory neurones in the 'barrel field' in layer (L) 4 in slices of young (postnatal day 12-15) rat somatosensory cortex. The majority of interconnected excitatory neurones were spiny stellate cells with an asymmetrical dendritic arborisation largely confined to a single barrel. The remainder were star pyramidal cells with a prominent apical dendrite terminating in L2/3 without forming a tuft. 2. Excitatory synaptic connections were examined between 131 pairs of spiny L4 neurones. Single presynaptic action potentials evoked unitary EPSPs with a peak amplitude of 1.59 +/- 1.51 mV (mean +/- s. d.), a latency of 0.92 +/- 0.35 ms, a rise time of 1.53 +/- 0.46 ms and a decay time constant of 17.8 +/- 6.3 ms. 3. At 34-36 C, the coefficient of variation (c.v.) of the unitary EPSP amplitude was 0. 37 +/- 0.16 and the percentage of failures to evoke an EPSP was 5.3 +/- 7.8 %. The c.v. and failure rate decreased with increasing amplitude of the unitary EPSP. 4. Postsynaptic glutamate receptors in spiny L4 neurones were of the AMPA and NMDA type. At -60 mV in the presence of 1 mM Mg2+, NMDA receptors contributed 39.3 +/- 12.5 % to the EPSP integral. In Mg2+-free solution, the NMDA receptor/AMPA receptor ratio of the EPSC was 0.86 +/- 0.64. 5. The number of putative synaptic contacts established by the projection neurone with the target neurone varied between two and five with a mean of 3.4 +/- 1.0 (n = 11). Synaptic contacts were exclusively found in the barrel in which the cell pair was located and were preferentially located on secondary to quarternary dendritic branches. Their mean geometric distance from the soma was 68.8 +/- 37.4 microm (range, 33.4-168.0 microm). The number of synaptic contacts and mean EPSP amplitude showed no significant correlation. 6. The results suggest that in L4 of the barrel cortex synaptic transmission between spiny neurones is largely restricted to a single barrel. The connections are very reliable, probably due to a high release probability, and have a high efficacy because of the compact structure of the dendrites and axons of spiny neurones. Intrabarrel connections thus function to amplify and distribute the afferent thalamic activity in the vertical directions of a cortical column.
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PMID:Reliable synaptic connections between pairs of excitatory layer 4 neurones within a single 'barrel' of developing rat somatosensory cortex. 1056 43


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