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)

We have studied extracellular ionic changes induced by iontophoretic application of excitatory amino acids in rat hippocampal slices. In contrast to kinetics of changes in [Ca2+]o, kinetics of changes in [K+]o, [Na+]o, [Cl-]o as well as in extracellular space size were comparable for different glutamate receptor agonists. Thus, alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA), quisqualate (quis), and kainate caused reductions in [Ca2+]o followed by an increase of [Ca2+]o above baseline, whereas glutamate, aspartate, N-methyl-D-aspartate (NMDA), and DL-homocysteic acid caused only reductions in [Ca2+]o. After blocking the NMDA receptors with ketamine and 2-amino-5- phosphonovaleric acid (2-APV), glutamate-induced decreases in [Ca2+]o were followed by an overshoot. Reduction of the transmembrane Na+ gradient by lowering [Na+]o, blocking of the Na(+)-K+ ATPase by lowering [K+]o, and application of ouabain blocked the overshoots after quis application, whereas vanadate, a blocker of the Ca(2+)-Mg2+ ATPase, had no effects. Lithium enhanced the reductions in [Ca2+]o and blocked the overshoots. Amiloride also reduced the overshoots. All organic Ca2+ entry blockers diminished reductions of [Ca2+]o but increased the overshoots. Inorganic Ca2+ antagonists had variable effects. Ni2+ had similar effects as the organic Ca2+ entry blockers while Cd2+ reduced both the [Ca2+]o decreases as well as the subsequent overshoots. Co2+ had initially a similar action as Ni2+. With prolonged application, [Ca2+]o decreases became augmented and, during wash, overshoots could no longer be elicited. We suggest that the overshoots in [Ca2+]o are due to a combined effect of extracellular space shrinkage and activation of the Na+/Ca2+ exchangers. This would imply that NMDA receptor activation blocks extrusion of Ca2+ from the cells. We tested the hypothesis that quis-induced intracellular Ca2+ release and extrusion of Ca2+ from the cells contributed to the overshoots. Dantrolene was without effect on the quis-induced signals, while ryanodine reduced the overshoots. Caffeine on the other hand diminished the [Ca2+]o decreases with no effects on the overshoots. To test for possible second messenger routes by which NMDA receptor activation might slow Ca2+ extrusion from cells, we investigated the effects of arachidonic acid and N-monomethyl-D- arginine on the quis-induced signals. While these agents reduced decreases in [Ca2+]o, they had no clear effects on the overshoots. Thus a possible route by which NMDA receptor activation may affect Ca2+ extrusion from cells has still to be elucidated.
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PMID:Pharmacological properties of excitatory amino acid induced changes in extracellular calcium concentration in rat hippocampal slices. 129 71

Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism. Deficits of magnesium are prevalent due to inadequate intake or malabsorption and due to the renal loss of magnesium that occurs in certain disease states (alcoholism, diabetes) and with drug therapy (diuretics, aminoglycosides, cisplatin, digoxin, cyclosporin, amphotericin B). Protracted deficits of magnesium in humans and animals result in neurological disturbances, including hyperexcitability, convulsions and various psychiatric symptoms ranging from apathy to psychosis, some of which can be reversed with magnesium supplementation, others requiring correction of the dysregulation mechanism. Although the role of magnesium in neuronal function is not completely understood, a lowering of CSF or brain magnesium can induce epileptiform activity and there is an association between decreased CSF magnesium and the development of seizures. CSF concentrations of magnesium are normally higher than magnesium plasma ultrafiltrate (diffusible) concentrations due to the active transport of magnesium across the blood-brain barrier. Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than the changes observed in plasma magnesium concentrations. Decreases in CSF magnesium concentrations correlate with the alterations observed in extracellular brain magnesium concentrations in animals following the dietary deprivation of magnesium. CSF magnesium concentrations can readily be repleted following magnesium supplementation, although high dose magnesium therapy, such as that used in the treatment of convulsions in eclampsia, will only increase CSF magnesium concentrations to a very limited degree (approximately 11-18 per cent) above physiological concentrations. Greater increases in CSF magnesium may occur in neonates since neonatal swine, following treatment with magnesium, have CSF magnesium concentrations that are similar to their plasma concentrations. There has been a recent resurgence of interest in magnesium deficiency and its neurological consequences due to the finding that magnesium, at physiological concentrations, blocks N-methyl-D-aspartate (NMDA) receptors in neurones. NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in vertebrate CNS. Magnesium deficiency produces epileptiform activity in the CNS which can be blocked by NMDA receptor antagonists. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium. Further studies are necessary to increase our understanding of the neurological implications of magnesium deficit in the central nervous system.
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PMID:Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms. 129 67

((+-)-1,-2,3-bis-[(4-Methoxyphenyl)-methoxy]propyl)-1H-imidazole (SC 38249) and its 4-methoxyphenetyl analogue (SKF 96365) have been recently reported to block not only voltage-operated Ca2+ channels, but also the channels (second messenger-operated) that open after receptor activation of polyphosphoinositide hydrolysis in smooth muscle fibers and platelets. Fura-2 fluorescence studies in cerebellar neurons, glial and PC12 cells confirmed these effects of SC38249 and in addition demonstrated that the drug causes an inhibition of Ca2+ extrusion, presumably via the Ca2+ ATPase. This effect was particularly evident when [Ca2+]i was increased, regardless of treatment (glutamate or ionomycin). In contrast, the NMDA receptor channel activated by glutamate was not affected by SC 38249.
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PMID:Multiple actions of SC 38249: the blocker of both voltage-operated and second messenger-operated Ca2+ channels also inhibits Ca2+ extrusion. 216 44

Upon addition of the cardiac glycoside ouabain to cultured cerebellar granule cells, an immediate increase in intracellular free sodium is evoked mediated by two pathways, a voltage-sensitive channel blocked by tetrodotoxin and a channel sensitive to flunarizine. Ouabain induces a steady plasma membrane depolarization in low Ca2+ medium; whereas in the presence of Ca2+, a distinct discontinuity is observed always preceded by a large increase in intracellular free Ca2+ ([Ca2+]c). The plateau component of the increase can be inhibited additively by the L-type Ca2+ channel antagonist nifedipine, the spider toxin Aga-Gl, and the NMDA receptor antagonist MK-801. Single-cell imaging reveals that the [Ca2+]c increase occurs asynchronously in the cell population and is not dependent on a critical level of extracellular glutamate or synaptic transmission between the cells. A prolonged release of glutamate is also observed that is predominantly Ca2+ dependent for the first 6-10 min after the evoked increase in [Ca2+]c. This release is four times as large as that observed with 50 mM KCl and is predominantly exocytotic because release was inhibited by tetanus toxin, the V-type ATPase inhibitor bafilomycin, and Aga-Gl. It is proposed, therefore, that ouabain induces a period of membrane excitability culminating in a sustained exocytosis above that observed upon permanent depolarization with KCl.
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PMID:Modulation of ion gradients and glutamate release in cultured cerebellar granule cells by ouabain. 753 7

The effects of acute insulin-induced hypoglycemia on the cerebral NMDA receptor in the newborn were examined by determining [3H]MK-801 binding as an index of NMDA receptor function in 6 control and 7 hypoglycemic piglets. In hypoglycemic animals, the glucose clamp technique with constant insulin infusion was used to maintain a blood glucose concentration of 1.2 mmol/l for 120 min before obtaining cerebral cortex for further analysis; controls received a saline infusion. Concentrations of glucose, lactate, ATP, and PCr were measured in cortex, and Na+,K(+)-ATPase activity was determined in a brain cell membrane preparation. [3H]MK-801 binding was evaluated by: (1) saturation binding assays over the range of 0.5-50 nM [3H]MK-801 in the presence of 100 microM glutamate and glycine; and (2) binding assays at 10 nM [3H]MK-801 in the presence of glutamate and/or glycine at 0, 10, or 100 microM. Blood and brain glucose concentrations were significantly lower in hypoglycemic animals than controls. There was no change in brain ATP with hypoglycemia, but PCr was decreased 80% compared to control (P < 0.05). Na+,K(+)-ATPase activity was 13% lower in hypoglycemic animals (P < 0.05). Based on saturation binding data, hypoglycemia had no effect on the number of functional receptors (Bmax), but the apparent affinity was significantly increased, as indicated by a decrease in the Kd (dissociation constant) from the control value of 8.1 +/- 1.6 nM to 5.5 +/- 2.1 nM (P < 0.05). Augmentation of [3H]MK-801 binding by glutamate and glycine alone or in combination was also significantly greater in the hypoglycemic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of acute hypoglycemia on the cerebral NMDA receptor in newborn piglets. 753 27

Elevated levels of potassium (K+) promote maturation and survival of cerebellar granule neurons in culture. When switched from a culture medium containing high K+ (25 mM) to one with low K+ (5 mM) mature granule neurons undergo death by apoptosis. The mechanism by which high K+ promotes neuronal survival (and conversely inhibits apoptosis) is unclear. Several pieces of evidence indicate that an increase in intracellular calcium (Ca2+) resulting from depolarization mediated-influx of extracellular Ca2+ is necessary. We examined the effect of thapsigargin on granule neuron cultures. Thapsigargin is an inhibitor of the endoplasmic reticular Ca2+ ATPase causing a depletion of Ca2+ from internal stores. This treatment would therefore be expected to raise intracellular cytosolic Ca2+ without membrane depolarization. We find that treatment of mature neurons with thapsigargin at doses > or = 5 nM inhibits death resulting from the lowering of extracellular K+. The survival effect of thapsigargin was not affected by inhibitors of extracellular Ca2+ influx including nifedipine, verapamil, methoxyverapamil, Mg2+, and Ni2+, nor was it inhibited by the NMDA receptor antagonist, MK801. We have further examined whether thapsigargin could substitute for elevated K+ during the maturation of granule cells. Unexpectedly, treatment of younger (immature) neuronal cultures with the same dose of thapsigargin (5 nM) induced cell death. DNA fragmentation analysis suggested that death was due to apoptosis and not toxicity. As observed with the survival effect on mature neurons, the lethal effect of thapsigargin on immature granule cells was not prevented by inhibitors of Ca2+ influx.
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PMID:Opposing effects of thapsigargin on the survival of developing cerebellar granule neurons in culture. 761 2

In summary, we propose that acute ammonia intoxication leads to increased extracellular concentration of glutamate in brain and results in activation of the NMDA receptor. Activation of this receptor mediates ATP depletion and ammonia toxicity since blocking the NMDA receptor with MK-801 prevents both phenomena. Ammonia-induced metabolic alterations (in glycogen, glucose, pyruvate, lactate, glutamine, glutamate, etc) are not prevented by MK-801 and, therefore, it seems that they do not play a direct role in ammonia-induced ATP depletion nor in the molecular mechanism of acute ammonia toxicity. The above results suggest that ammonia-induced ATP depletion is due to activation of Na+/K(+)-ATPase, which, in turn, is a consequence of decreased phosphorylation by protein kinase C. This can be due to decreased activity of PKC or to increased activity of a protein phosphatase. We also show that L-carnitine prevents glutamate toxicity in primary neuronal cultures. The results shown indicate that carnitine increases the affinity of glutamate for the quisqualate type (including metabotropic) of glutamate receptors. Also, blocking the metabotropic receptor with AP-3 prevents the protective effect of L-carnitine, indicating that activation of this receptor mediates the protective effect of carnitine. We suggest that the protective effect of carnitine against acute ammonia toxicity in animals is due to the protection against glutamate neurotoxicity according to the above mechanisms.
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PMID:Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine. 774 Oct 17

Injection of large doses of ammonia into rats leads to depletion of brain ATP. However, the molecular mechanism leading to ATP depletion is not clear. The aim of the present work was to assess whether ammonium-induced depletion of ATP is mediated by activation of the NMDA receptor. It is shown that injection of MK-801, an antagonist of the NMDA receptor, prevented ammonia-induced ATP depletion but did not prevent changes in glutamine, glutamate, glycogen, glucose, and ketone bodies. Ammonia injection increased Na+,K(+)-ATPase activity by 76%. This increase was also prevented by previous injection of MK-801. The molecular mechanism leading to activation of the ATPase was further studied. Na+,K(+)-ATPase activity in samples from ammonia-injected rats was normalized by "in vitro" incubation with phorbol 12-myristate 13-acetate, an activator of protein kinase C. The results obtained suggest that ammonia-induced ATP depletion is mediated by activation of the NMDA receptor, which results in decreased protein kinase C-mediated phosphorylation of Na+,K(+)-ATPase and, therefore, increased activity of the ATPase and increased consumption of ATP.
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PMID:Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and Na+,K(+)-ATPase. 796 37

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

The effect of hypoxia on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the brain cell membrane of the newborn piglet was studied. Experiments were conducted on newborn piglets, 2-4 days of age, that were anesthetized and mechanically ventilated. Hypoxic hypoxia was induced in the experimental group by lowering the FiO2 to 5-7%. The control group was ventilated under normoxic conditions. Tissue hypoxia was documented biochemically by decreased levels of ATP and phosphocreatine (PCr) in the hypoxic group (52% and 81% lower than the normoxic group, respectively). [3H]MK-801 binding characteristics (Bmax = number of receptors, Kd = dissociation constant) were used as an index of NMDA receptor modification. In hypoxic brains, Bmax decreased from the control level of 1.13 +/- 0.15 pmol/mg protein to 0.68 +/- 0.23 pmol/mg protein (P < 0.01) and the Kd value decreased (reflecting increased affinity) from 9.46 +/- 1.68 nM in the control brains to 4.87 +/- 1.42 nM (P < 0.01) in the hypoxic brains. The Na+,K(+)-ATPase activity, an index of brain cell membrane function, decreased from a control value of 46.5 +/- 0.4 to 40.5 +/- 2.3 mumol inorganic phosphate (Pi) mg protein/h (P < 0.005) during hypoxia. The results of this study indicate that hypoxia in newborn piglets modifies the NMDA receptor in the cerebral cortex, resulting in an increased affinity of the receptor channel. Hypoxia-induced modification of the NMDA ion/receptor complex may be a potential mechanism of cerebral excitotoxicity.
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PMID:Hypoxia-induced modification of the N-methyl-D-aspartate receptor in the brain of the newborn piglet. 817 16


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