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)

Kainate (KA) receptors are a family of ionotropic glutamate receptors, which mediate the excitatory synaptic transmission in various areas of the mammalian CNS. We have studied the expression pattern of the genes encoding for KA receptor subunits (Glur5-1, Glur5-2, Glur6, Glur7, KA1 and KA2) in rat prenatal (E), postnatal and adult ventral mesencephalon (MES) and striatum (STR) and in fetal midbrain primary cultures. Each receptor subunit shows a unique area- and temporal-expression pattern. In MES the onset of both Glur5 subunits is delayed when compared to the other subunits. In addition, most of the transcripts for KA subunits gradually increase during embryonic development and show a slight decrease during the first postnatal week. Differently, Glur6 and KA2 mRNAs show a sharp increase at E14.5 and decrease thereafter, reaching the lowest levels during late embryonic and postnatal development. In the STR, the gene expression of all KA subunit mRNAs is higher during embryonic development than after birth, except KA1 transcripts, that show a peak at P5. In embryonic MES primary cultures, Glur5-2, Glur6 and KA2 mRNAs are higher at the beginning of the culture when compared to older cultures, while the other subunit mRNAs do not show significant variation throughout the days in vitro. Thus, all the KA receptor subunit transcripts appear independently regulated during MES and STR development, probably contributing to the establishment of the fine tuning of the excitatory circuits reciprocally established between these CNS areas.
Brain Res Mol Brain Res 2002 Jul 15
PMID:Ontogeny of kainate receptor gene expression in the developing rat midbrain and striatum. 1211 45

Interactions between gonadal steroid hormones and glutamatergic neurons participate in limbic and hypothalamic functions. Glutamate receptors are divided into metabotropic and ionotropic receptors. Among ionotropic receptors, N-methyl-D-aspartate (NMDA) is involved in a variety of neurophysiological processes. In turn, NMDA receptors are composed of subunits from two families: NR1 and NR2. Recently, molecular studies have shown that the expression of NMDA-2D receptor is regulated by estrogen. Although the expression patterns of NMDA-2D and ERalpha in the rodent brain appear to overlap, it remained to be determined whether or not these two receptors co-exist, in vivo, at the level of single neurons. To test the hypothesis that NMDA-2D and ERalpha messenger ribonucleic acid (mRNA) are co-expressed in the same neurons of the adult mouse brain, we used a dual-label in situ hybridization technique. Neuronal populations were identified with digoxigenin-tagged complementary RNA probes for NMDA-2D and 35S-labeled cRNA probes for ERalpha. Our results demonstrate that a majority of the ERalpha-positive neurons also express NMDA-2D mRNA. Quantitative examination of the cellular expression in the ventromedial and arcuate nuclei of the hypothalamus (VMH and Arc) showed that 52.5% and 61.5%, respectively, of the neurons endowed with ERalpha mRNA also contain NMDA-2D mRNA. In the amygdala, 51% of ERalpha-positive cells also contain NMDA-2D mRNA. These findings provide the first anatomical evidence that ER and NMDA-2D receptors can be found in the same hypothalamic and amygdaloid neurons. Co-expression of ERalpha and NMDA-2D receptors supports the hypothesis of the interactions between glutamate receptors and estrogens in brain regions where estrogens control female reproductive behaviors and neuroendocrine functions.
Brain Res Mol Brain Res 2002 Jul 15
PMID:Colocalization of estrogen receptor alpha and NMDA-2D mRNAs in amygdaloid and hypothalamic nuclei of the mouse brain. 1211 50

Glutamate is the principal excitatory neurotransmitter within the mammalian CNS, playing an important role in many different functions in the brain such as learning and memory. In this study, a combination of molecular biology, X-ray structure determinations, as well as electrophysiology and binding experiments, has been used to increase our knowledge concerning the ionotropic glutamate receptor GluR2 at the molecular level. Five high-resolution X-ray structures of the ligand-binding domain of GluR2 (S1S2J) complexed with the three agonists (S)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol-4-yl]propionic acid (2-Me-Tet-AMPA), (S)-2-amino-3-(3-carboxy-5-methylisoxazol-4-yl)propionic acid (ACPA), and (S)-2-amino-3-(4-bromo-3-hydroxy-isoxazol-5-yl)propionic acid (Br-HIBO), as well as of a mutant thereof (S1S2J-Y702F) in complex with ACPA and Br-HIBO, have been determined. The structures reveal that AMPA agonists with an isoxazole moiety adopt different binding modes in the receptor, dependent on the substituents of the isoxazole. Br-HIBO displays selectivity among different AMPA receptor subunits, and the design and structure determination of the S1S2J-Y702F mutant in complex with Br-HIBO and ACPA have allowed us to explain the molecular mechanism behind this selectivity and to identify key residues for ligand recognition. The agonists induce the same degree of domain closure as AMPA, except for Br-HIBO, which shows a slightly lower degree of domain closure. An excellent correlation between domain closure and efficacy has been obtained from electrophysiology experiments undertaken on non-desensitising GluR2i(Q)-L483Y receptors expressed in oocytes, providing strong evidence that receptor activation occurs as a result of domain closure. The structural results, combined with the functional studies on the full-length receptor, form a powerful platform for the design of new selective agonists.
J Mol Biol 2002 Sep 06
PMID:Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core. 1221 17

Neurons contain a protein factor capable of binding DNA elements normally bound by the transcription factor NF-kappaB. However, several lines of evidence suggest that this neuronal kappaB-binding factor (NKBF) is not bona fide NF-kappaB. We have identified NKBF from cultures of neocortical neurons as a complex containing proteins related to Sp1. This complex was bound by antibodies to Sp1, Sp3, and Sp4 and was competed from binding to an NF-kappaB element by an oligonucleotide containing an Sp1-binding site. This Sp1 oligonucleotide detected an abundant factor in neuronal nuclei that migrated in electrophoretic mobility shift assays at a position consistent with NKBF. Expression of transfected Sp1 stimulated transcription in a manner dependent upon a kappaB cis-element. Similar to our previous reports for NKBF (Mao, X., Moerman, A. M., Lucas, M. M., and Barger, S. W. (1999) J. Neurochem. 73, 1851-1858 and Moerman, A. M., Mao, X., Lucas, M. M., and Barger, S. W. (1999) Mol. Brain Res. 67, 303-315), the activity of the Sp1-related factor was reduced by activation of ionotropic glutamate receptors, consistent with proteolytic degradation of all three Sp1-related factors. Expression of the N-methyl-d-aspartate receptor-1 (NR1) subunit of glutamate receptors correlated with the activity of the Sp1-related factor, specifically through an Sp1 element in the NR1 promoter. These data provide the first evidence that Sp1 or related family members are responsible for kappaB-binding activity and are involved in a negative feedback for NR1 in central nervous system neurons.
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PMID:Neuronal kappa B-binding factors consist of Sp1-related proteins. Functional implications for autoregulation of N-methyl-D-aspartate receptor-1 expression. 1224 44

Neurotransmitter receptors (neuroreceptors) are classified into two types, G protein-coupled receptors (GPCRs) and ligand-gated ion channels. The former occupies a small part of the large GPCR superfamily, whereas the latter consists of three superfamilies. In these superfamilies, humans and rodents share almost the same set of neuroreceptor genes. This neuroreceptor gene set is good material to examine the degree of selective constraint exerted on each member gene of a given superfamily. If there are any neuroreceptor genes under the degree of selective constraint that is very different from that of the other member genes, they may have influenced the functional features characteristic of human neural activities. With the aim of identifying such neuroreceptor genes, we collected sequence data of orthologous neuroreceptor genes for humans, mice, and rats by database searches. This data set included ortholog pairs for 141 kinds of neuroreceptor genes, which covered almost the whole set of neuroreceptor genes known to be expressed in the human brain. The degree of selective constraint was estimated by computing the ratio (d(N)/d(S)) of the number of nonsynonymous substitutions to that of synonymous substitutions. We found that the d(N)/d(S) ratio ranged widely and its distribution fitted a gamma distribution. In particular, we found that four neuroreceptor genes are under the significantly relaxed selective constraint. They are an ionotropic glutamate receptor subunit NMDA-2C, two GABA(A) receptor subunits, i.e., GABA(A)-epsilon and GABA(A)-theta, and a dopamine receptor D4. Interestingly, these neuroreceptors have been reported to be associated with cognitive abilities such as memory and learning, and responsiveness to novel stimuli. These cognitive abilities can influence the behavioral features of an individual. Thus, it suggests that the relaxed-constraint neuroreceptor genes have evolved, assuring that the nervous system responds to a variety of stimuli with proper flexibility.
Mol Biol Evol 2002 Nov
PMID:Identification of neurotransmitter receptor genes under significantly relaxed selective constraint by orthologous gene comparisons between humans and rodents. 1241 98

Fast synaptic inhibition in the brain is largely mediated by ionotropic GABA receptors, which can be subdivided into GABAA and GABAC receptors based on pharmacological and molecular criteria. GABAA receptors are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are implicated in several diseases including epilepsy, anxiety, depression, and substance abuse. In addition, modulating the efficacy of GABAergic neurotransmission may play a key role in neuronal plasticity. Recent studies have begun to reveal that the accumulation of ionotropic GABAA receptors at synapses is a highly regulated process that is facilitated by receptor-associated proteins and other cell-signaling molecules. This review focuses on recent experimental evidence detailing the mechanisms that control the assembly and transport of functional ionotropic GABAA receptors to cell surface sites, in addition to their stability at synaptic sites. These regulatory processes will be discussed within the context of the dynamic modulation of synaptic inhibition in the central nervous system (CNS).
Mol Neurobiol
PMID:Mechanisms of GABAA receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission. 1242 59

1. Guanosine-5'-monophosphate (GMP) was evaluated as a neuroprotective agent against the damage observed in rat hippocampal slices submitted to an in vitro model of ischemia with or without the presence of the ionotropic glutamate receptor agonist, Kainic acid (KA). 2. Cellular injury was evaluated by MTT reduction, lactate dehydrogenase(LDH) release assay, and measurement of intracellular ATP levels. 3. In slices submitted to ischemic conditions, 1 mM GMP partially prevented the decrease in cell viability induced by glucose and oxygen deprivation and the addition of KA. 4. KA or N-methyl-D-aspartate (NMDA) receptor antagonists, gamma-D-glutamylamino-methylsulfonate (GAMS) or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, 20 microM) also prevented toxicity in hippocampal slices under ischemic conditions, respectively. 5. The association of GMP with GAMS or MK-801 did not induce additional protection than that observed with GMP or that classical glutamate receptor antagonists alone. 6. GMP, probably by interacting with ionotropic glutamate receptors, attenuated the damage caused by glucose and oxygen deprivation in hippocampal slices. This neuroprotective action of GMP in this model of excitotoxicity is of outstanding interest in the search for effective therapies against ischemic injury.
Cell Mol Neurobiol 2002 Jun
PMID:Neuroprotective effect of GMP in hippocampal slices submitted to an in vitro model of ischemia. 1246 74

The lectin Concanavalin A (ConA) has long been known to potentiate current responses of native and recombinant ionotropic glutamate receptors (iGluRs), apparently by inhibition of receptor desensitization. We compared the effects of a broad range of lectins with different carbohydrate specificities on recombinant AMPA (GluR1) and kainate receptors (GluR6) expressed in Xenopus oocytes. Interestingly, the extent of inhibition of desensitization appears to depend on the sugar preference of lectins at kainate (KA) receptors, but not at alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. None of the lectins potentiated current responses at non-glycosylated GluRs produced in tunicamycin-treated oocytes, demonstrating the requirement of lectin interaction with carbohydrate moieties of the receptors. At AMPA receptors, potentiation of current responses afforded by ConA and the well-known inhibitor of desensitization, cyclothiazide (CTZ), are additive, suggesting that the lectin and CTZ act independently. Current amplitudes of GluR1(L479Y), a nondesensitizing mutant, however, could not be further increased by ConA.
Mol Cell Neurosci 2002 Dec
PMID:Inhibition by lectins of glutamate receptor desensitization is determined by the lectin's sugar specificity at kainate but not AMPA receptors. 1250 87

Systemic administration of kainic acid in C57BL/6 and FVB/N mice induces a comparable level of seizure induction yet results in differential susceptibility to seizure-induced cell death. While kainate administration causes severe hippocampal damage in mice of the FVB/N strain, C57BL/6 mice display no demonstrable cell loss or damage. At present, while the cellular mechanisms underlying strain-dependent differences in susceptibility remain unclear, some of this variation is assumed to have a genetic basis. As glutamate receptors are thought to participate in seizure induction and the subsequent neuronal degeneration that ensues, previous studies have proposed that variation in the precise subunit composition of glutamate receptors may result in differential susceptibility to excitotoxic cell death. Thus, we chose to examine the relationship between the cellular distribution and expression of glutamate receptor subunit proteins and cell loss within the hippocampus in mouse strains resistant and susceptible to kainate-induced excitotoxicity. Using semi-quantitative Western blot techniques and immunohistochemistry with the use of antibodies that recognize subunits of the KA (GluR5,6,7), AMPA (GluR1, GluR2, and GluR4), and NMDA (NMDAR1 and NMDAR2A/2B) receptors, we found no significant strain-dependent differences in the expression or distribution of these glutamate receptor subunits in the intact hippocampus. Following kainate administration, expression changes in ionotropic glutamate receptor subunits paralleled the development of susceptibility to cell death in the FVB/N strain only. Strain differences in hippocampal vulnerability to kainate-induced status epilepticus are not due to glutamate receptor protein expression.
Brain Res Mol Brain Res 2003 Apr 10
PMID:Differences in ionotropic glutamate receptor subunit expression are not responsible for strain-dependent susceptibility to excitotoxin-induced injury. 1267 Jul 4

To determine the in vivo targets of long-lasting actions of TrkB signaling on synaptic function we analyze synaptic components of excitatory and inhibitory circuits in the cerebral cortex of trkB (-/-) mice. First, we show that K(+)-evoked glutamate and GABA release from forebrain mutant synaptosomes was decreased. Moreover, the dependence of regulated exocytosis on the SNARE SNAP-25 and the Ca(2+)-dependent neurotransmitter release were also impaired in trkB (-/-) mice. We also analyzed postsynaptic glutamate and GABA(A) ionotropic receptors in cortical areas of trkB mutant mice. By using Western blot we observed decreased levels of the AMPA receptor subunits GluR2/3 and GluR4 in trkB (-/-) forebrains. In contrast, the forebrain of mutant mice exhibited increased levels of the GABA(A) receptor subunit alpha3 and alpha5 and a reduction of the gamma2 subunit. Immunocytochemical analysis showed that the hippocampus and neocortex of mutant mice exhibited decreased numbers of interneurons positive for distinct AMPA and GABA(A) receptor subunits. Furthermore, alteration of inhibitory circuits in trkB (-/-) mice was also shown by the low expression of the GABA-synthesizing enzyme glutamic acid decarboxylase in mutant cortical areas. The present results indicate that long-lasting TrkB signaling is required for the precise adjustment of neurotransmitter release and for the correct composition of the fast glutamatergic and GABAergic receptor subunits in vivo.
Mol Cell Neurosci 2003 Feb
PMID:Ca(2+)-evoked synaptic transmission and neurotransmitter receptor levels are impaired in the forebrain of trkb (-/-) mice. 1267 31


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