Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcriptional and translational regulation of glutamate receptor expression determines one of the key phenotypic features of neurons in the brain--the properties of their excitatory synaptic receptors. Up- and down-regulation of various glutamate receptor subunits occur throughout development, following ischemia, seizures, repetitive activation of afferents, or chronic administration of a variety of drugs. The promoters of the genes that encode the NR1, NR2B, NR2C, GluR1, GluR2, and KA2 subunits share several characteristics that include multiple transcriptional start sites within a CpG island, lack of TATA and CAAT boxes, and neuronal-selective expression. In most cases, the promoter regions include overlapping Sp1 and GSG motifs near the major initiation sites, and a silencer element, to guide expression in neurons. Manipulating the levels of glutamate receptors in vivo by generating transgenic and knockout mice has enhanced understanding of the role of specific glutamate receptor subunits in long-term potentiation and depression, learning, seizures, neural pattern formation, and survival. Neuron-specific glutamate receptor promoter fragments may be employed in the design of novel gene-targeting constructs to deliver future experimental transgene and therapeutic agents to selected neurons in the brain.
 ...
PMID:Genetic regulation of glutamate receptor ion channels. 1033 Oct 83

Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA)-receptor subtype of glutamate receptor in a number of brain areas. The mechanism of ethanol action has been investigated by means of patch-clamp recording of ionic currents and fura-2 measurement of intracellular Ca2+ concentration in cell culture systems; the subunit composition of NMDA receptors and their influence on the effect of ethanol was determined by molecular biology methods. Ethanol does not appear to interact with NMDA either at the glutamate recognition site of the receptor, or at any of the hitherto known multiple modulatory sites, such as the glycine or polyamine site. Moreover, ethanol does not cause an open channel block by itself and fails to interact with Mg2+ at the site where it causes open channel block. The ability of ethanol to inhibit responses to NMDA is dependent on the subunit combination of NMDA receptors. The NR1/NR2A and NR1/NR2B combinations are preferentially sensitive to ethanol inhibition. Chronic treatment with ethanol leads to an increase of the NMDA receptor number at the transcriptional and posttranscriptional level; the receptor function is also facilitated. This causes withdrawal-type seizures after termination of chronic treatment with ethanol. The inhibition of NMDA receptors by ethanol leads to the depression of excitatory synaptic potentials mediated by this type of excitatory amino acid receptor. Ethanol-induced disturbances in certain regions of the brain, i.e. hippocampus, nucleus accumbens or locus coeruleus may lead to cognitive disorders or drug dependence. Brain slices containing the locus coeruleus may be used as an in vitro test system to investigate the addictive properties of ethanol.
 ...
PMID:Ethanol-induced inhibition of NMDA receptor channels. 1040 99

This manuscript summarizes mouse mutants for ionotropic glutamate receptors that were generated by different laboratories to analyze the function of the NMDA and AMPA receptors in the mouse. Thus, NMDA receptor mutant mice that were generated by the "knock-in" technology demonstrate that the NR1 and the NR2B subunits participate in the formation of NMDA receptors that are involved in vital functions like breathing and suckling of a newborn mouse. Mice that lack NR2A, -2C, and -2D subunits were described to be viable and have been used to study the role of NMDA receptors in adult mice. The depletion of the GluR-B subunit revealed an NMDA receptor-independent form of long-term potentiation (LTP). This AMPA receptor-mediated LTP at CA3/CA1 synapses was also observed in mice that carry an editing-deficient GluR-B allele even though these mice die prematurely after heavy epileptic seizures. In other mutants, the intracellular COOH-terminal domain of the NMDA receptor was truncated; and when compared to NMDA receptor "knock-out" mice, a functional knock-out of the NMDA receptor was observed. However, in the synapses of NR2AC/AC mutants, gatable NMDA receptors were synaptically activated, indicating that the knock-out phenotypes mediated by the COOH-terminally truncated NMDA receptors appear to reflect defective intracellular signaling.
 ...
PMID:Mice with genetically modified NMDA and AMPA receptors. 1041 26

Changes in the subunit stoichiometry of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) alters its channel properties, and may enhance or reduce neuronal excitability in temporal lobe epilepsy patients. This study determined whether hippocampal NMDA receptor subunit mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsy cases. Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. These findings indicate that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A-D hybridization densities that vary by subfield and clinical-pathological category. In temporal lobe epilepsy patients, these findings support the hypothesis that in dentate granule cells NMDA receptors are increased, and excitatory postsynaptic potentials should be strongly NMDA mediated compared with nonseizure autopsies. HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases.
 ...
PMID:Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients. 1048 65

Earlier work has suggested that Fyn tyrosine kinase plays an important role in synaptic plasticity. To understand the downstream targets of Fyn signaling cascade in neurons, we generated transgenic mice expressing either a constitutively activated form of Fyn or native Fyn in neurons of the forebrain. Transgenic mice expressing mutant Fyn exhibited higher seizure activity and were prone to sudden death. Mice overexpressing native Fyn did not show such an obvious epileptic phenotype, but they exhibited accelerated kindling in response to once-daily stimulation of the amygdala. Tyrosine phosphorylation of at least three proteins was enhanced in the forebrains of both native and mutant fyn transgenic mice; tyrosine phosphorylation of these three proteins was reduced in fyn knockout mice, suggesting that they are substrates of Fyn. One of these proteins was identified as the subunit 2B (NR2B) of the N-methyl-D-aspartate (NMDA) receptor. Administration of MK-801, a noncompetitive NMDA receptor antagonist, retarded kindling in mice overexpressing native Fyn, as well as wild-type mice, suggests that the accelerated kindling in mice overexpressing Fyn is also mediated by the NMDA receptor activity. Our results thus suggest that tyrosine phosphorylation by Fyn might be involved in regulation of the susceptibility of kindling, one form of the NMDA receptor-mediated neuronal plasticity.
 ...
PMID:Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice. 1048 60

For the development of new drugs for hitherto untreatable epilepsy, it is necessary to clarify the basic pathophysiology involved in such epileptic seizures and find the target site. This review focused on molecular events related to the expression and expansion of the epileptic focus which are the target of novel antiepileptics. Immediate early genes such as c-fos followed by expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been evidenced as initial important phenomena in the cascade of molecular systems that develop and complement the transient neuronal excitation to long-term neuronal plasticity. Non-receptor type tyrosine kinase Fyn in the Src family has been suggested to promote kindling development via tyrosine phosphorylation of the NMDA-receptor subunit, NR2B. The cause of abnormality in the inhibitory system is induced by lowering of glutamate-dependent GABA release in the epileptic focus within the hippocampus in human temporal epilepsy. This is probably attributed to a decrease in GABA transporters. Regarding abnormality of the excitatory system, there is an increase in glutamate release prior to convulsive seizures, an enhancement of NMDA receptor responsiveness and high levels of AMPA receptors related to convulsion after completion of kindling. In gene analysis of human familiar epilepsy, abnormalities and point mutations have recently been found in the following genes: KCNQ 2 and KCNQ3, coding for K+ channels; CHRNA4 of the nicotinic receptor subunit alpha 4; and the cystatin B gene. In epilepsy model mice, EL mice with several gene mutations known to be involved in the seizures, the El-1 gene contains an abnormality of the ceruloplasmin gene. SER (spontaneously epileptic rat: zi/zi, tm/tm), a double mutant, manifests a deletion of the region containing the aspartoacylase gene related to the tm gene. Since an increase in N-acetyl-L-aspartate (NAA) is observed in the SER brain, NAA may serve to evoke seizures.
 ...
PMID:[Molecular mechanism underlying epileptic seizure: forwards development of novel drugs for untreatable epilepsy]. 1055 79

The purification, characterization, and synthesis of conantokin-R (Con-R), an N-methyl-D-aspartate (NMDA) receptor peptide antagonist from the venom of Conus radiatus, are described. With the use of well defined animal seizure models, Con-R was found to possess an anticonvulsant profile superior to that of ifenprodil and dizocilpine (MK-801). With voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs, Con-R exhibited the following order of preference for NR2 subunits: NR2B approximately NR2A > NR2C >> NR2D. Con-R was without effect on oocytes expressing the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 or the kainate receptor subunit GluR6. In mouse cortical neurons voltage-clamped at -60 mV, Con-R application produced a slowly developing block of inward currents evoked by 10 microM NMDA and 1 microM glycine (IC(50) = 350 nM). At 3 microM, Con-R did not affect gamma-aminobutyric acid- or kainate-evoked currents. Con-R prevented sound-induced tonic extension seizures in the Frings audiogenic seizure-susceptible mice at i.c.v. doses below toxic levels. It was also effective at nontoxic doses in CF#1 mice against tonic extension seizures induced by threshold (15 mA) and maximal (50 mA) stimulation, and it partially blocked clonic seizures induced by s.c. pentylenetetrazol. In contrast, MK-801 and ifenprodil were effective only at doses approaching (audiogenic seizures) or exceeding (electrical and pentylenetetrazol seizures) those required to produce significant behavioral impairment. These results indicate that the subtype selectivity and other properties of Con-R afford a distinct advantage over the noncompetitive NMDA antagonists MK-801 and ifenprodil. Con-R is a useful new pharmacological agent for differentiation between the anticonvulsant and toxic effects of NMDA antagonists.
 ...
PMID:In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus. 1060 79

Changes in mRNA levels of N-methyl-D-aspartate receptor (NR) subunits were studied in a rat model of withdrawal from forced ethanol ingestion over a period of 8 days. In part, this model may reflect the epsilon-type of human alcoholism according to Jellinek (College University Press, New Haven; 1972). The epsilon-type is characterized by dipsomania over a period of several days, recurring every few months and often followed by ethanol-induced seizures. Seizures may be modulated by an increased glutamatergic neurotransmission to excitatory or inhibitory neurons on the basis of a changed gene expression of NR subunits. This hypothesis promoted the present study. Film autoradiograms and emulsion-coated brain sections following labeling of cholinergic and GABAergic neuron populations were evaluated. NR subunit 1 (NR1) expression, studied with a probe recognizing all NR1 transcripts, was unchanged after withdrawal from chronic ethanol treatment compared to control animals. Using probes specific for different splice segments of NR1, however, we found that, in ethanol-treated rats, the expression of NR1-2 was decreased in all, and that of NR1-4 in all but one, areas investigated (only single label experiments were performed with NR1 splice variants). Withdrawing rats revealed a higher expression of NR subunit 2A (NR2A) mRNA in GABAergic neurons. No changes could be observed at the regional level. Conversely, NR2B mRNA was not substantially altered in cholinergic and GABAergic neurons, but showed a decrease over brain areas. For both, NR2C and NR2D, no ethanol-related changes of mRNA expression were observed. A link between such differential alterations in NR mRNA subunit expression and ethanol-induced seizures in withdrawing alcoholics of the epsilon-type seems possible.
 ...
PMID:Changes in NMDA receptor subunit gene expression in the rat brain following withdrawal from forced long-term ethanol intake. 1068 78

Although serine proteases and their receptors are best known for their role in blood coagulation and fibrinolysis, the CNS expresses many components of an extracellular protease signaling system including the protease-activated receptor-1 (PAR1), for which thrombin is the most effective activator. In this report we show that activation of PAR1 potentiates hippocampal NMDA receptor responses in CA1 pyramidal cells by 2.07 +/- 0.27-fold (mean +/- SEM). Potentiation of neuronal NMDA receptor responses by thrombin can be blocked by thrombin and a protein kinase inhibitor, and the effects of thrombin can be mimicked by a peptide agonist (SFLLRN) that activates PAR1. Potentiation of the NMDA receptor by thrombin in hippocampal neurons is significantly attenuated in mice lacking PAR1. Although high concentrations of thrombin can directly cleave both native and recombinant NR1 subunits, the thrombin-induced potentiation we observe is independent of NMDA receptor cleavage. Activation of recombinant PAR1 also potentiates recombinant NR1/NR2A (1.7 +/- 0.06-fold) and NR1/NR2B (1.41 +/- 0.11-fold) receptor function but not NR1/NR2C or NR1/NR2D receptor responses. PAR1-mediated potentiation of recombinant NR1/NR2A receptors occurred after activation with as little as 300 pm thrombin. These data raise the intriguing possibility that potentiation of neuronal NMDA receptor function after entry of thrombin or other serine proteases into brain parenchyma during intracerebral hemorrhage or extravasation of plasma proteins during blood-brain barrier breakdown may exacerbate glutamate-mediated cell death and possibly participate in post-traumatic seizure. Furthermore, the ability of neuronal protease signaling to control NMDA receptor function may also have roles in normal brain development.
 ...
PMID:Potentiation of NMDA receptor function by the serine protease thrombin. 1084 28

Rats become susceptible to audiogenic seizures (AS) when they are exposed to intense noise during a certain critical period of development (priming). Antagonism of N-methyl-D-aspartate (NMDA) receptor NR2B subunit by injecting an antagonist ifenprodil at priming enhanced the later susceptibility to AS. An weak NR2A antagonist, dextromethorphan, did not show such effects while it significantly suppressed the manifestation of AS in already susceptible post-weaning (primed) rats. These results indicate that NR2B plays an important role in the developmental regulation of the auditory system involved in AS but this subunit has a minor relevance to the manifestation of AS in the later life.
 ...
PMID:Effects of N-methyl-D-aspartate receptor subunit antagonists on regulation of susceptibility to audiogenic seizures in rats. 1087 80


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