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

Natural (GM1) and semisynthetic [113-Neu-5-AcGgOse4-2-D-erythro-1,3- dihydroxy-2-dichloroacetylamide-4-trans-octadecene (LIGA20)] glycosphingolipids, given parenterally, protect neurones against glutamate-induced death without producing the side effects typical of glutamate receptor antagonists. Chronic glutamate-related neurotoxicity (e.g., in recurring strokes in elderly hypertensive patients, and in Parkinson disease) could be prevented also by glycosphingolipids treatment, but this therapeutic intervention will require a protracted administration of orally active glycosphingolipids. Here we demonstrate that 3-6 h after oral administration of 68 mumol/kg of LIGA20 and GM1 to rats, the brain content of LIGA20 is 50-fold higher than that of GM1. The brain concentration of LIGA20 remains elevated for at least 12-24 h. Because the LIGA20 that reaches the brain is slowly metabolized, repeated oral administrations of this glycosphingolipid can yield to its accumulation in brain, and can yield various brain levels depending on the dose and frequency of drug administration. In contrast this is not possible with GM1, which given orally for 7 d, cannot accumulate in brain in pharmacologically significant concentrations.
Mol Chem Neuropathol 1994 Jan
PMID:Brain content of glycosphingolipids after oral administration of monosialogangliosides GM1 and LIGA20 to rats. 791 19

The subcellular processes that correlate with early learning and memory formation in the chick and sensitive periods for this learning are discussed. Imprinting and passive avoidance learning are followed by a number of cellular processes, each of which persists for a characteristic time in certain brain regions, and may culminate in synaptic structure modification. In the chick brain, the NMDA subtype of glutamate receptor appears to play an important role in both memory formation and sensitive periods during development, similar to its demonstrated role in neural plasticity in the mammalian brain. Two important findings have emerged from the studies using chickens. First, memory formation appears to occur at multiple sites in the forebrain and, most importantly, it appears to "flow" from one site to another, leaving neurochemical traces in each as it moves on. Second, the memory is laid down either in different sites or in different subcellular events in the left and right forebrain hemispheres. Hence, we are alerted to the possibility of similar asymmetrical processes occurring in memory consolidation in the mammalian brain. The similarities between early memory formation and experience-dependent plasticity of the brain during development are discussed.
Mol Neurobiol
PMID:The molecular neurobiology of early learning, development, and sensitive periods, with emphasis on the avian brain. 791 26

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two structurally-related neurotrophins synthesized in dentate gyrus granule cells and pyramidal neurons of the hippocampal formation. These neurons receive excitatory glutamatergic afferents from the entorhinal cortex via the angular bundle/perforant path. In the present study, we tested whether electrophysiological stimulation of this glutamatergic pathway modifies NGF or BDNF messenger RNA (mRNA) expression in vivo. Within hours following brief trains of high frequency angular bundle stimulation, the levels of mRNA encoding both neurotrophins were increased exclusively in granule cells of the ipsilateral dentate gyrus. The increase in neurotrophic factor mRNA expression was found to be mediated through the N-methyl-D-aspartate (NMDA) glutamate receptor subtype, and occurred in the absence of seizure. These findings provide evidence that neurotrophic factor mRNA levels in the hippocampal formation are increased by direct activation of excitatory afferents originating in the entorhinal cortex. We suggest that the function of some neurotrophin-responsive neuronal populations may depend upon the integrity and activity of neurons in the entorhinal cortex, a population of neurons reported to be compromised in patients with Alzheimer's disease.
Brain Res Mol Brain Res 1994 Apr
PMID:Neurotrophic factor mRNA expression in dentate gyrus is increased following in vivo stimulation of the angular bundle. 791 2

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

Numerous studies over the past decade have established a role(s) for protein phosphorylation in modulation of synaptic efficiency. This article reviews this data and focuses on putative functions of Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) which is highly concentrated at these synapses which utilize glutamate as the neurotransmitter. Evidence is presented that CaM-kinase II can phosphorylate these glutamate receptor/ion channels and enhance the ion current flowing through them. This may contribute to mechanisms of synaptic plasticity that are important in cellular paradigms of learning and memory such as long-term potentiation in the hippocampus.
Mol Cell Biochem 1993 Nov
PMID:Calcium/calmodulin-dependent protein kinase II: role in learning and memory. 793 66

Messenger RNA (mRNA) for several subunits of the GABAA receptor was measured in the cortex of mice chemically kindled with FG 7142. At 10 days after the final FG 7142 injection, beta 2 and gamma 2S subunit mRNA were significantly increased. At 31 days, alpha 1, alpha 3, beta 2, and gamma 2L mRNA were elevated. In contrast, levels of mRNA for four subunits of the glutamate receptor in the cortex of FG 7142-kindled mice killed at 31 days were not significantly increased. Previous investigations have shown a reduction in GABA-gated chloride channel function and density in mice kindled with FG 7142, and the increases in subunit mRNA found in the present studies may be a response to these decreases. These results indicate that chemical kindling produces long-lasting changes in expression of genes coding for specific neurotransmitter receptor subunits.
Brain Res Mol Brain Res 1994 Mar
PMID:GABAA and glutamate receptor subunit mRNAs in cortex of mice chemically kindled with FG 7142. 801 88

A substantial body of research implicates L-cysteine sulfinic acid (L-CSA) as a neurotransmitter. However, all physiological actions of L-CSA that have been pharmacologically characterized are mediated by cross-activation of glutamate receptors, and no receptor has been identified that is primarily activated by L-CSA. We report that a receptor exists in adult rat hippocampus that is activated by L-CSA but is insensitive to several other endogenous excitatory amino acids (EAAs), including L-glutamate, L-aspartate, and L-homocysteic acid. This receptor is coupled to an increase in the activity of phospholipase D (PLD). The L-CSA-induced PLD response is not blocked by ionotropic glutamate receptor antagonists but is mimicked by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid. The agonist pharmacology of the PLD-coupled response is generally similar to that of mGluRs but clearly differs from that of any particular mGluR that has been characterized to date. Furthermore, this receptor is not significantly blocked by (RS)-alpha-methyl-4-carboxyphenylglycine, which blocks a variety of mGluR-mediated responses. L-CSA has little effect on mGluRs coupled to phosphoinositide hydrolysis or the potentiation of cAMP responses in adult hippocampus, indicating that L-CSA is not a broad mGluR agonist. It is commonly thought that EAAs act on the same receptor families, all of which use glutamate as their primary agonist. However, the finding that L-CSA acts on a glutamate-insensitive receptor suggests that different receptor families might exist for different EAAs.
Mol Pharmacol 1994 Jun
PMID:L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity. 802 10

We isolated a human glutamate receptor subunit 7 (GluR-7) cosmid after high stringency screening of a human genomic placental library using a rat GluR-7 cDNA as a probe. A 614-bp fragment of the GluR-7 cosmid was sequenced, and an exon that encodes 53 amino acids was found between two introns. The exon exhibited 89% and 96% identity at the nucleotide and amino acid levels, respectively, with the corresponding region of rat GluR-7. The human GluR-7 was classified as a kainate subtype glutamate receptor based on its homology to rat GluR-7. Using somatic cell hybrid analysis, human GluR-7 was localized to chromosome 1. Fine mapping analysis using FISH localized the gene to 1p33-34. Since glutamate receptors of the kainate subtype have been implicated in neurodegenerative disorders, establishing the precise map position of human GluR-7 subunit is an important step towards evaluating this locus as a candidate for mutations in neurodegenerative disorders.
Somat Cell Mol Genet 1993 Nov
PMID:Chromosomal localization of gene for human glutamate receptor subunit-7. 812 18

In situ hybridization histochemistry was used to localize the mRNAs coding for four alpha-aminoisoxazole propionic acid-sensitive glutamate receptor subunits in human brain (age range 51-95 years, postmortem delay 4.5-10 h). High levels of the B receptor subunit mRNA were present in all the studied regions, followed by the A-subunit and the C-subunit. Only very low levels of the D-subunit mRNA were detected. In hippocampus, the mRNA coding for the B-subunits of the glutamate receptor was observed in granule cells of dentate gyrus and in the pyramidal cells of Ammon's horn. In cortex, the highest levels of glutamate receptor subunit mRNAs were found in layer I and layers III-IV of entorhinal and temporal cortex, although significant levels were also observed in the other cell layers. A differential distribution was seen in cerebellum where the A-subunit mRNA is expressed mainly by Purkinje cells, while the B-subunit mRNA is present in the internal granule cell layer. These results correlate well with previous data from autoradiographic studies on the localization of excitatory amino acid binding sites in human brain and pinpoint the cells where these receptors are synthesized. In situ hybridization in the hippocampus of patients affected by Alzheimer's disease (age range 77-82 years, postmortem delay 19-25.5 h) revealed a decrease on the content of the mRNAs coding for these excitatory amino acid receptors, while an increase was detected in surgically dissected epileptic human hippocampi. These results corroborate and extend the previous data from in vitro autoradiography and suggest alteration of the excitatory amino acid disfunction during these neurodegenerative processes.
Brain Res Mol Brain Res 1994 Jan
PMID:Excitatory amino acid AMPA receptor mRNA localization in several regions of normal and neurological disease affected human brain. An in situ hybridization histochemistry study. 816 24

It was previously demonstrated that daily administration of N-methyl-D-aspartate (NMDA) to primary cultures of cerebellar granule neurons for 5 days in vitro mediates an increase in the relative content of mRNAs encoding selected subunits of the gamma-aminobutyric acid (GABA)A receptor. This analysis was extended using a competitive polymerase chain reaction assay with internal standards to quantitate changes that occur in the absolute amounts of selected GABAA receptor subunit mRNAs in cerebellar granule neurons in vitro after the single administration of nontoxic doses of either NMDA or glutamate. For these studies, we focused on the alpha 1, alpha 5, and alpha 6 receptor subunit mRNAs and examined their absolute contents in cultures maintained in low KCl (12.5 mM), maintained in low KCl and treated with NMDA (10 microM) for 24 hr, or maintained in high KCl (25 mM). The absolute amounts of each mRNA varied in these paradigms; whereas the alpha 1 and alpha 5 receptor subunit mRNAs increased in response to NMDA-selective glutamate receptor stimulation, the alpha 6 receptor subunit mRNA did not. The time course of the alpha 1 and alpha 5 mRNA increases, dose dependence, and effects of glutamate in the presence or absence of MK-801 were also analyzed. Treatment of cultures maintained in 12.5 mM KCl with 5 microM glutamate resulted in comparable changes in the alpha 1 and alpha 5 receptor subunit mRNA contents, and a somewhat smaller increase in the alpha 6 mRNA content was observed. Using corresponding GABAA receptor subunit-specific antibodies, it was shown that the observed mRNA changes are accompanied by increased expression of alpha 1- and alpha 5-like receptor subunit immunoreactivity. Collectively, these data demonstrate that signal transduction mechanisms triggered by NMDA-selective glutamate receptor stimulation differentially modulate the levels of selected GABAA receptor subunit mRNAs and the corresponding proteins they encode.
Mol Pharmacol 1994 Apr
PMID:Quantitative changes in alpha 1 and alpha 5 gamma-aminobutyric acid type A receptor subunit mRNAs and proteins after a single treatment of cerebellar granule neurons with N-methyl-D-aspartate. 818 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>