Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of N-methyl-D-aspartate (NMDA) receptors is required for induction of some lasting changes in nervous system structure and function. The cellular mechanisms involved in transducing receptor stimulation into long-lasting changes in cellular activity are unknown. Immediate-early genes (IEGs) have been implicated in the conversion of short term stimuli to long term changes in cellular phenotype, by regulation of gene expression. Activation of NMDA receptors on dentate gyrus neurons triggers the transcriptional activation of several IEGs. To determine whether the same intracellular pathways transduce the signal from this ligand-gated ion channel to the nucleus, we compared NMDA induction of two IEGs. NMDA was sufficient to produce a striking increase in both c-fos and NGFI-A mRNAs in dentate granule neurons, in a calcium-dependent manner. The induction of both IEGs was blocked by structurally distinct inhibitors of phospholipase A2, an enzyme that catalyzes phospholipid degradation and formation of arachidonic acid. Arachidonic acid itself is catalyzed to biologically active metabolites by multiple enzymes, including cyclooxygenase and lipoxygenase. Selective inhibitors of cyclooxygenase attenuated NMDA induction of c-fos but not NGFI-A. Conversely, structurally distinct inhibitors of lipoxygenase blocked NMDA induction of NGFI-A but not c-fos. The signaling pathways linking NMDA receptors to the transcriptional activation of c-fos and NGFI-A are related but distinct. We suggest that phospholipase A2 and the arachidonic acid cascade play a pivotal role in NMDA receptor regulation of gene expression.
Mol Pharmacol 1995 Jun
PMID:N-methyl-D-aspartate receptors activate transcription of c-fos and NGFI-A by distinct phospholipase A2-requiring intracellular signaling pathways. 760 50

Schizophrenia is associated with a complex pattern of alterations in the glutamatergic system of the brain. Previous studies have shown a reduced density of some hippocampal non-N-methyl-D-aspartate (non-NMDA) receptors which is accompanied by a loss of encoding receptor mRNA. We have extended this work using in situ hybridization histochemistry with oligonucleotide probes specific for two non-NMDA receptor transcripts, GluR1 and GluR2, in right and left medial temporal lobe sections from 9 schizophrenics and 14 matched normal controls. Both mRNAs were found to be decreased bilaterally and to a similar degree in the hippocampal formation in schizophrenia. Analysis of autoradiograms showed a regional loss of GluR1 and GluR2 mRNAs in dentate gyrus, CA4, CA3 and subiculum. GluR2 mRNA was also reduced in parahippocampal gyrus. These reductions ranged from 25% to 70% in terms of 35S nCi/g tissue equivalents. Additionally we measured grain density for the mRNAs over individual pyramidal neurons in each area. GluR1 and GluR2 mRNAs were less abundant per neuron in CA4 and CA3 in schizophrenia than in controls. GluR2 mRNA was also reduced significantly in parahippocampal gyrus neurons, with an increase in the proportion of GluR1 mRNA to GluR2 mRNA in this cell population. No asymmetries in expression of GluR1 and GluR2 were found in normal or schizophrenic brains. These data further the evidence for reduced non-NMDA receptor expression in the medial temporal lobe in schizophrenia. They confirm the decrease in GluR1 mRNA and show that there are similar losses of GluR2 mRNA in the hippocampal formation. The pattern of changes in the two mRNAs suggests a common mechanism which is unknown but which may be a correlate of the neurodevelopmental abnormalities postulated to underlie the disease. The reduction of GluR2 mRNA but not GluR1 mRNA in parahippocampal gyrus neurons in schizophrenia may have functional consequences given the calcium permeability of non-NMDA receptors lacking the GluR2 subunit.
Brain Res Mol Brain Res 1995 Apr
PMID:Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. 760 9

Using a baculovirus expression vector system, the zeta 1 subunit of the mouse N-methyl-D-aspartate (NMDA) receptor channel was expressed in Spodoptera frugiperda insect cells. The peptide corresponding to the C-terminus of the zeta 1 subunit was synthesized by using the multiple antigen peptide (MAP) system, and an antibody to the synthetic peptide was produced. Immunoblotting using the newly developed antibody revealed the major 122-kDa and the minor 104-kDa protein bands. The effect of tunicamycin on the immunoblots and [35S]methionine/[35S]cysteine metabolic radiolabeling suggested that the two bands corresponded to glycosylated and non-N-glycosylated forms, respectively. Membranes prepared from insect cells infected with the recombinant virus had the binding activity of antagonist ligand 5,7-[3-3H]dichlorokynurenate (DCKA) of a glycine recognition domain of the receptor. Both immunofluorescence labeling and the [3H]DCKA binding assays also showed a greater level of expression (Bmax = 51 pmol/mg protein) in the insect cells. The ligand binding characteristics of the receptors expressed in insect cells suggested that the single zeta 1 subunit protein has glycine antagonist binding properties comparable to those of the native NMDA receptor channels. The lack of DCKA-binding activity of the non-N-glycosylated NMDA receptor expressed in the presence of tunicamycin suggested that N-linked oligosaccharide is essentially required for expression of a functional receptor in insect cells. This is the first report describing the importance of N-glycosylation for the acquisition of ligand binding to NMDA receptor channel subunit protein.
Brain Res Mol Brain Res 1995 May
PMID:Expression and characterization of the zeta 1 subunit of the N-methyl-D-aspartate (NMDA) receptor channel in a baculovirus system. 760 35

Nicotinic acetylcholine receptors (nAChRs), like other calcium permeable channel receptors, may play a crucial role during neuronal development. We have characterized nAChRs in developing mouse cerebellar granule cells in primary culture. L-[3H]Nicotine, [3H]cytisine and [125I]alpha-bungarotoxin binding experiments revealed the presence of a single class of saturable and specific high affinity binding sites for each ligand. The expression of these nicotinic binding sites followed a developmental pattern reaching a maximum during the establishment of excitatory amino acid synaptic contacts. Immunolabeling with monoclonal antibodies to nAChR subunits revealed the presence of alpha 4 and beta 2 subunits in most neurons. Moreover, some neuronal cells displayed a somatic as well as a neuritic localization for the alpha 7 subunit as shown by [125I]alpha-bungarotoxin autoradiography. The reverse transcription-polymerase chain reaction (RT-PCR) detected the presence of mRNAs for alpha 3, alpha 4, alpha 5, alpha 7, beta 2 and beta 4 nAChR subunits. Non-neuronal cells did not express nAChRs, as shown by [3H]nicotine and [125I]alpha-bungarotoxin binding, immunocytochemistry and PCR. Maximum Ca2+ influx elicited by nicotine, and partly sensitive to alpha-bungarotoxin, was observed around 10-14 days after plating. This correlated with the time period at which the highest number of nicotine binding sites was detected. Sensitivity to several NMDA receptor antagonists as well as to removal of endogenous glutamate by pyruvate transaminase treatment revealed a glutamatergic component in the nicotine stimulated calcium influx. The time-dependent specific nAChR expression and the potential association between nAChRs and NMDA receptor activation suggest that nAChRs may regulate glutamatergic activity during synaptogenesis in cerebellar granule cells.
Brain Res Mol Brain Res 1995 May
PMID:Characterization of nicotinic acetylcholine receptors expressed in primary cultures of cerebellar granule cells. 760 40

The present results indicate that during sexual maturation the APOA-MBH from rats of 30 days of age released significantly higher quantities of GnRH than the tissue from 16-day-old rats (P < 0.01). The addition of NMDA, an agonist of the excitatory amino acids system (EAAs), to the medium after 30 min of incubation significantly increased (P < 0.01) the GnRH release in normal rats of both ages and this increase was significantly (P < 0.01) higher in 30-day-old rats (to 661%) than in rats of 16 days of age (to 273%). The administration of estrogen-progesterone (EP) to rats of 16 days of age did not modify the GnRH release response to NMDA. On the contrary, at 30 days of age EP administration significantly potentiated the GnRH release response to NMDA since while in the control group NMDA increased the GnRH release to 630%, in the EP-pretreated group this was to around 4700% (P < 0.01). EP pretreatment of prepubertal rats decreases the hypothalamic release of aspartate and glutamate, the excitatory amino acids involved in NMDA neurotransmission and glycine but increases EAAs release in peripubertal rats. On the basis of these results it is proposed that the increase in EAAs release by the hypothalamus is directly connected with the onset of puberty and that the maturation of the positive feedback effect of ovarian hormones on gonadotropin secretion is related to the maturation of the capacity of EP to increase hypothalamic EAAs. Before this maturational event EP inhibits EAAs release as well as gonadotropin release (prepubertal rats). NMDA receptor stimulation leads to a positive mechanism which increases the release of Asp and Glu from APOA-MBH both in prepubertal and peripubertal rats, but EP potentiates this mechanism only in peripubertal rats. This could be an additional neuroendocrine mechanism involved in the increase of gonadotropin during sexual maturation which induces the onset of puberty and the preovulatory discharge of these pituitary hormones.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Hypothalamic excitatory amino acid system during sexual maturation in female rats. 762 77

In the present study, we investigated the effects of chronic ethanol exposure on NMDA-mediated increase in intracellular calcium concentration ([Ca2+]i) by means of fluorescent measurement of [Ca2+]i with Fura-2AM in mammalian cortical cultured neurons, and the radioligand [3H]MK-801 binding to cortical neuronal membranes. Chronic exposure of the cortical neurons to ethanol (50 mM, 5 days) did not produce any change in the cell protein, morphological appearance, and the resting [Ca2+]i; however, it significantly enhanced the NMDA-mediated increase in [Ca2+]i. The EC50 value of NMDA was not significantly altered following chronic ethanol exposure, however, its Emax value was increased by approximately 45%. Furthermore, chronic ethanol exposure increased the specific [3H]MK-801 binding in cortical neuronal membrane preparation by approximately 30%. The enhancement of the NMDA-mediated increase in [Ca2+]i and the increase in [3H]MK-801 specific binding were reversed following 48 h ethanol withdrawal. Additionally, this enhanced NMDA response and the increased [3H]MK-801 specific binding were susceptible to blockade by the concomitant chronic exposure of the cortical neurons to the NMDA receptor competitive (20 microM CPP), and non-competitive (1 microM MK-801) antagonists, but not by the non-NMDA receptor antagonist, CNQX (10 microM), and the L-type calcium channel blocker, nitrendipine (10 microM). Taken together, these results suggest that chronic ethanol exposure upregulated the NMDA receptor function and binding in cortical cultured neurons, and this increased NMDA receptor function is a NMDA receptor-mediated process. This altered NMDA receptor function may be responsible for the chronic ethanol-induced behavioral consequences and withdrawal syndrome associated with chronic ethanol exposure.
Brain Res Mol Brain Res 1995 Jun
PMID:Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons. 763 84

Aurintricarboxylic acid (ATA) is an endonuclease inhibitor which has been shown to block apoptotic cell death. We have now demonstrated that ATA is also an inhibitor of the Ca(2+)-activated neutral protease (calpain), a class of cytosolic enzyme that may also be activated during apoptosis. The two major calpain isoforms (mu- and m-calpain) were both inhibited by ATA with IC50's of 22 microM and 10 microM, respectively. The autolysis of purified mu-calpain was prevented by ATA in a concentration-dependent manner. Using casein zymography, it was found that the inhibition of mu-calpain by ATA was reversible. Finally, in a fetal rat cerebrocortical culture model of excitotoxicity, pre- and post-treatment of ATA (50 microM) reduced N-methyl-D-aspartate (NMDA)-induced spectrin breakdown and neuronal death, while application of ATA concurrent to NMDA challenge alone had no effect. This pattern of protection could not be explained by simple NMDA receptor antagonism. We thus propose that the neuroprotective effect of ATA could be in part due to its ability to inhibit calpain.
Biochem Mol Biol Int 1995 Jun
PMID:Aurintricarboxylic acid is an inhibitor of mu- and m-calpain. 766 33

The present study was performed to determine if 1-methyl-4-phenylpyridinium (MPP+) affects binding of [3H](-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate ([3H]MK-801), [3H]glutamate and [3H]glycine to the rat and monkey striatal N-methyl-D-aspartate (NMDA) receptor. We found that MPP+ non-competitively inhibits [3H]MK-801 binding with IC50 values between 80 and 330 microM depending on the species and the concentration of glutamate and glycine. MPP+ also partially inhibited [3H]glycine binding without affecting [3H]glutamate binding. We conclude that MPP+ is not an agonist at the NMDA receptor but at high concentrations inhibits NMDA receptor function.
Res Commun Mol Pathol Pharmacol 1995 May
PMID:Effects of 1-methyl-4-phenylpyridinium on radioligand binding to the NMDA receptor complex. 767 Aug 45

Many actions of the classical gonadal and adrenal steroid hormones are at the level of transcriptional regulation. Recent studies have shown, however, that endogenous brain metabolites of steroids exert important nongenomic modulatory effects on neuronal mechanisms. Potentiation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor by the neurosteroid pregnenolone sulfate (PS) was studied using cultured hippocampal neurons and patch-clamp techniques. The magnitude of NMDA-activated whole-cell currents was approximately doubled in the presence of 100 microM PS. The dose-response curve of PS action showed significant potentiation above 250 nM and a half-maximal effect at approximately 29 microM. Maximum potentiation was reached within 25 sec, and the potentiation was completely reversed with 60 sec of washout. The enhancement of the NMDA current is probably not due to activation of a new ionic conductance, because the reversal potential of the I-V curve did not shift in the presence of PS. Potentiation is specific for the NMDA subtype of glutamate receptor; non-NMDA currents showed only a slight inhibition (approximately 6%) in the presence of 50 microM PS. Potentiation of the NMDA current by PS occurred in the presence of saturating concentrations of NMDA and glycine, indicating that at saturating concentrations of the coagonists PS does not change the affinity between the coagonists and the NMDA receptor. The dose-response relations for NMDA and glycine were shifted slightly to the left, and the percent potentiation was significantly higher for lower concentrations of coagonists, suggesting that at low concentrations of the coagonists PS may slightly increase their affinity for the NMDA receptor. The fractional open time (nPo) of single NMDA-activated channels was potentiated by PS in patch-clamp recordings using both the outside-out and cell-attached configurations. The potentiation of nPo resulted from increases in the frequency of opening and in the mean channel open time. No effect was seen on single-channel conductances.
Mol Pharmacol 1993 May
PMID:Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons. 768 17

In primary cultures of striatal neurons, stimulation of N-methyl-D-aspartic acid (NMDA) receptors or associative activation (but not separate activation) of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and metabotropic glutamate receptors (mGluR) strongly increased arachidonic acid (AA) release via activation of phospholipase A2 (PLA2). Depolarizing agents, such as veratridine, were as potent as NMDA in stimulating AA release. However, increasing the intracellular Ca2+ concentration via voltage-sensitive Ca2+ channels did not result in a significant stimulation of PLA2. Substitution of sodium by lithium, a monovalent cation that does not participate in the Na+/Ca2+ exchanger activity but permeates ionotropic glutamate receptor channels, blocked AA release induced by veratridine or AMPA plus mGluR agonists. It also reduced the NMDA-induced AA release, to a lesser extent. The contribution of the Na+/Ca2+ exchanger to the activation of PLA2 after veratridine, NMDA receptor, or AMPA receptor plus mGluR stimulation was confirmed by using a selective inhibitor of the Na+/Ca2+ exchanger.
Mol Pharmacol 1993 Jun
PMID:Stimulation by glutamate receptors of arachidonic acid release depends on the Na+/Ca2+ exchanger in neuronal cells. 768 47


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