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)

Many neurological disorders are accompanied by abnormal nerve activity. However, the exact causes of this abnormal nervous activity has never been determined. Based upon my research, I propose a theory that the underlying cause of many types of neurological disorders such as minor epilepsy and narcolepsy is an abnormally functioning Na+/K+ ATPase pump at the molecular framework of the brain, notably the brainstem reticular formation (locus coerulus) and cerebellum in this particular case. The excessive and repetitive nerve activity within localized areas of the brain caused by abnormally functioning molecular Na+/K+ ATPase ion pumps may be the primary and true causes of many different types of neurological disorders since constant depolarizations of the cell membrane causes abnormally excessive amounts of certain neurotransmitters to be released. The type of neurological disorder may be a function of the abnormally occurring Na+/K+ ATPase molecular ion pump's localization within the neurological framework of the brain. To focus on my theory of repetitive nervous activity from abnormal inhibitive or defective Na+/K+ ATPase pumps, I have chosen to analyze minor epilepsy and narcolepsy intentionally. What is found is that the abnormal release of neurotransmitters during epileptic seizures or narcoleptic sleep episodes is secondary to the abnormal neuronal systematic framework underlying Na+/K+ membrane potentials since an abnormally inhibited or defective Na+/K+ ATPase pump has a direct electrogenic effect on the membrane potential.
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PMID:Abnormal cortical unit activity of the reticular formation. 785 71

A Ca(2+)- or Mg(2+)-stimulated ecto-ATPase is thought to regulate the hydrolysis of extracellular ATP in nervous tissues. The hydrolysis of nucleotide triphosphates (NTPs) was analyzed in brain microsomal fractions from crosses of DBA/2J (D2) and C57BL/6J (B6) mice. The nucleotide triphosphatase (NTPase) activity was significantly reduced in D2 mice as compared to B6 mice, and B6D2F1 hybrids had activities intermediate to the parentals. A significant positive correlation was found between the hydrolysis of four NTPs (ATP, CTP, GTP and UTP) in 24 B6 x D2 (BXD) recombinant inbred (RI) strains of mice and in 80 B6D2F1 x D2 backcross mice. The RI strains and backcross mice fell into two distinct groups with respect to the NTPase activity. Linkage of NTPase activity was suggested with the chromosome 2 markers, D2Mit6 and Ass-1, in the RI strains, and was confirmed by analysis of other markers in the backcross population. These data suggest that the Ca(2+)- or Mg(2+)-stimulated hydrolysis of NTPs, designated Ntp, is regulated by a single gene located on proximal chromosome 2. Although an association was observed previously between Ca(2+)-ATPase activity and susceptibility to audiogenic seizures (AGS), no significant association was observed for the expression of Ntp and AGS susceptibility.
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PMID:Genetic analysis of nucleotide triphosphatase activity in the mouse brain. 805 15

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

Transient changes in extracellular potassium concentration ([K+]o) and field potentials were evoked by 4-aminopyridine (4-AP; 50-100 microM) and recorded with ion-selective microelectrodes in CA1b, CA3b and dentate sectors of adult rat hippocampal slices. Long-lasting field potentials recurred at a frequency of approximately 1/60 s (0.016 +/- 0.003 Hz) in association with increases in [K+]o which were largest and most sustained in the dendritic regions where afferent fibers terminate (dentate > CA1 > CA3) and in the hilus. In stratum radiatum of CA1 or stratum moleculare of the dentate these fields had a peak amplitude of 1.4 +/- 0.29 mV, duration 8.3 +/- 1.6 s, and were accompanied by increases in [K+]o of 1.8 +/- 0.22 mM that lasted 32 +/- 5.5 s (n = 17 slices). Interictal epilentiform potentials, which were brief (< 0.2 s) and more frequent at approximately 1/3 s (0.30 +/- 0.02Hz) were also present in CA1, CA3 and the hilus and associated with small increases in [K+]o (< or = 0.5 mM, duration < or = 2 s). Interictal activity was blocked by 6-cyano-7-nitroquinoxalone-2,3-dione (CNQX; 5-20 microM); the slow, less frequent potentials were resistant to both CNQX and DL-2-amino-5-phosphonovaleric acid (APV; 50 microM) and reversibly blocked (or attenuated by approximately 80%) by bicuculline methiodide (BMI) (25-100 microM). The BMI-sensitive potentials were also abolished by baclofen (100 microM), an effect which was reversed by 2-OH-saclofen (100 microM). Focal application of KCI or GABA in the absence of 4-AP evoked long-lasting field and [K+]o potentials which were similar to those evoked by 4-AP but more sustained. The proportional relationship between the amplitudes of field and K+ potentials with GABA closely resembled that observed for 4-AP; in contrast the slope of KC1-evoked responses was lower. Our results demonstrate that in the adult rat hippocampus 4-AP induces in many different regions accumulations of [K+]o in synchrony with the long-lasting field potentials, which are known to correspond to an intracellular long-lasting depolarization of the pyramidal cells. These changes are smaller than those which occur in the immature rat hippocampus--which may be related to differences in Na-K-ATPase and susceptibility to seizures. These events involve the activation of GABAA receptors, are under the modulatory control of GABAB receptors, and likely arise from the activity of GABAergic interneuron and/or afferent terminals. The long-lasting field potentials appear to reflect mainly the direct depolarizing actions of GABA and to much more limited extent the associated accumulation of [K+]o.
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PMID:Extracellular K+ accumulations and synchronous GABA-mediated potentials evoked by 4-aminopyridine in the adult rat hippocampus. 874 Feb 10

The present study was undertaken to evaluate the antiseizure activity spectrum of insulin against various behavioral seizure models in rats. Insulin was injected intraperitoneally (i.p.) at a test dose of 1 U/kg. Dextrose (3 g/kg) was administered simultaneously with insulin to counteract its hypoglycemic effect and induce a normoglycemic state. Insulin was found to significantly decrease the incidence, intensity and mortality rate and prolong the latency of generalized tonic-clonic convulsions induced by pentylenetetrazole (60 mg/kg i.p.) and significantly decrease the intensity and mortality rate and prolong the latency of generalized tonic-clonic convulsions induced by penicillin (2000 U/intracerebrocortical). Insulin was not only found to prolong the latency of all the seizure components but was found to reduce the incidence of focal myoclonic twitches and generalized tonic-clonic convulsions induced by kainic acid (12 mg/kg i.p.) as well. Insulin was shown to be ineffective to suppress ouabain (5 micrograms/intracerebroventricular) induced seizures. These findings indicate that insulin possesses a broad spectrum of antiseizure activity in rats. Interaction with brain Na(+)-K(+)-ATPase has been discussed as a possible mechanism of action.
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PMID:Antiseizure activity of insulin: insulin inhibits pentylenetetrazole, penicillin and kainic acid-induced seizures in rats. 895 15

1. Phenytoin has been used with much clinical success against all types of epileptiform seizures, except petit mal epilepsy, for over 50 years. Its mechanism of action, however, is still open to interpretation. 2. Several potential targets for phenytoin action have been identified within the central nervous system. These include the Na-K-ATPase, the GABAA receptor complex, ionotropic glutamate receptors, calcium channels and sigma binding sites. 3. To date, though, the best evidence hinges on the inhibition of voltage-sensitive Na+ channels in the plasma membrane of neurons undergoing seizure activity. Quieter nerve cells are far less affected. Moreover, the fact that phenytoin also has important cardiac antiarrhythymic effects and can inhibit Na+ influx into cardiac cells supports the idea that the primary target of phenytoin is, indeed, the Na+ channel.
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PMID:Basis of the antiseizure action of phenytoin. 898 Oct 53

Low Mg2+-induced epileptiform activity in the entorhinal cortex is characterized by an initial expression of seizure-like events followed by late recurrent discharges. Both these forms of activity as well as the transition between them were blocked by serotonin. In contrast, serotonin had little effect upon the epileptiform activity in areas CA3 and CA1 of the hippocampus. Both forms of epileptiform activity in the entorhinal cortex are sensitive to N-methyl-D-aspartate receptor antagonists and it is shown here that serotonin blocked both types of epileptiform activity through an effective concentration-dependent reduction of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials in deep layer entorhinal cortex cells. Serotonin also prolonged or even prevented the transition between the two types of epileptiform activity and we suggest that this may be through activation of the Na+/K+-ATPase. The resistance of epileptiform activity in CA1 and CA3 to serotonin was most likely related to the inability of serotonin to reduce Schaffer collateral-evoked excitatory postsynaptic potentials. Given the strong serotonergic inputs to both the hippocampus and entorhinal cortex, the differential sensitivity of the two regions to serotonin suggests functional differences. In addition since the late recurrent discharges in the entorhinal cortex are resistant to all clinically used anticonvulsants, serotonin may open new avenues for the development of novel anticonvulsant compounds.
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PMID:Serotonin blocks different patterns of low Mg2+-induced epileptiform activity in rat entorhinal cortex, but not hippocampus. 901 29

The aim of this study was to investigate the brain cortex Na(+)-K+ ATPase activity in rats made diabetic by streptozotocin and epileptic by pentylenetetrazol. Streptozotocin diabetic rats showed a significant decrease in brain cortex Na(+)-K+ ATPase activity whereas the pentylenetetrazol treatment caused no significant change in enzyme activity. On the other hand, no brain cortex Na(+)-K+ ATPase activity could be detected in all the diabetic rats treated with pentylenetetrazol. Our results concluded that reduced Na(+)-K+ ATPase activity in streptozotocin diabetic rats may contribute to the pathogenesis of metabolic complications of the central nervous system, and that the undetectable enzyme activity in diabetic convulsing rats may result from considerable damage or necrosis of brain tissue during pentylenetetrazol seizures.
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PMID:Brain cortex Na(+)-K+ ATPase activities in streptozotocin-diabetic and pentylenetetrazol-epileptic rats. 936 17

A single cerebroventricular injection of ethacrynic acid (EA), a Cl(-)-ATPase inhibitor, induces generalized tonic-clonic convulsions in mice. To clarify whether such convulsive stimulus triggers a long-lasting rearrangement of the neural circuitry culminating in seizure susceptibility, we examined molecular, cellular and behavioral changes following the EA-induced seizure. The expression of immediate early gene c-fos mRNA as an index for cellular activation increased biphasically, with an early transient increase at 60 min and a late prolonged increase on the 10th to 14th day post-EA administration, most remarkably in the hippocampus and pyriform cortex. On the 14th day post-EA seizure, subconvulsive dose of kainic acid (5-17.5 mg/kg) caused severe (stage 5) seizure in 77% of the mice, with 70% mortality. In addition, the expression of nerve growth factor (NGF) also showed biphasic increases with close spatiotemporal correlation with c-fos expression. Moreover, the number of cell somata and the density of axon fibers of parvalbumin (PARV)-positive cells, a subpopulation of GABAergic interneurons, decreased in area dentata, CA1 and CA3 on the 7th and 14th day post-EA seizure. In area dentata and CA1, the density of glutamic acid decarboxylase (GAD)-positive cells also decreased on the 14th day. Thus, the transient EA-induced seizures appear to develop seizure susceptibility by causing damage of a subpopulation of inhibitory interneurons along with increases in the expression of c-fos and NGF in limbic structures.
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PMID:Long-lasting c-fos and NGF mRNA expressions and loss of perikaryal parvalbumin immunoreactivity in the development of epileptogenesis after ethacrynic acid-induced seizure. 1040 97

Genetic linkage studies in rodents and humans have identified specific chromosomal regions harboring seizure susceptibility genes. We have identified a novel polymorphism in the human alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase (NaK-pump), a candidate gene for human temporal lobe epilepsy (TLE) based on its chromosomal location and function in ion homeostasis. The polymorphism consists of a four base pair insertion 12 base pairs upstream of the start of exon 2. We performed an association study between this polymorphism and TLE. Our study did not find a significant difference in the frequency of this polymorphism between TLE patients and controls, indicating that this variation is not a major susceptibility factor. However, since the number of patients studied so far is small and the functional consequence of the polymorphism is unknown, the variation may yet be found to play a minor role in increased risk for seizure susceptibility. In contrast to the findings in TLE patients and controls, we did find a significant difference in the frequency of the variation between African Americans and persons of European descent. This finding demonstrates the potential effect of population stratification on studies of this type and supports the growing use of parental and familial samples for controls in association studies. Further study of this polymorphism is warranted as it may be involved in other disease processes for which there are known ethnic-specific susceptibilities. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:79-83, 2000.
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PMID:Lack of association between temporal lobe epilepsy and a novel polymorphism in the alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase. 1068 57


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