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)

Changes in gene expression after kindled seizures were examined using microdissection of discrete brain areas and Northern and slot blot analyses. Experimental animals were kindled with either of two protocols: (1) a paradigm in which 50 Hz/10 s stimulus trains were delivered every 30 min through hippocampal electrodes (12 stimulations every other day for 4 days) and (2) a traditional approach in which 50 Hz/10 s stimulus trains were given to the hippocampus three times daily for 16 days. Rats were sacrificed 24 h or 30 days after the last kindled seizure. We first examined the possibility that kindling may affect transcription of mRNA for neurotransmitter receptors. We found significant decreases (22-58%) in AMPA/kainate activated glutamate receptor mRNAs (GluR1, -2, -3 mRNAs) in hippocampus, amygdala/entorhinal cortex and in frontoparietal cortex 24 h but not 30 days after rapidly kindled seizures. However, changes in GABA receptor alpha 1, alpha 2, alpha 4 or beta 1 mRNAs were not observed in any brain region 30 days after traditional kindling or 24 h after rapidly kindled seizures. In addition, we tested whether changes in the expression of proenkephalin could be detected after kindling. We found significant increases (1.7-10 fold) in proenkephalin mRNA in the frontoparietal cortex, hippocampus and in the amygdala/entorhinal cortex 24 h but not 30 days after rapidly kindled seizures. Our findings suggest that changes in glutamate receptor and proenkephalin gene expression are robust, acute sequelae to kindled seizures and may be involved in kindling.
Brain Res Mol Brain Res 1994 Jul
PMID:Changes in glutamate receptor and proenkephalin gene expression after kindled seizures. 752 14

High-affinity glutamate uptake (HAGU) transporters rapidly remove released glutamate from the synaptic cleft. If HAGU is suppressed, neurotoxic concentrations of excitatory amino acids may accumulate. To seek further evidence in support of the neurotoxicity of endogenous glutamate in the developing brain, we assessed the neurotoxicity of the selective HAGU inhibitor L-trans-2,4-pyrrolidine dicarboxylate (L-PDC) in postnatal day 7 (PND 7) rats. The hippocampus of PND 7 rats is susceptible to EAA agonist-mediated injury; features of injury include atrophy and neuronal loss. Since HAGU is energy-dependent, we hypothesized that moderate hypoxia would increase L-PDC-mediated injury by further suppressing HAGU. L-PDC was stereotaxically injected into dorsolateral hippocampus of PND 7 rats (568 nmol, n = 20). Prior to return to the dam, rats were divided into two groups, one of which was subjected to moderate hypoxia (3 h, FiO2 = 0.08) (n = 11; 2 died acutely). On PND 12, hippocampal neuropathology was assessed by a blinded observer using a five-point scale and also by measuring hippocampal cross-sectional areas with computerized image analysis. Three brains were excluded from analysis, since markedly asymmetric tissue sectioning precluded valid side-to-side comparison of hippocampal areas. Injection of L-PDC alone elicited focal pyramidal cell loss (6/7); in the (L-PDC + hypoxia) group, injury was significantly increased (median scores: L-PDC = 2; [L-PDC + hypoxia] = 3.5; p < 0.005). Hippocampal atrophy was noted only after L-PDC + hypoxia (4/8) (percent right-left difference in mean hippocampal area [+/- SE]: L-PDC = 2.5% [+/- 2.6]; [L-PDC + hypoxia] = 8.9% [+/- 3.2]; p < 0.02). In tissue from PND 7 rats, L-PDC (10 microM) inhibited hippocampal synaptosomal HAGU by > 85%; at the same concentration, L-PDC did not displace [3H]glutamate from NMDA- or AMPA-sensitive hippocampal binding sites. These results support the hypothesis that increased synaptic accumulation of endogenous excitatory amino acid neurotransmitters may produce hippocampal injury in perinatal rodents.
Mol Chem Neuropathol
PMID:The glutamate uptake inhibitor L-trans-2,4-pyrrolidine dicarboxylate is neurotoxic in neonatal rat brain. 753 31

The preovulatory gonadotropin surge is induced by progesterone in the cycling female rat or in the ovariectomized estrogen-treated female rat after adequate estrogen-priming activity is present. The source of progesterone under physiological conditions could be the ovary and/or the adrenal. Since the GnRH neuron does not possess estrogen and progesterone receptors, its function is modulated by other CNS neurotransmitters and neurosecretory products. Among these, excitatory amino acids (EAAs) have now been shown to play an important role in the regulation of pulsatile gonadotropin release, induction of puberty and preovulatory and steroid-induced gonadotropin surges. Glutamate, the major endogenous EAA exerts its action through ionotropic and metabotropic receptors. The ionotropic receptors consist of two major classes, the NMDA (N-methyl-D-aspartate) and non-NMDA: kainate and AMPA (DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. EAA receptors are found in hypothalamic areas involved with reproduction. While both NMDA and non-NMDA receptors are involved in the regulation of LH secretion, the NMDA receptors appear to be involved with the regulation of puberty and FSH secretion as well. Steroids increase the release rates of glutamate and aspartate in the preoptic area during the gonadotropin surge. Steroids may also regulate the hypothalamic AMPA receptors.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Glutamate: a major neuroendocrine excitatory signal mediating steroid effects on gonadotropin secretion. 762 74

Intrahippocampal injection of the endogenous excitotoxin quinolinic acid (QUIN) induces seizures together with local, delayed neurodegeneration in specific cell layers. In situ hybridization histochemistry was used to study the spatio-temporal pattern of expression of neurotrophins (NTFs) after this treatment. As in other excitatory paradigms, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA levels increased dramatically and transiently in dentate gyrus after the administration of 120 nmol of QUIN to the left hippocampus. BDNF, but not NGF, mRNA also increased in the hippocampal pyramidal cell layer, mainly in the CA1 field. Neurotrophin-3 (NT3) mRNA levels decreased in dentate gyrus, practically disappeared around 12 h after the insult and returned to basal levels four days later. A very different pattern of expression of NTFs was found locally: (a) upregulation of NGF and BDNF mRNAs expression was prevented in a spherical region of 1-2 mm diameter around the injection site, (b) a delayed increase in NT3 mRNA levels, beginning at 12 h and lasting for at least 4 days after the administration of QUIN, was found in the same region, in cell layers showing neurodegeneration. Pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg, 30 min before the insult), partially blocked the increase in both BDNF and NGF mRNAs, as well as the decrease in NT3, in the contralateral hippocampus. However, this treatment did not prevent the QUIN-induced local downregulation of NGF and BDNF. Treatment with the AMPA/kainate antagonist NBQX (30 mg/kg, 15 and 5 min before, and 10 min after the insult) did not influence the effect of QUIN upon NGF or BDNF mRNA levels, although it partially prevented the hippocampal contralateral decrease in NT3 mRNA. In conclusion, the present study strongly supports previous work concerning different regulation of BDNF/NGF respect to NT3 in seizure inducing paradigms. Moreover, the different and to some extent opposite regulation of NTFs in the hippocampal region contiguous to the injection site, respect to the remaining hippocampus, suggests a differential regulation of NTFs in QUIN-induced neurodegenerative and seizural processes. Finally, our pharmacological data, (i) show that the upregulation of NGF and BDNF mRNAs, indirectly induced by QUIN, is not mediated by AMPA receptors, and (ii) suggest other effects for QUIN, apart from the stimulation of NMDA receptors.
Brain Res Mol Brain Res 1994 Oct
PMID:Differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNAs in adult rat brain after intrahippocampal injection of quinolinic acid. 785 71

The role of kainate/AMPA excitatory amino acid receptors in D-amphetamine (AMPH)-induced behavioral changes and the induction of immediate early gene and preprodynorphin (PPD) mRNA in various regions of rat forebrain was investigated with quantitative in situ hybridization histochemistry. Three hours after a single injection of AMPH (5 mg/kg, i.p.), PPD mRNA and mRNA of the transcription factor zif/268, but not c-fos, was increased in dorsal striatum (caudate). Zif/268 mRNA was also increased in the sensorimotor cortex. Pretreatment of rats with DNQX, a kainate/AMPA receptor antagonist, did not affect the behaviors elicited by AMPH. However, the AMPH-stimulated increase in PPD and zif/268 mRNA levels in striatum, but not zif/268 mRNA in cortex, was blocked by DNQX pretreatment. In contrast, DNQX alone attenuated basal (constitutive) levels of zif/268 mRNA expression in sensorimotor cortical, but not in striatal, neurons. These studies indicate that kainate/AMPA receptors mediate the induction of zif/268 and PPD mRNA expression in the caudate nucleus induced by a single injection of AMPH. The fact that DNQX blocked genomic, but not behavioral, responses to acute AMPH suggests that kainate/AMPA receptor mechanisms may be involved in the long-term (possibly sensitizing) effects, rather than the acute effects, of the drug. In addition, tonic kainate/AMPA receptor stimulation may play a key role in maintaining constitutive expression of the zif/268 gene in cortical neurons.
Brain Res Mol Brain Res 1994 Nov
PMID:Role of kainate/AMPA receptors in induction of striatal zif/268 and preprodynorphin mRNA by a single injection of amphetamine. 787 42

Antibodies to functional glutamate receptor subunits were utilized as probes to characterize glutamatergic receptors in human postmortem brain tissue. Crude membranes from rat, monkey, and various dissected human postmortem brain regions were fractionated by SDS-PAGE and electrotransferred to nitrocellulose. Using antisera raised against rat antigens for AMPA/kainate (GluR1-3) and kainate (GluR5) glutamate receptor subunits, we have been able to detect specific bands on Western blots in rat, monkey, and human postmortem brain tissue. These antisera recognized bands at approx 105 kDa for the GluR1-3 and 115 kDa for GluR5 in humans, monkeys, and rats. All of these glutamate receptor subtypes appear to be glycosylated. We observed varying levels of expression in the human brain areas examined, with the highest degree of expression in the hippocampus and temporal cortex for AMPA/kainate receptor subunits, and in the cortex and cerebellum for the kainate receptor subunits. In addition, considerable heterogeneity in expression was observed between protein, NCAM. Our studies indicate that glutamatergic receptor protein changes related to various human diseases states may be examined in human postmortem tissue by Western blotting techniques utilizing these antibodies raised to the rat protein.
J Mol Neurosci 1993
PMID:Glutamate receptor subtype expression in human postmortem brain. 791 35

AMPA receptors are comprised of individual subunits, and the divalent cation permeability of assembled AMPA receptors is determined by a single amino acid residue in the second transmembrane region of the GluR-B subunit. At this site, GluR-B subunits contain an arginine while other AMPA receptor subunits contain glutamine. Interestingly, the murine gene for GluR-B actually specifies a glutamine at the divalent cation permeability site. The appearance of arginine and not glutamine in the mature GluR-B protein is thought to be a result of RNA editing of the GluR-B messenger RNA. In that AMPA receptors are thought to mediate the bulk of fast excitatory signalling within the mammalian central nervous system, this process of RNA editing may play a pivotal role in normal neural function by mediating divalent cation permeability of AMPA receptors. Disruptions of RNA editing could lead to phenotypically altered AMPA receptors, with implications for pathogenic brain processes. We report that the human GluR-B gene sequence is also edited such that there is a difference between the human GluR-B gene and the complementary DNA (cDNA), as demonstrated both with allele-specific polymerase chain reaction (PCR) and restriction enzyme digestion of PCR products. Thus, as in the rodent brain, RNA editing of an AMPA receptor subunit appears to be an important process in the human brain. Disruptions of RNA editing may have neuropathological consequences.
Brain Res Mol Brain Res 1994 Mar
PMID:RNA editing of a human glutamate receptor subunit. 801 89

Eleven oligonucleotides directed against mRNA for AMPA, NMDA and metabotropic glutamate receptor subtypes were hybridized to rat coronal brain sections containing the suprachiasmatic nucleus (SCN). These oligonucleotides were hybridized to tissue samples collected at midday and midnight phases of the circadian cycle. Glutamate receptor mRNA for the AMPA subunits GluR1, GluR2 and GluR4, and the NMDA receptor subtype NMDAR1, were heavily expressed in the SCN and surrounding areas. The mRNA for the metabotropic glutamate subunit mGluR1 was only lightly expressed in the SCN. In contrast, mRNA for NMDAR2A, NMDAR2B, NMDAR2C and GluR3 was not detected in the SCN. The mRNA found to be expressed in the rat SCN was similar in samples collected at midday and midnight, suggesting no circadian variation in endogenous SCN glutamate receptors at these two times of the light-dark cycle.
Brain Res Mol Brain Res 1994 Jun
PMID:In situ hybridization of antisense mRNA oligonucleotides for AMPA, NMDA and metabotropic glutamate receptor subtypes in the rat suprachiasmatic nucleus at different phases of the circadian cycle. 809 74

The presence of non-NMDA glutamate receptors in the rat sympathetic and parasympathetic ganglia was examined by immunocytochemistry using specific antibodies against AMPA-type excitatory amino acid receptor subunits (GluR1-4). Three kinds of antibodies specific to the GluR1, GluR2 and 3, and GluR4 subunits were used. The superior cervical ganglion and pterygopalatine ganglion were examined as representatives of sympathetic and parasympathetic ganglia. In the superior cervical ganglion, GluR1- and GluR2/3-like immunoreactivity was observed in most principal neurons and SIF cells. In contrast, GluR4-like immunoreactivity was not observed in the principal cells; however, SIF cells exhibited intense immunoreactivity of GluR4. In the pterygopalatine ganglion, the profile of the immunoreactivity was similar to that seen in the superior cervical ganglia. The subunit compositions between the principal cells and SIF cells were different, whereas the compositions in cell species involved in the autonomic ganglia, sympathetic and parasympathetic ganglia were identical. This suggests that glutamate is another important preganglionic transmitter together with acetylcholine, and the responses elicited in the principal cells and SIF cells might be different because of the difference in subunit composition.
Brain Res Mol Brain Res 1993 Sep
PMID:Sympathetic and parasympathetic ganglia express non-NMDA type glutamate receptors: distinct receptor subunit composition in the principle and SIF cells. 823 38

Two cDNA clones encoding putative ionotropic glutamate receptor subunits were isolated from a brain cDNA library of a freshwater fish, Oreochromis sp. The deduced amino acid sequences of these two cDNAs, fGluR2 alpha and fGluR2 beta, display the highest sequence identity (85%) to that of the rat GluR2 (AMPA receptor subunit) and they contain an arginine codon at the Q/R editing site of the TM2 segment. Genomic sequence analysis of the exons encoding the TM2 reveals the presence of an arginine codon at the Q/R site, suggesting that the RNA editing mechanism acting in the mammalian GluR2 does not operate at the homologous site in these two fish genes. In contrast to the absence of RNA editing at the Q/R site, transcripts of fGluR2 alpha and fGluR2 beta are subjected to RNA editing at a second site, the R/G site. A splicing variant of fGluR2 alpha, fGluR2 alpha-c, with a shorter C-terminal sequence was found; however, no C-terminal splicing variant of fGluR2 beta was detected in the mature fish. Similar to the mammalian AMPA receptor, variants created by the alternate choice of flip and flop modules were found among transcripts of fGluR2 alpha-c and fGluR2 beta. The amino acid sequences of flip and flop modules of fGluR2 beta are identical to that of the rat GluR2, whereas the amino acid sequences of the flip and flop modules of fGluR2 alpha-c differ from the invariant consensus sequences of the rat AMPA receptor subunits.
Brain Res Mol Brain Res 1996 Jan
PMID:Characterization of two fish glutamate receptor cDNA molecules: absence of RNA editing at the Q/R site. 871 47


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