Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kainate receptor glutamate receptor 6 (GluR6) subunit-deficient and c-Jun N-terminal kinase 3 (JNK3)-null mice share similar phenotypes including resistance to kainite-induced epileptic seizures and neuronal toxicity (Yang, D. D., Kuan, C-Y., Whitmarsh, A. J., Rincon, M., Zheng, T. S., Davis, R. J., Rakis, P., and Flavell, R. (1997) Nature 389, 865-869; Mulle, C., Seiler, A., Perez-Otano, I., Dickinson-Anson, H., Castillo, P. E., Bureau, I., Maron, C., Gage, F. H., Mann, J. R., Bettler, B., and Heinemmann, S. F. (1998) Nature 392, 601-605). This suggests that JNK activation may be involved in GluR6-mediated excitotoxicity. We provide evidence that post-synaptic density protein (PSD-95) links GluR6 to JNK activation by anchoring mixed lineage kinase (MLK) 2 or MLK3, upstream activators of JNKs, to the receptor complex. Association of MLK2 and MLK3 with PSD-95 in HN33 cells and rat brain preparations is dependent upon the SH3 domain of PSD-95, and expression of GluR6 in HN33 cells activated JNKs and induced neuronal apoptosis. Deletion of the PSD-95-binding site of GluR6 reduced both JNK activation and neuronal toxicity. Co-expression of dominant negative MLK2, MLK3, or mitogen-activated kinase kinase (MKK) 4 and MKK7 also significantly attenuated JNK activation and neuronal toxicity mediated by GluR6, and co-expression of PSD-95 with a deficient Src homology 3 domain also inhibited GluR6-induced JNK activation and neuronal toxicity. Our results suggest that PSD-95 plays a critical role in GluR6-mediated JNK activation and excitotoxicity by anchoring MLK to the receptor complex.
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PMID:Kainate receptor activation induces mixed lineage kinase-mediated cellular signaling cascades via post-synaptic density protein 95. 1115 98

Dysiherbaine (DH) is a marine sponge-derived amino acid that causes seizures upon injection into mice. In this report we investigate the behavioral effects and characterize the pharmacological activity of DH. DH induced convulsive behaviors in mice with ED(50) values of 13 pmol/mouse, i.c.v. and 0.97 mg/kg, i.p. In rat brain synaptic membranes DH displaced binding of [3H]kainic acid (KA) and [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) with K(i) values of 26 and 153 nM, respectively; in contrast, DH did not displace the N-methyl-D-aspartic acid (NMDA) receptor ligand [3H]CGS-19755. DH displaced [3H]KA from recombinant GluR5 and GluR6 kainate receptor subunits expressed in HEK293 cells with K(i) values of 0.74 and 1.2 nM, respectively. In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, DH evoked inward currents from both AMPA and KA receptors with EC(50) values of 9.7 microM and 210 nM, respectively. AMPA receptor currents were blocked by GYKI 53655, whereas KA receptor currents were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Surprisingly, in calcium imaging experiments we found that DH also activated recombinant mGluR5 receptors but did not activate mGluR1 receptors. DH did not activate glutamate transporters or gamma-aminobutyric acid A (GABA(A)) receptors. These results indicate that DH is a potent non-NMDA-type agonist with very high affinity for KA receptors, as well as a subtype-selective mGluR agonist. DH possesses the most potent epileptogenic activity among the amino acids yet identified. This novel excitatory amino acid may prove useful for evaluating the physiological and pathological roles of non-NMDA receptors, especially KA receptors, in the central nervous system.
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PMID:Pharmacological properties of the potent epileptogenic amino acid dysiherbaine, a novel glutamate receptor agonist isolated from the marine sponge Dysidea herbacea. 1116 Jun 54

The ionotropic glutamate receptor subunit GluR6 undergoes developmentally and regionally regulated Q/R site RNA editing that reduces the calcium permeability of GluR6-containing kainate receptors. To investigate the functional significance of this editing in vivo, we engineered mice deficient in GluR6 Q/R site editing. In these mutant mice but not in wild types, NMDA receptor-independent long-term potentiation (LTP) could be induced at the medial perforant path-dentate gyrus synapse. This indicates that kainate receptors with unedited GluR6 subunits can mediate LTP. Behavioral analyses revealed no differences from wild types, but mutant mice were more vulnerable to kainate-induced seizures. Together, these results suggest that GluR6 Q/R site RNA editing may modulate synaptic plasticity and seizure vulnerability.
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PMID:The role of RNA editing of kainate receptors in synaptic plasticity and seizures. 1118 93

Posttranscriptional editing of mRNA is a phenomenon that generates molecular heterogeneity and functional variety. With the intention to test if RNA editing plays a role in pathological processes, which contribute to seizure maintenance, we examined the ratio of the unedited (Q) to edited (R) form of the AMPA receptor subunit GluR2 and kainate receptor subunits GluR5 and GluR6 in the hippocampus and temporal cerebral cortex, both excised from patients with pharmacoresistant temporal lobe epilepsies. We compared the data with samples from nonepileptic human control tissue (autopsy tissue). The ratio of Q/R editing was analyzed by means of reverse transcription-polymerase chain reaction followed by a restriction enzyme assay. We found that the editing efficiency for the kainate receptor subunits GluR5 and GluR6 was significantly higher in temporal cortex than in normal controls. The alteration in GluR5 and GluR6 mRNA editing in the neocortical tissue may reflect an adaptive reaction of ongoing seizure activity to prevent excessive Ca(2+) influx.
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PMID:RNA editing at the Q/R site for the glutamate receptor subunits GLUR2, GLUR5, and GLUR6 in hippocampus and temporal cortex from epileptic patients. 1144 54

Excitotoxicity is a process in which glutamate or other excitatory amino acids induce neuronal cell death. Accumulating evidence suggests that excitotoxicity may contribute to human neuronal cell loss caused by acute insults and chronic degeneration in the central nervous system. The immediate early gene (IEG) c-fos encodes a transcription factor. The c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes. Emerging evidence suggests that c-fos is essential in regulating neuronal cell survival versus death. Although c-fos is induced by neuronal activity, including kainic acid-induced seizures, whether and how c-fos is involved in excitotoxicity is still unknown. To address this issue, we generated a mouse in which c-fos expression is largely eliminated in the hippocampus. We found that these mutant mice have more severe kainic acid-induced seizures, increased neuronal excitability and neuronal cell death, compared with control mice. Moreover, c-Fos regulates the expression of the kainic acid receptor GluR6 and brain-derived neurotrophic factor (BDNF), both in vivo and in vitro. Our results suggest that c-fos is a genetic regulator for cellular mechanisms mediating neuronal excitability and survival.
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PMID:c-fos regulates neuronal excitability and survival. 1192 68

Kainate receptors (KARs) on CA1 pyramidal cells make no detectable contribution to EPSCs. We report that these receptors have a metabotropic function, as shown previously for CA1 interneurons. Brief kainate exposure caused long-lasting inhibition of a postspike potassium current (I(sAHP)) in CA1 pyramidal cells. The pharmacological profile was independent of AMPA receptors or the GluR5 subunit, indicating a possible role for the GluR6 subunit. KAR inhibition of I(sAHP) did not require ionotropic action or network activity, but was blocked by the inhibitor of pertussis toxin-sensitive G proteins, N-ethylmaleimide (NEM), or the PKC inhibitor calphostin C. These data suggest how KARs, putatively containing GluR6, directly increase excitability of CA1 pyramidal cells and help explain the propensity for seizure activity following KAR activation.
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PMID:Metabotropic-mediated kainate receptor regulation of IsAHP and excitability in pyramidal cells. 1193 45

We have previously demonstrated that kainate receptors (KA-Rs) are acutely inhibited by ethanol (EtOH). Here we show that KA-Rs are also affected by long-term EtOH exposure. Whole-cell recordings of pharmacologically isolated KA-R-mediated currents in cultured hippocampal neurons revealed that exposure to 80 mM EtOH for 3 days followed by a 24 h withdrawal period increased KA-R current densities. Quantitative confocal microscopy showed that expression of GluR6/7 subunits increases after ethanol withdrawal in these neurons. Since KA-Rs control hippocampal excitability and seizure generation, we postulate that upregulation of these receptors may have a role in the pathophysiology of alcohol withdrawal syndrome.
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PMID:Ethanol withdrawal upregulates kainate receptors in cultured rat hippocampal neurons. 1209 52

(2S,2R)-4-Methylglutamic acid (SYM 2081), a potent selective agonist of GluR5 and GluR6 kainate receptor subtypes, applied at the dose of 15.5 mg/kg, equal to its CD(16) value (i.e., a dose required to induce convulsions in 16% of mice), significantly decreased the electroconvulsive threshold from 7.0 to 5.8 mA. When administered at the dose of 11.5 mg/kg, equal to 75% of its CD(16), it markedly attenuated the protective activity of phenobarbital and diphenylhydantoin, but not that of valproate, carbamazepine, or diazepam against maximal electroshock-induced seizures in mice. The respective ED(50) values were increased from 18.5 to 23.8 mg/kg for phenobarbital, and from 11.7 to 14.7 mg/kg for diphenylhydantoin. Since the free plasma levels of both antiepileptic drugs were not influenced by SYM 2081, the pharmacokinetic interaction does not seem to be involved in the observed results. In conclusion, low-affinity kainate receptor-mediated events might be a factor reducing the protective efficacy of some antiepileptic drugs. Furthermore, the activation of GluR5 and GluR6 kainate receptor subtypes by endogenous glutamate during seizures may be associated with the drug-resistance phenomenon.
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PMID:Low-affinity kainate receptor-mediated events reduce the protective activity of phenobarbital and diphenylhydantoin against maximal electroshock in mice. 1250 14

Rhythmic electrical activity is ubiquitous in neuronal networks of the brain and is implicated in a multitude of different processes. A prominent example in the healthy brain is electrical oscillations in the gamma-frequency band (20-80 Hz) in hippocampal and neocortical networks, which play an important role in learning, memory and cognition. An example in the pathological brain is electrographic seizures observed in certain types of epilepsy. Interestingly the activation of kainate receptors (KARs) plays an important role in synaptic physiology and plasticity, and can generate both gamma oscillations and electrographic seizures. Electrophysiological recordings of extracellular gamma oscillations and intracellular currents in a hippocampal slice combined with computer modelling can shed light on the expression loci of KAR subunits on single neurones and the distinct roles subunits play in rhythmic activity in the healthy and the pathological brain. Using this approach in wild-type (WT) and KAR knockout mice it has been shown that KAR subunits GluR5 and GluR6 have similar functions during gamma oscillations and epileptiform bursts and that small changes in the overall activity in the hippocampal area CA3 can tilt the balance between excitation and inhibition and cause the neuronal network to switch from gamma oscillations to epileptiform bursts.
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PMID:Kainate receptors and rhythmic activity in neuronal networks: hippocampal gamma oscillations as a tool. 1551 34

The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurones in chronic epilepsy. Here we analysed the effects of one-sided lateral EC (LEC) and temporoammonic (alvear) path lesion on the development and properties of 4-aminopyridine-induced seizures. Electroencephalography (EEG) analysis of freely moving rats identified that the lesion increased the latency of the hippocampal seizure significantly and decreased the number of brief convulsions. Seizure-induced neuronal c-fos expression was reduced in every hippocampal area following LEC lesion. Immunocytochemical analysis 40 days after the ablation of the LEC identified sprouting of cholinergic and calretinin-containing axons into the dentate molecular layer. Region and subunit specific changes in the expression of ionotropic glutamate receptors (iGluRs) were identified. Although the total amount of AMPA receptor subunits remained unchanged, GluR1(flop) displayed a significant decrease in the CA1 region. An increase in NR1 and NR2B N-methyl-d-aspartate (NMDA) receptor subunits and KA-2 kainate receptor subunit was identified in the deafferented layers of the hippocampus. These results further emphasize the importance of the lateral entorhinal area in the spread and regulation of hippocampal seizures and highlight the potential role of the rewiring of afferents and rearrangement of iGluRs in the dentate gyrus in hippocampal convulsive activity.
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PMID:Lateral entorhinal cortex lesions rearrange afferents, glutamate receptors, increase seizure latency and suppress seizure-induced c-fos expression in the hippocampus of adult rat. 1618 16


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