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)

Long-term neurotoxicity of carbamazepine was studied in cultured cerebellar granule cells. Treatment of cells with carbamazepine for 3 days induced a dose-dependent neurotoxicity detected by a loss of [3H]ouabain binding to Na+,K(+)-ATPase, and [3H]N-methyl scopolamine binding to muscarinic cholinergic receptors as well as by direct morphologic examination. NMDA protected against carbamazepine-induced toxicity and this protection was blocked by 2-amino-5-phosphono-valerate (APV). The neurotoxicity induced by carbamazepine may be involved in the teratogenic and adverse effects of overdose associated with the treatment of manic-depressive illness and seizures.
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PMID:Carbamazepine-induced neurotoxicity and its prevention by NMDA in cultured cerebellar granule cells. 135 29

Direct and indirect evidence suggests that Na+/K(+)-ATPase activity is reduced or insufficient to maintain ionic balances during and immediately after episodes of ischemia, hypoglycemia, epilepsy, and after administration of excitotoxins (glutamate agonists). Recent results show that inhibition of this enzyme results in neuronal death, and thus a hypothesis is proposed that a reduction and/or inhibition of this enzyme contributes to producing the central neuropathy found in the above disorders, and identifies potential mechanisms involved. While the extent of inhibition of Na+/K(+)-ATPase during ischemia, hypoglycemia and epilepsy may be insufficient to cause neuronal death by itself, unless the inhibition is severe and prolonged, there are a number of interactions which can lead to a potentiation of the neurotoxic actions of glutamate, a prime candidate for causing part of the damage following trauma. Presynaptically, inhibition of the Na+/K(+)-ATPase destroys the sodium gradient which drives the uptake of acidic amino acids and a number of other neurotransmitters. This results in both a block of reuptake and a stimulation of the release not only of glutamate but also of other neurotransmitters which modulate the neurotoxicity of glutamate. An exocytotic release of glutamate can also occur as inhibition of the enzyme causes depolarization of the membrane, but exocytosis is only possible when ATP levels are sufficiently high. Postsynaptically, the depolarization could alleviate the magnesium block of NMDA receptors, a major mechanism for glutamate-induced neurotoxicity, while massive depolarization results in seizure activity. With less severe inhibition, the retention of sodium results in osmotic swelling and possible cellular lysis. A build-up of intracellular calcium also occurs via voltage-gated calcium channels following depolarization and as a consequence of a failure of the sodium-calcium exchange system, maintained by the sodium gradient.
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PMID:Inhibition of sodium-potassium-ATPase: a potentially ubiquitous mechanism contributing to central nervous system neuropathology. 166 97

A key mechanism of brain injury after cerebral ischaemia is supposed to be the iron-dependent formation of highly reactive oxygen free radicals initiated by the intracellular accumulation of calcium and promoted by the excess release of glutamate. Oxido-reductive processes (formation of superoxide radicals and lipid peroxidation) are mediated through NMDA-receptors, while non-NMDA receptors, associated with (or being a part of) Na,K-ATPase, are responsible for postischaemic brain swelling. The hypothesis was put forward for consideration that release of glutamate (and other related endogenous excitatory amino acids) due to depolarization in the early minutes of ischaemia and (non)-NMDA antagonists may have roles in the development and prevention of metabolic brain impairment and cytotoxic oedema, respectively, in the ischaemic state.
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PMID:Excitatory amino acid receptors, oxido-reductive processes and brain oedema following transient ischaemia in gerbils. 198 77

Cultured neurons of chick embryo cerebral hemispheres were used as an in vitro system for investigating the influence of several drugs on neuronal cell viability and metabolic activity under hypoxic conditions. Hypoxia was induced by addition of sodium cyanide to the nutrient medium, which led to a rapid depletion of energy stores. The ATP level of the cells and the protein content of the cultures were used to characterize the degree of neuronal damage after cytotoxic hypoxia and recovery, respectively, recovery lasting 15 min or 3 days. Various calcium antagonists, NMDA-antagonists, central depressants, central stimulants, nootropics, and miscellaneous drugs were tested. NMDA-antagonists and central depressants consistently protected the neurons against alterations caused by hypoxia. However, only one (flunarizine) out of five calcium antagonists, two (naftidrofuryl, pyritinol) out of 13 nootropics, the kappa-agonist ketazocine, and the ATPase inhibitor ouabaine exerted neuroprotection. The in vitro model seems to be suitable for testing neuroprotective drug effects and to be a valuable supplement for in vivo experiments, especially when the cellular mechanism of drug action has to be clarified.
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PMID:Cultured neurons for testing antihypoxic drug effects. 230 52

In Huntington's disease neuronal degeneration mainly involves medium-sized spiny neurons. It has been postulated that both excitotoxic mechanisms and energy metabolism failure are implicated in the neuronal degeneration observed in Huntington's disease. In central neurons, > 40% of the energy released by respiration is used by Na+/K+ ATPase to maintain ionic gradients. Considering that impairment of Na+/K+ ATPase activity might alter postsynaptic responsivity to excitatory amino acids (EAAs), we investigated the effects of the Na+/K+ ATPase inhibitors, ouabain and strophanthidin, on the responses to different agonists of EAA receptors in identified medium-sized spiny neurons electrophysiologically recorded in the current- and voltage-clamp modes. In most of the cells both ouabain and strophanthidin (1-3 microM) did not cause significant change in the membrane properties of the recorded neurons. Higher doses of either ouabain (30 microM) or strophanthidin (30 microM) induced, per se, an irreversible inward current coupled to an increase in conductance, leading to cell deterioration. Moreover, both ouabain (1-10 microM) and strophanthidin (1-10 microM) dramatically increased the membrane depolarization and the inward current produced by subcritical concentrations of glutamate, AMPA and NMDA. These concentrations of Na+/K+ ATPase inhibitors also increased the membrane responses induced by repetitive cortical activation. In addition, since it had previously been proposed that dopamine mimics the effects of Na+/K+ ATPase inhibitors and that dopamine agonists differentially regulate the postsynaptic responses to EAAs, we tested the possible modulation of EAA-induced membrane depolarization and inward current by dopamine agonists. Neither dopamine nor selective dopamine agonists or antagonists affected the postsynaptic responses to EAAs. Our experiments show that impairment of the activity of Na+/K+ ATPase may render striatal neurons more sensitive to the action of glutamate, lowering the threshold for the excitotoxic events. Our data support neither the role of dopamine as an ouabain-like agent nor the differential modulatory action of dopamine receptors on the EAA-induced responses in the striatum.
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PMID:Vulnerability of medium spiny striatal neurons to glutamate: role of Na+/K+ ATPase. 758 22

Carbon monoxide (CO) induces a long-lasting alteration in cerebellar alpha 3-Na,K-ATPase independent of [Na+] but linked to cGMP synthesis and localized to Purkinje neurons. The action of CO is absent in Purkinje neuron-deficient mice, mimicked by 8-Br-cGMP, and blocked by inhibition of PKG. Glutamate (Glu) and metabotropic agonists mimic the action of CO, an effect that requires PKC and is associated with CO synthesis. These data suggest that CO regulates Na,K-ATPase through cGMP and PKG, and that Glu regulates CO through mGluRs. This system is also modulated by NMDA agonists and nitric oxide, possibly via Glu release, as well as by free radicals. These findings offer a mechanism by which CO, Glu, and free radicals can exert specific effects on synaptic transmission (relevant to long-term changes in cell excitability), as well as more general actions on energy metabolism (relevant to the pathophysiology of excitotoxicity).
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PMID:The cellular Na+ pump as a site of action for carbon monoxide and glutamate: a mechanism for long-term modulation of cellular activity. 771 40

This study tests the hypothesis that magnesium, a selective non-competitive antagonist of the NMDA receptor, will attenuate hypoxia-induced alteration in NMDA receptors and preserve MK-801 binding characteristics during cerebral hypoxia in vivo. Anesthetized, ventilated and instrumented newborn piglets were divided into three groups: normoxic controls were compared to untreated hypoxic and Mg(2+)-treated hypoxic piglets. Cerebral hypoxia was induced by lowering the FiO2 to 5-7% and confirmed biochemically by a decrease in the levels of phosphocreatine (82% lower than control). The Mg(2+)-treated group received MgSO4 600 mg/kg over 30 min followed by 300 mg/kg administered during 60 min of hypoxia. Plasma Mg2+ concentrations increased from 1.6 +/- 0.1 mg/dl to 17.7 +/- 3.3 mg/dl. 3H-MK-801 binding was used as an index of NMDA receptor modification. The Bmax in control, hypoxic and Mg(2+)-treated hypoxic piglets was 1.09 +/- 0.17, 0.70 +/- 0.25 and 0.96 +/- 0.14 pmoles/mg protein, respectively. The Kd for the same groups were 10.02 +/- 2.04, 4.88 +/- 1.43 and 8.71 +/- 2.23 nM, respectively. The Bmax and Kd in the hypoxic group were significantly lower compared to the control and Mg(2+)-treated hypoxic groups, indicating a preservation of NMDA receptor number and affinity for MK-801 during hypoxia with Mg2+. The activity of Na+, K+ ATPase, a marker of neuronal membrane function, was lower in the hypoxic group compared to the control and Mg(2+)-treated hypoxic groups. These findings show that MgSO4 prevents the hypoxia-induced modification of the NMDA receptor and attenuates neuronal membrane dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effect of MgSO4 infusion on nmda receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet. 803 41

This investigation examined the relationship between alteration of Ca(2+)-transport systems and cytotoxicity in vitro for a number of neuroactive chemicals including environmental pollutants. 45Ca2+ uptake as a measure of Ca2+ sequestration was determined in mitochondria and microsomes isolated from cerebella of adult male Long-Evans hooded rats by differential centrifugation. Ca2+ extrusion, measured as Ca(2+)-ATPase activity, was determined in synaptosomes prepared by sucrose density gradient. Cytotoxicity (lactate dehydrogenase leakage) was assessed in primary cultures of cerebellar granule cells from 6- to 8-day-old Long-Evans rats. N-Methyl-D-aspartic acid (NMDA) did not alter synaptosomal Ca(2+)-ATPase activity or 45Ca2+ uptake in mitochondria and microsomes. However, chlorpromazine (CPZ), aluminum (Al), permethrin (PER), and deltamethrin (DEL) inhibited Ca2+ sequestration by mitochondria and microsomes. The IC50 values (microM) for CPZ, Al, PER, and DEL were 67.8, 671, 4.2, and 91.2 for mitochondrial 45Ca2+ uptake, and 129.9, 1384, > 50, and > 200 for microsomal 45Ca2+ uptake, respectively. CPZ, PER, and DEL also inhibited synaptosomal Ca(2+)-ATPase activity in a concentration-dependent manner with IC50 values of 62.5, > 400, and 246.9 microM, indicating an effect on the Ca(2+)-extrusion process. Al increased Ca(2+)-ATPase activity (EC50 = 833 microM). Although NMDA did not inhibit Ca(2+)-transport systems, it was cytotoxic at 250 microM and higher concentrations after 2 hr of exposure. Similarly, CPZ was cytotoxic at concentrations of 25 and 10 microM after 4 hr exposure. However, PER, DEL, and Al were not cytotoxic at any concentration up to 500 microM. Of all the chemicals tested, CPZ was the most potent in inhibiting Ca(2+)-transporting systems and was also cytotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of selected neuroactive chemicals on calcium transporting systems in rat cerebellum and on survival of cerebellar granule cells. 825 84

In primary cultures of cerebellar neurons glutamate neurotoxicity is mainly mediated by activation of the NMDA receptor, which allows the entry of Ca2+ and Na+ into the neuron. To maintain Na+ homeostasis, the excess Na+ entering through the ion channel should be removed by Na+,K(+)-ATPase. It is shown that incubation of primary cultured cerebellar neurons with glutamate resulted in activation of the Na+,K(+)-ATPase. The effect was rapid, peaking between 5 and 15 min (85% activation), and was maintained for at least 2 h. Glutamate-induced activation of Na+,K(+)-ATPase was dose dependent: It was appreciable (37%) at 0.1 microM and peaked (85%) at 100 microM. The increase in Na+,K(+)-ATPase activity by glutamate was prevented by MK-801, indicating that it is mediated by activation of the NMDA receptor. Activation of the ATPase was reversed by phorbol 12-myristate 13-acetate, an activator of protein kinase C, indicating that activation of Na+,K(+)-ATPase is due to decreased phosphorylation by protein kinase C. W-7 or cyclosporin, both inhibitors of calcineurin, prevented the activation of Na+,K(+)-ATPase by glutamate. These results suggest that activation of NMDA receptors leads to activation of calcineurin, which dephosphorylates an amino acid residue of the Na+,K(+)-ATPase that was previously phosphorylated by protein kinase C. This dephosphorylation leads to activation of Na+,K(+)-ATPase.
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PMID:Glutamate induces a calcineurin-mediated dephosphorylation of Na+,K(+)-ATPase that results in its activation in cerebellar neurons in culture. 852 95

Organotypic transverse medullary slices (obex level) from six-day-old rats, cultured for two to four weeks in chemically defined medium contained rhythmically discharging neurones which were activated by CO2 and H+. The mechanisms underlying this rhythmicity and the spread of excitation and synaptic transmission within this organotypic tissue were examined by modifying the composition of the external solution. Our findings showed that (1) Exposure to tetrodotoxin (0.2 microM) or to high magnesium (6 mM) and low calcium (0.2 mM) concentrations abolished periodic activity. (2) Neither the blockade of GABAergic potentials with bicuculline methiodide (200 microM) and/or hydroxysaclofen (200 microM) nor the blockade of glycinergic potentials with strychnine hydrochloride (100 microM) abolished rhythmicity. (3) While atropine sulphate (5 microM) was ineffective in modulating periodic discharges nicotine (100 microM) - like CO2-shortened the intervals between the periodic events; hexamethonium (50-100 microM) reduced both periodic and aperiodic activity. (4) Exposure to the NMDA antagonist 2-aminophosphonovaleric acid (50 microM) suppressed periodic events only transiently. In the presence of 2-aminophosphonovaleric acid rhythmicity recovered. However, the AMPA-antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10-50 microM), abolished periodic activity reversibly within less than 5 min. When 6-cyano-7-nitroquinoxaline-2,3-dione and nicotine were administered simultaneously periodic events persisted for up to 10 min. These findings indicate that synaptic excitatory drive is a prerequisite for the generation of rhythmic discharges of medullary neurones in this preparation. This drive may activate voltage-dependent channels or it may facilitate endogenous cellular mechanisms which initiate oscillations of intracellular calcium concentration. To test the latter possibility (5) calcium antagonists were added to the bath saline. The organic calcium antagonists verapamil and flunarizine (50-100 microM each) and the inorganic calcium antagonists cobalt (2 mM) and magnesium (6 mM) suppressed periodic activity and abolished or weakened the chemosensitivity towards CO2/acidosis. (6) Dantrolene (10 microM). an inhibitor of intracellular calcium release decreased the periodicity, while thapsigargin (2 microM) which blocks endoplasmic Ca(2+)-ATPase, transiently accelerated the occurrence of periodic events. (7) Oscillations of intracellular free calcium concentrations in Fura-2 AM-loaded cells were weakened or abolished by cobalt (2 mM). The results of (5)-(7) indicate that transmembrane calcium fluxes as well as intracellular Ca(2+)-release and -clearance mechanisms are a prerequisite for intracellular free calcium oscillations which may be important in the generation of rhythmic discharges in medullary neurones.
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PMID:Rhythm generation in organotypic medullary cultures of newborn rats. 877 Jun 53


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