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)

GluR1 and GluR2 cDNAs encoding non-NMDA subtypes of glutamate receptor were isolated from a rat brain cDNA library by Boulter et al. (Science, 249 (1990) 1033-1037). Functional receptors activated by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and glutamate were expressed in Xenopus oocytes injected with GluR1, GluR2 or a mixture of GluR1 and GluR2 RNAs. In GluR1-expressed oocytes, 1 mM aniracetam potentiated AMPA-induced currents by 99 +/- 10% (mean +/- S.E.M., n = 5) and glutamate-induced currents by 140 +/- 8% (n = 4), but little affected kainate-induced currents. Aniracetam was effective from a concentration of 0.1 mM, and it exhibited more conspicuous effects with the increase of the dose. In oocytes injected with GluR1 plus GluR2 RNAs, aniracetam more markedly potentiated current responses to AMPA and glutamate than those in oocytes injected with GluR1 RNA alone. For example, 1 mM aniracetam potentiated AMPA-induced currents by 396 +/- 76% (n = 4) and glutamate-induced currents by 970 +/- 65% (n = 5) in oocytes injected with 10% GluR1 and 90% GluR2 RNAs. In these oocytes, however, the potentiation of kainate-induced currents by 1 mM aniracetam was only 8 +/- 5% (n = 4). Thus, we conclude that the potentiation of the AMPA/kainate receptor by aniracetam depends on both species of agonists and subunit composition of the receptor.
Brain Res Mol Brain Res 1992 Nov
PMID:Agonist- and subunit-dependent potentiation of glutamate receptors by a nootropic drug aniracetam. 128 Dec 52

We have studied the effect of intrahippocampal administration of quinolinic acid (QUIN) on the temporal expression of mRNAs encoding the immediate early genes (IEGs) c-fos and NGFI-A, by in situ hybridization histochemistry. After administration of QUIN to the left hippocampus, expression of mRNA of both IEGs was transiently stimulated. Maximal expression was found between 1 and 3 h. mRNA of both IEGs was simultaneously expressed in the ipsilateral and contralateral sides in the granule cell layer of the dentate gyrus, the pyramidal cell layer of the CA1 and CA3 fields as well as in the cortex. After pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg i.p. -30 min) the increased expression of both IEGs was partially prevented in the hippocampus and completely in the cortex. No inhibition was observed after treatment with the AMPA antagonist NBQX (30 mg/kg i.p. -15, -5 and +10 min). Additional delayed expression of both IEGs was observed in the ipsilateral hippocampus. This expression was related to cell damage. Twelve h after QUIN administration, c-fos and NGFI-A mRNAs were present in the dentate gyrus. After 4 days, only c-fos mRNA was observed in the dentate gyrus and CA1 field while no NGFI-A mRNA was detected. The present results show that the effect of QUIN is mediated by NMDA and not by AMPA receptors.
Brain Res Mol Brain Res 1992 Nov
PMID:Administration of quinolinic acid in the rat hippocampus induces expression of c-fos and NGFI-A. 128 Dec 56

We have studied the effect of excitatory amino acids on the expression of mRNA for the immediate early genes c-fos, c-jun, jun-B, and NGF-1A in isolated cortical astrocytes. The expression of the different genes was induced by 100 microM kainate, quisqualate, AMPA and high concentrations of K+ (140 mM). NMDA did not induce the expression of any of the genes studied. The effect of quisqualate stimulation was not inhibited by the antagonist CNQX or by withdrawal of external Ca2+. In contrast the kainate effect was abolished by CNQX but not by the removal of external Ca2+. However, elevated K+ induced c-fos only when calcium was present in the external medium. These findings suggest that type-1 astrocytes lack NMDA receptors and that the induction of genes by quisqualate and kainate is in part independent of the presence of calcium in the external medium and may be mediated through second messenger pathways.
Brain Res Mol Brain Res 1992 Dec
PMID:Regulation of gene expression in astrocytes by excitatory amino acids. 133 35

Injection of N-methyl-D-aspartate (NMDA, 7.5 micrograms) kainate (1 microgram) or quisqualate (2 micrograms) into the rat dorsal hippocampus induced wet-dog shakes and convulsions. As shown by an in situ immunohistochemical analysis, 3 h after the excitatory amino acids injections the rats displayed a bilateral profound elevation of the proenkephalin and prodynorphin mRNA levels in dentate gyrus granule cells (2-3 or 1.5-2 fold higher than control levels, respectively). Pretreatment of rats with D-amino-phosphonovalerate (D-APV, 10 micrograms), a selective antagonist of NMDA receptor, prevented the behavioral and biochemical changes evoked by NMDA. The changes in the behavior and gene expression evoked by kainate or quisqualate were diminished in rats which received 6-cyano-7-nitroquinoxaline-2,3-dion (CNQX, 2 micrograms), a putative antagonist of quisqualate and kainate receptors. The study demonstrated that activation of NMDA, quisqualate or kainate receptors in the hippocampus induced seizures associated with a marked increase in the proenkephalin (PENK) and the prodynorphin (PDYN) gene expression in the rat dentate gyrus.
Brain Res Mol Brain Res 1992 Jan
PMID:The effects of excitatory amino acids on proenkephalin and prodynorphin mRNA levels in the hippocampal dentate gyrus of the rat; an in situ hybridization study. 134 33

A glutamate receptor was purified from Triton X-100-solubilized bovine cerebellum membranes. The purification was carried out in two steps: affinity chromatography using a spider toxin (Joro spider toxin; JSTX) immobilized on a lysine-agarose column, and a Mono Q anion exchange column. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the purified active fraction showed a single band with Coomassie Blue staining, which migrated with a M(r) = 130,000. The specific [3H]amino-3-hydroxy-5-methyl-isoxazole propionate ([3H]AMPA) binding activity of the affinity-purified fraction was 2095-fold higher than that of the crude soluble fraction. Lineweaver-Burk plot analysis showed a Kd of 12.7 nM [3H]AMPA in the purified fraction. The purified fraction was examined with patch-clamp recording methods in reconstituted liposomes. A glutamate-activated channel was observed and was inhibited with JSTX. The rank order of potency of agonists inducing channel currents was AMPA = glutamate greater than quisqualate much greater than kainate greater than NMDA. Thus, there is strong evidence that the 130 kDa protein is a purified component of the native AMPA type glutamate channel of bovine cerebellum.
Brain Res Mol Brain Res 1992 May
PMID:Purification of AMPA type glutamate receptor by a spider toxin. 137 71

N-Methyl-D-aspartate (NMDA) receptors play an important role in the development of neuronal connections in the retina and visual cortex, and in synaptic plasticity in the hippocampus. The objective of this study was to determine whether the sensitivity of hippocampal NMDA receptors to magnesium, glycine or NMDA changes during development. Xenopus oocytes were injected with mRNA prepared from hippocampi from rats of different ages, and NMDA receptor properties studied under voltage clamp. Voltage-dependent block of the NMDA receptor by magnesium was studied with voltage steps of -90 mV to -30 mV, in increments of 10 mV, during application of 100 microM NMDA, 3 microM glycine and 0-1000 microM Mg2+. The IC50 of Mg2+ for blocking NMDA receptor-mediated currents varied e-fold (2.72-fold) for approximately every 15 mV of membrane potential in the middle range of membrane potential (-70 to -50 mV), but the relationship between log[IC50] for Mg2+ and membrane potential was not linear, as would be expected for simple channel block. The slopes of the curves did not change with development, indicating no change in the voltage-dependence of Mg2+ block with age. However, the IC50 of Mg2+ block did change with age at every membrane potential tested. NMDA receptors expressed from mRNA isolated from 14-15 day old rats were nearly 2-fold less sensitive to block by Mg2+ (IC50 = 33 microM at -60 mV) than those from 1-2 day old rats (IC50 = 18 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1991 Sep
PMID:Regulation of hippocampal NMDA receptors by magnesium and glycine during development. 166 12

The physiology and pharmacology of willardiine and bromowillardiine, structural analogues of quisqualate, were studied in cultured postnatal rat hippocampal neurons using whole-cell voltage-clamp techniques. These agonists appear to act at a shared non-N-methyl-D-aspartate (non-NMDA) receptor-channel complex and gate nonselective cationic currents. Willardiine currents desensitize rapidly and to a much greater degree than bromowillardiine currents. In addition, the brominated compound produces steady state currents that are 5 times larger than those produced by willardiine at saturation. Bromowillardiine is also a more efficacious excitotoxin, producing about 3-fold greater acute neuronal damage than willardiine at saturating concentrations. These results suggest that agonist structure affects the ability of non-NMDA agonists to induce desensitization and add support to the hypothesis that receptor desensitization serves to limit acute excitotoxicity in cultured neurons.
Mol Pharmacol 1991 Jul
PMID:Effects of bromowillardiine and willardiine on non-N-methyl-D-aspartate receptors in postnatal rat hippocampal neurons. 167 51

The accumulation of free fatty acid (FFA) in the brain occurs within minutes of anoxia, induced by exposing mice to a 100% N2 atmosphere. The rate of FFA release is high within the first minute and continues to increase moderately hereafter. FFA is apparently accumulated at the highest concentration in the cerebral hemispheres. The release of FFA can be inhibited partly by CNS depressants like N6-cyclopentyladenosine, pentobarbital, ethanol, or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3(2H)-one (THIP). Antiadrenergic compounds such as reserpine, clondine, or prazosine were also found to be active. The N2 anoxia was initially and temporarily associated with motor excitation termed fight and flight reaction. This behavior could be reduced by administration of N6-cyclopentyl-adenosine, pentobarbital, ethanol, reserpine, and prazosine, but not by THIP or clonidine. The glutamate antagonist MK-801 inhibited the fight and flight reaction, but did not affect the FFA accumulation. The data are consistent with the view that brain anoxia initially increases FFA by receptor-mediated polyphosphoinositide breakdown and that the alpha-1 adrenergic receptor is one of the receptors involved. The data also indicate that the fight and flight reaction is dissociated from the events that lead to FFA release, and may involve the stimulation of glutaminergic NMDA receptors.
Mol Chem Neuropathol 1991 Dec
PMID:Pharmacological manipulations of anoxia-induced free fatty acid accumulation in the mouse brain. 183 55

Gonadal steroids are important hormonal signals that regulate the activity of LHRH synthesizing and releasing neurons. Aside from a direct effect through the feedback mechanisms exerted at hypothalamic and/or anterior pituitary level, gonadal steroids may modify the rhythmic LHRH release by modulating other systems affecting LHRH neurons. 1. In ovariectomized E2-treated female rats, progesterone is able to evoke LHRH release from the perifused hypothalamus without affecting LH and FSH release. 2. Excitatory amino acids (EAA) and their related analogs (NMDA and kainate) are known to stimulate LH release in young rats. When tested in a perifusion system on hypothalamic and anterior pituitary tissues, they differentially stimulate the release of LHRH (NMDA) and of LH (KA); their effect on both structures is markedly reduced following orchidectomy. It appears that gonadal steroids might exert a facilitatory action on the neurosecretory activity of LHRH neurons as well as a modulatory influence on the effect of EAA.
J Steroid Biochem Mol Biol 1991
PMID:Sex steroids and the control of LHRH secretion. 195 16

Huntington's disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.
Mol Chem Neuropathol 1990 Mar
PMID:Huntington's disease as a model for mood disorders. Clues from neuropathology and neurochemistry. 214 28


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