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: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spontaneous recurrent seizures (SRS) are the major clinical characteristic of epilepsy. In this study, using a SRS-behavior test combined with linker capture subtraction (LCS) to identify genes altered in their expression in response to a single kainic acid (KA)-induced SRS at 3 weeks in the rat hippocampal formation. Dot blot analysis of the differentially expressed cDNA fragments with LCS showed the down-regulation of one cDNA related to SRS, which was designated epilepsy-related gene 1 (ERG1). Northern blot analysis showed that ERG1 mRNA was reduced by KA administration with and without SRS, but more so with SRS. This differential expression had also been confirmed by in situ hybridization, which showed that ERG1 mRNA was down-regulated in the dorsal dentate granule cells (dDGCs) of the hippocampal formation, but remarkable up-regulated in the amygdalohippocampal area (AHi), posteromedial cortical amygdaloid nucleus (PMCo) and perirhinal cortex (PRh). The complete cDNA of ERG1 was cloned, sequenced (AF142097). It encodes a Rattus homologue of N-ethylmaleimide-sensitive fusion protein (NSF), which is an ATPase that plays a key role in mediating docking and/or fusion of transport vesicles in the multi-step pathways of vesicular transport. Sequence analysis revealed that ERG1 has high sequence similarity with the cDNA of the Mus musculus suppressor of K(+) transport growth defect (SKD2), N-ethylmaleimide(NEM)-sensitive fusion protein of Chinese hamster and human NEM-sensitive factor (HSU03985).
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PMID:A spontaneous recurrent seizure-related Rattus NSF gene identified by linker capture subtraction. 1122 66

The effect of nantenine, an aporphine alkaloid, on ATPase K+-dependent dephosphorylation was evaluated using p-nitrophenylphosphate (p-NPP) as substrate. Basal K+-p-NPPase activity was significantly increased with 3 x 10(-4) M, remained unchanged with 3 x 10(-6) M, 3 x 10(-5) M but was reduced with 7.5 x 10(-4) M and 1 x 10(-3) M nantenine, whereas Mg2+-p-NPPase activity was not modified. Kinetic studies showed that K+-p-NPPase inhibition by nantenine is competitive to KCl but non-competitive to substrate p-NPP, whereas K+-p-NPPase stimulation by nantenine is non-competitive to KCl but competitive to p-NPP. These data suggest that there may be two acceptor sites for nantenine in p-NPPase, one eliciting stimulation and the other inhibition of K+-dependent p-NPP hydrolysis. Considering the biphasic action of nantenine on seizures and the correlation between decreased ATPase activity and seizure development, alkaloid anticonvulsant effect observed at low nantenine doses is attributable to the stimulation of phosphatase activity whereas the convulsant effect at high alkaloid doses seems related to Na+, K+-ATPase inhibition.
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PMID:In vitro dose dependent inverse effect of nantenine on synaptosomal membrane K+-p-NPPase activity. 1131 51

NSF is a cytosolic ATPase implicated in a variety of cellular functions including synaptic vesicle exocytosis. Here we report a lethal mutation in the Drosophila homolog of NSF (dNSF1). Lethality staging and rescue experiments with the wild type dNSF1 transgene show that NSF1 is critically required during early larval stages and during late pupariation. Lethality in larval stages is associated with defects in neurogenesis as evidenced by an overall reduction in synapse size and synapse branching. Moreover, escaper adults, though showing abnormal seizure-like paralytic behavior, are normal in terms of synaptic transmission as assayed by electroretinograms. Taken together, these data indicate a role for NSF in neural growth and branching in addition to its documented role in synaptic transmission.
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PMID:Lethal comatose mutation in Drosophila reveals possible role for NSF in neurogenesis. 1138 12

Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome and maternally inherited Leigh's syndrome have been associated with T8993G point mutations in the mitochondrial adenosine triphosphatase 6 gene. Typically, NARP syndrome is characterized by developmental delay, seizures, dementia, retinitis pigmentosa, ataxia, sensory neuropathy, and proximal weakness. Usually, there is a correlation between the percentage of mutated mitochondrial DNA and clinical severity, and when mutated mitochondrial DNA is > 90%, it is often seen with Leigh's syndrome. We now report a family with mitochondrial DNA T8993G mutation in eight living members, five with mutant mitochondrial DNA >90% and one with 20% mutant mitochondrial DNA. However, their clinical features include variable combinations of seizures, behavior problems, learning disability, mental retardation, sensorineural deafness, cerebellar ataxia, and proximal muscle weakness. No retinitis pigmentosa was found in all eight living members, including a 56-year-old grandmother. Only one dead female relative was diagnosed with Leigh's syndrome on the neuropathologic examination at age 22 years, when she died of an accident. High mitochondrial DNA T8993G mutation is not always associated with typical features of Leigh's and NARP syndromes.
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PMID:High mitochondrial DNA T8993G mutation (<90%) without typical features of Leigh's and NARP syndromes. 1145 54

Cerebral perfusion single photon emission computed tomography (SPECT) has been used to confirm the localization of the epileptic focus and the evaluation of seizure. Recently, diffusion-weighted MR imaging (DWI) has been recognized for evaluation of seizure activity. We describe a case of transient seizure activity demonstrated by Tc-99m HMPAO SPECT and DWI. This patient was a 61-year-old woman with a 10-month history of right middle cerebral artery (MCA) infarction who had a generalized seizure during MRI. DWI immediately after seizure showed transient hyperintensity in the right frontal gray matter and the white matter, and these apparent diffusion coefficients (ADC) were transiently decreased. This transient hyperintensity on DWI corresponded to transient hyperperfusion identifying the epileptic focus on interictal Tc-99m HMPAO SPECT. Transient sustained seizure activity might cause these changes on DWI and SPECT. It was considered that interictal Tc-99m HMPAO SPECT showed the delayed hyperperfusion caused by excitatory neuronal overaction and DWI showed cytotoxic edema seizure-induced by energy failure of the membrane-bound Na/K-ATPase pump.
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PMID:Transient seizure activity demonstrated by Tc-99m HMPAO SPECT and diffusion-weighted MR imaging. 1154

In the rat pilocarpine model, 1 h of status epilepticus caused significant inhibition of Mg(2+)/Ca(2+) ATPase-mediated Ca(2+) uptake in cortex endoplasmic reticulum (microsomes) isolated immediately after the status episode. The rat pilocarpine model is also an established model of acquired epilepsy. Several weeks after the initial status epilepticus episode, the rats develop spontaneous recurrent seizures, or epilepsy. To determine whether inhibition of Ca(2+) uptake persists after the establishment of epilepsy, Ca(2+) uptake was studied in cortical microsomes isolated from rats displaying spontaneous recurrent seizures for 1 year. The initial rate and total Ca(2+) uptake in microsomes from epileptic animals remained significantly inhibited 1 year after the expression of epilepsy compared to age-matched controls. The inhibition of Ca(2+) uptake was not due to individual seizures nor an artifact of increased Ca(2+) release from epileptic microsomes. In addition, the decreased Ca(2+) uptake was not due to either selective isolation of damaged epileptic microsomes from the homogenate or decreased Mg(2+)/Ca(2+) ATPase protein in the epileptic microsomes. The data demonstrate that inhibition of microsomal Mg(2+)/Ca(2+) ATPase-mediated Ca(2+) uptake in the pilocarpine model may underlie some of the long-term plasticity changes associated with epileptogenesis.
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PMID:Chronic inhibition of cortex microsomal Mg(2+)/Ca(2+) ATPase-mediated Ca(2+) uptake in the rat pilocarpine model following epileptogenesis. 1167 60

Activation of muscarinic cholinergic receptors produces oscillations in the hippocampal slice that resemble the theta rhythm, but also may produce abnormal synchronous activity that is more characteristic of epileptiform activity. We used pilocarpine, a muscarinic agonist and convulsant, and an elevation in extracellular potassium (5-7.5 mM) to produce synchronous neuronal activity that was prolonged (>2 s) and mimicked synchronization noted during seizures in vivo (ictal activity). In the CA3 region of adult rat hippocampal slices, prolonged ictal oscillations consisted of rhythmic field potentials occurring at 4-10 Hz for up to 30 s (ictal duration) that occurred in a regular periodic pattern every 12-166 s (ictal interval). The duration and interval between ictal oscillations were measured before and after application of drugs to define determinants of ictal occurrence. High threshold calcium channel antagonists (nifedipine and verapamil) blocked ictal activity. Release of calcium from intracellular stores also appeared to be important for ictal synchronization because ictal activity was blocked by dantrolene, an inhibitor of calcium release from intracellular stores, and by thapsigargin which blocks the ATPase that maintains intracellular calcium stores. These suppressive effects appeared to be postsynaptic because nifedipine, dantrolene, and thapsigargin had no effect on evoked fEPSPs. Enhancement of presynaptic inhibition by activation of GABA(B) or adenosine A(1) receptors suppressed ictal activity and depressed the amplitude of evoked population synaptic potentials. The results point to an important role for high threshold calcium channels and release of calcium from intracellular stores in addition to strength of synaptic connections in generation of prolonged oscillations that underlie seizure activity.
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PMID:Suppression of pilocarpine-induced ictal oscillations in the hippocampal slice. 1194 8

Mitochondrial disorders associated with defects in the respiratory chain can be attributable to mutations in the mitochondrial genome (mitochondrial DNA) or the nuclear genome (nuclear DNA). Because the brain is highly dependent on oxidative metabolism, encephalopathy is a common presentation, and epilepsy is a clinical hallmark of many of these conditions. Although most mutations in mitochondrial DNA do not present in infancy, a few mutations in the adenosine triphosphatase gene cause maternally inherited Leigh disease and infantile epilepsy. Early-onset epilepsy is more commonly associated with defects of nuclear genes encoding subunits of respiratory chain complexes or proteins needed for the correct assembly and functioning of the complexes. These defects generally cause autosomal recessive Leigh disease. In this review, the frequency and types of epilepsy (particularly early-onset seizures) are compared according to a genetic classification of the mitochondrial disorders.
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PMID:Mitochondrial disorders. 1259 54

The Na+/K+ ATPase asymmetrically distributes sodium and potassium ions across the plasma membrane to generate and maintain the membrane potential in many cell types. Although these pumps have been hypothesized to be involved in various human neurological disorders, including seizures and neurodegeneration, direct genetic evidence has been lacking. Here, we describe novel mutations in the Drosophila gene encoding the alpha (catalytic) subunit of the Na+/K+ ATPase that lead to behavioral abnormalities, reduced life span, and severe neuronal hyperexcitability. These phenotypes parallel the occurrence of extensive, age-dependent neurodegeneration. We have also discovered that the ATPalpha transcripts undergo alternative splicing that substantially increases the diversity of potential proteins. Our data show that maintenance of neuronal viability is dependent on normal sodium pump activity and establish Drosophila as a useful model for investigating the role of the pump in human neurodegenerative and seizure disorders.
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PMID:Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants. 1259 16

The present study investigated the anticonvulsant and convulsant profiles of nantenine, an aporphine alkaloid found in several vegetal species. At lower doses (20-50 mg/kg, i.p.) the alkaloid proved to be effective in inhibiting pentylenotetrazol- (PTZ 100 mg/kg, s.c.) and maximal electroshock-induced seizures (80 mA, 50 pulses/s, 0.2 s), suggesting its potential as an anticonvulsant drug. However, at higher doses (> or = 75 mg/kg, i.p.) a convulsant activity was observed. Comparing the present in vivo nantenine effects on seizures with previous in vitro biphasic action on Na+, K+-ATPase activity, the convulsant effect appears to be related to inhibition of these phosphatase at high doses whereas anticonvulsant effect, observed at low doses, seems attributable to its stimulation and the resultant decrease of Ca2+-influx into the cell.
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PMID:Nantenine alkaloid presents anticonvulsant effect on two classical animal models. 1367 44


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