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)

In response to different cellular stresses, a family of protein kinases phosphorylates eIF2alpha (alpha subunit of eukaryotic initiation factor-2), contributing to regulation of both general and genespecific translation proposed to alleviate cellular injury or alternatively induce apoptosis. Recently, we reported eIF2alpha(P) (phosphorylated eIF2alpha) in the brain during SE (status epilepticus) induced by pilocarpine in mice, an animal model of TLE (temporal lobe epilepsy) [Carnevalli, Pereira, Longo, Jaqueta, Avedissian, Mello and Castilho (2004) Neurosci. Lett. 357, 191-194]. We show in the present study that one eIF2alpha kinase family member, PKR (double-stranded-RNA-dependent protein kinase), is activated in the cortex and hippocampus at 30 min of SE, reflecting the levels of eIF2alpha(P) in these areas. In PKR-deficient animals subjected to SE, eIF2alpha phosphorylation was clearly evident coincident with activation of a secondary eIF2alpha kinase, PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. The extent of eIF2alpha phosphorylation correlated with the inhibition of protein synthesis in the brain, as determined from polysome profiles. We also found that C57BL/6 mice, which enter SE upon pilocarpine administration but are more resistant to seizure-induced neuronal degeneration, showed very low levels of eIF2alpha(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2alpha contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2alpha phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.
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PMID:Phosphorylation of the alpha subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus. 1649 39

Seizure is a form of excessive neuronal excitation and seizure-induced neuronal damage has profound effects on the prognosis of epilepsy. In various seizure models, the inactivation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) occurs during seizure activity preceding neuronal cell death. CaMKII is a multifunctional protein kinase enriched in the brain and involved in various ways the regulation of neuronal activity. CaMKII inactivation during seizure activity may modify neuronal cell survival after seizure. However, the mechanism for CaMKII inactivation and its consequence after seizure recovery remain to be elucidated yet. In the present study, we employed a prolonged seizure model by systemic injection of kainic acid into rats and biochemically examined the activity state of CaMKII. In status epilepticus induced by kainic acid, not only the inactivation of CaMKII in brain homogenate, but also a shift in the distribution of CaMKII protein from the soluble to particulate fraction occurred in both hippocampus and parietal cortex. The particulate CaMKII showed a large decrease in the specific activity and a concurrent large increase in the autophosphorylation ratio at Thr-286 (alpha) and at Thr-287 (beta). In contrast, the soluble CaMKII showed normal or rather decreased specific activity and autophosphorylation ratio. After 24 h of recovery from kainic acid-induced status epilepticus, all such changes had disappeared. On the other hand, the total amount of CaMKII was decreased by 35% in hippocampus and 20% in parietal cortex, but the existing CaMKII was indistinguishable from those of controls in terms of the autonomous activity ratio, specific activity and autophosphorylation ratio. Thus, CaMKII inactivation in kainic acid-induced status epilepticus seems to be derived not from simple degradation of the enzyme, but from the formation of the autophosphorylated, inactivated and sedimentable CaMKII. Such a form of CaMKII may be important during pathological conditions in vivo in preventing excessive CaMKII activation due to Ca2+ overload.
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PMID:A mechanism for the inactivation of Ca2+/calmodulin-dependent protein kinase II during prolonged seizure activity and its consequence after the recovery from seizure activity in rats in vivo. 1663 8

The transcription factor DeltaFosB (also referred to as FosB2 or FosB[short form]) is an important mediator of the long-term plasticity induced in brain by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of DeltaFosB is that, once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The mechanisms underlying this apparent stability, however, have remained unknown. Here, we demonstrate that DeltaFosB is a relatively stable transcription factor, with a half-life of approximately 10 h in cell culture. Furthermore, we show that DeltaFosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in DeltaFosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2. These findings constitute the first evidence that DeltaFosB is phosphorylated and demonstrate that phosphorylation contributes to its stability, which is at the core of its ability to mediate long-lasting adaptations in brain.
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PMID:Regulation of DeltaFosB stability by phosphorylation. 1668 4

Neuronal excitability is inhibited by somatostatin, which might play important roles in seizure and neuroprotection. The possibility of whether the effect of somatostatin on neurotransmission is susceptible to desensitization was investigated. We tested the effects of prolonged exposure to somatostatin on 0.1 mM extracellular Mg(2+) concentration ([Mg(2+)](o))-induced intracellular free Ca(2+) concentration ([Ca(2+)](i)) spikes in cultured rat hippocampal neurons using fura-2-based microfluorimetry. Reducing [Mg(2+)](o) to 0.1 mM elicited repetitive [Ca(2+)](i) spikes. These [Ca(2+)](i) spikes were inhibited by exposure to somatostatin-14. The inhibitory effects of somatostatin were blocked by pretreatment with pertussis toxin (PTX, 100 ng/ml) for 18-24 h. Prolonged exposure to somatostatin induced a desensitization of the somatostatin-induced inhibition of [Ca(2+)](i) spikes in a concentration-dependent manner. The somatostatin-induced desensitization was retarded by the nonspecific protein kinase C (PKC) inhibitor staurosporin (100 nM) or chronic treatment with phorbol dibutyrate (1 microM) for 24 h, but not by the protein kinase A inhibitor KT5720. The desensitization was significantly retarded by the novel PKCepsilon translocation inhibitor peptide (1 microM). In addition, suramin (3 microM), an inhibitor of G-protein-coupled receptor kinase 2 (GRK2), caused a reduction in the desensitization. After tetrodotoxin (TTX, 1 microM) completely blocked the low [Mg(2+)](o)-induced [Ca(2+)](i) spikes, glutamate-induced [Ca(2+)](i) transients were slightly inhibited by somatostatin and the inhibition was desensitized by prolonged exposure to somatostatin. These results indicate that the prolonged activation of somatostatin receptors induces the desensitization of somatostatin-induced inhibition on low [Mg(2+)](o)-induced [Ca(2+)](i) spikes through the activation of GRK2 and partly a novel PKCepsilon in cultured rat hippocampal neurons.
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PMID:Desensitization of somatostatin-induced inhibition of low extracellular magnesium concentration-induced calcium spikes in cultured rat hippocampal neurons. 1687 4

Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclin-dependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.
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PMID:c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes. 1689 24

Epilepsy, a disorder of recurrent seizures, is a common and frequently devastating neurological condition. Available therapy is only symptomatic and often ineffective. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help identify molecular targets for drugs that could prevent epilepsy. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of epileptogenesis have been established. Here, we review current insights into the molecular signaling mechanisms underlying epileptogenesis, focusing on limbic epileptogenesis. Study of different models reveals that activation of various receptors on the surface of neurons can promote epileptogenesis; these receptors include ionotropic and metabotropic glutamate receptors as well as the TrkB neurotrophin receptor. These receptors are all found in the membrane of a discrete signaling domain within a particular type of cortical neuron--the dendritic spine of principal neurons. Activation of any of these receptors results in an increase Ca2+ concentration within the spine. Various Ca2+-regulated enzymes found in spines have been implicated in epileptogenesis; these include the nonreceptor protein tyrosine kinases Src and Fyn and a serine-threonine kinase [Ca2+-calmodulin-dependent protein kinase II (CaMKII)] and phosphatase (calcineurin). Cross-talk between astrocytes and neurons promotes increased dendritic Ca2+ and synchronous firing of neurons, a hallmark of epileptiform activity. The hypothesis is proposed that limbic epilepsy is a maladaptive consequence of homeostatic responses to increases of Ca2+ concentration within dendritic spines induced by abnormal neuronal activity.
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PMID:Molecular signaling mechanisms underlying epileptogenesis. 1703 45

We describe two siblings with neonatal hypocalcemic seizures whose mother took topiramate during both pregnancies. Apart from hypocalcemia, the patients had no identifiable etiology for their seizures. Although biochemical data suggested that the hypocalcemia was caused by hypoparathyroidism, no disorders typically associated with this condition were identified in the patients. We propose that topiramate exposure in utero led to hypoparathyroidism and subsequent hypocalcemia via effects on protein kinase A signaling, resulting in hypocalcemic seizures. Neonates exposed to topiramate in utero should be monitored for hypocalcemic seizures.
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PMID:Neonatal hypocalcemic seizures in siblings exposed to topiramate in utero. 1743 16

The Tottering (cacna1a(tg)) mouse arose as a consequence of a spontaneous mutation in cacna1a, the gene encoding the pore-forming subunit of the pre-synaptic P/Q-type voltage-gated calcium channel (VGCC, Ca(V)2.1). The mouse phenotype includes ataxia and intermittent myoclonic seizures which have been attributed to impaired excitatory neurotransmission at cerebellar granule cell (CGC) parallel fiber-Purkinje cell (PF-PC) synapses [Zhou YD, Turner TJ, Dunlap K (2003) Enhanced G-protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca(2+)-channel mutant mouse, tottering. J Physiol 547:497-507]. We hypothesized that the expression of cerebellar GABA(A) receptors may be affected by the mutation. Indeed, abnormal GABA(A) receptor function and expression in the cacna1a(tg) forebrain has been reported previously [Tehrani MH, Barnes EM Jr (1995) Reduced function of gamma-aminobutyric acid A receptors in tottering mouse brain: role of cAMP-dependent protein kinase. Epilepsy Res 22:13-21; Tehrani MH, Baumgartner BJ, Liu SC, Barnes EM Jr (1997) Aberrant expression of GABA(A) receptor subunits in the tottering mouse: an animal model for absence seizures. Epilepsy Res 28:213-223]. Here we show a deficit of 40.2+/-3.6% in the total number of cerebellar GABA(A) receptors expressed (gamma2+delta subtypes) in adult cacna1a(tg) relative to controls. [(3)H]Muscimol autoradiography identified that this was partly due to a significant loss of CGC-specific alpha6 subunit-containing GABA(A) receptor subtypes. A large proportion of this loss of alpha6 receptors was attributable to a significantly reduced expression of the CGC-specific benzodiazepine-insensitive Ro15-4513 (BZ-IS) binding subtype, alpha6betagamma2 subunit-containing receptors. BZ-IS binding was reduced by 36.6+/-2.6% relative to controls in cerebellar membrane homogenates and by 37.2+/-3.7% in cerebellar sections. Quantitative immunoblotting revealed that the steady-state expression level of alpha6 and gamma2 subunits was selectively reduced relative to controls by 30.2+/-8.2% and 38.8+/-13.1%, respectively, alpha1, beta3 and delta were unaffected. Immunohistochemically probed control and cacna1a(tg) cerebellar sections verified that alpha6 and gamma2 subunit expression was reduced and that this deficit was restricted to the CGC layer. Thus, we have shown that abnormal cerebellar P/Q-type VGCC activity results in a deficit of CGC-specific subtype(s) of GABA(A) receptors which may contribute to, or may be a consequence of the impaired cerebellar network signaling that occurs in cacna1a(tg) mice.
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PMID:Aberrant cerebellar granule cell-specific GABAA receptor expression in the epileptic and ataxic mouse mutant, Tottering. 1761 9

Acute cocaine toxicity is frequently associated with seizures. The mechanisms underlying the convulsant effect of cocaine are not well understood. Previously, we have shown that cocaine depresses whole-cell current evoked by gamma-aminobutyric acid (GABA) in hippocampal neurons freshly isolated from rats. Cocaine's effect was voltage-independent and concentration-dependent. In the present study, using whole-cell patch-clamp recording on rat neurons freshly isolated from hippocampus, we examined the intracellular mechanisms involved in cocaine's action. Increasing intracellular Ca(2+) concentration ([Ca]i) from 0.01 to 5 microM strongly increased the depressant effect of cocaine. By contrast, 1-[N, O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a specific antagonist of Ca/calmodulin-dependent protein kinase (CaMKII), attenuated or enhanced cocaine's action in different neurons: in three out of nine neurons dialysed with 5 microM KN-62,1 mM cocaine depressed GABA current by only 33%, but in another three out of nine neurons, cocaine depressed GABA current by as much as 83%. Chelerythrine (a specific CaCa(2+)/phospholipid-dependent protein kinase C [PKC] antagonist) had minimal effect on cocaine's action. We suggest that cocaine induces an increase in [Ca]i, which stimulates phosphatase activity and thus leads to dephosphorylation of GABA receptors. This dephosphorylation-mediated disinhibitory action may play a role in cocaine-induced convulsant states.
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PMID:Cocaine inhibition of GABA(A) current: role of dephosphorylation. 1772 11

l-Aspartyl (l-Asp) and l-asparaginyl residues in proteins isomerize or racemize to d,l-isoaspartyl (d,l-isoAsp) or d-aspartyl (d-Asp) residues during protein aging. These atypical aspartyl residues can interfere with the biological function of the protein and lead to cellular dysfunction. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a repair enzyme that facilitates conversion of l-isoAsp and d-Asp to l-Asp. PIMT deficient mice exhibit accumulation of l-isoAsp in several tissues and die, on average, 12 days after birth from progressive epileptic seizures with grand mal and myoclonus features. However, little is known about the molecular mechanisms by which accumulation of the aberrant residues leads to cellular abnormalities. In this study, we established PIMT-knockdown cells using a short interfering RNA expression system and characterized the resultant molecular abnormalities in intracellular signaling pathways. PIMT-knockdown cells showed significant accumulation of proteins with isomerized residues, compared to control cells. In the PIMT-knockdown cells, Raf-1, MEK, and ERK, members of the MAPK cascade, were hyperphosphorylated after EGF stimulation compared to control cells. These results suggest that PIMT repair of abnormal proteins is necessary to maintain normal MAPK signaling.
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PMID:Suppression of protein l-isoaspartyl (d-aspartyl) methyltransferase results in hyperactivation of EGF-stimulated MEK-ERK signaling in cultured mammalian cells. 1838 Dec


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