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

We assessed the development of electrogenic sodium pump (Na+ pump) activity in CA1 pyramidal neurons of rat hippocampal slices by studying the prolonged hyperpolarization which follows glutamate-induced depolarization (postglutamate hyperpolarization or PGH) at different postnatal ages. We also examined the development of membrane-bound enzyme in the hippocampal CA1 subfield with light microscopic immunocytochemistry and an antiserum against Na+,K(+)-ATPase. The PGH, which has previously been shown to be due to activation of an electrogenic Na+ pump in adult hippocampal CA1 neurons, was eliminated by strophanthidin, a Na+,K(+)-ATPase inhibitor, at all ages. It was unaffected by several potassium channel blockers, an intracellular calcium chelator, intracellular Cl- injection or tetrodotoxin (TTX) perfusion. The PGH thus appeared to be independent of K+ and Cl- conductances and produced by an electrogenic Na+ pump in adult and immature animals activated in large part by entry of Na+ through the glutamate receptor-channel complex. The size (integrated area) of the PGH was directly proportional to the area of preceding glutamate-induced depolarization (GD) and relatively voltage independent. Similar GDs could be elicited from postnatal day (P) 7 to P greater than or equal to 35, however, only very small PGHs were produced in neurons from P7-11 animals. A ratio of PGH area to GD area (PGH ratio) was calculated for each neuron and used to compare Na+ pump activity at different ages. There was a significant increase in the mean PGH ratio with age when P7-11, P21-25 and P35-39 groups were compared. Na+ pump activity estimated from the PGH ratio is very low in the first postnatal week but develops gradually over the first 5 weeks of life. Immunostaining for Na+,K(+)-ATPase in adult rat hippocampi revealed a punctate reaction product surrounding pyramidal cell bodies, whereas the staining was uniform along plasmalemma of dendrites in stratum radiatum and stratum oriens. By contrast, only minimum staining was present surrounding cell bodies and dendrites of P7 hippocampi and staining in stratum pyramidale was not punctate at this age. Na+,K(+)-ATPase activity estimated grossly from immunocytochemical staining is very low in the first postnatal week, increases during the first 5 weeks and develops a characteristic focal localization.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Postnatal development of electrogenic sodium pump activity in rat hippocampal pyramidal neurons. 137 39

Exposure of rat brain cortical slices to a medium lacking in glucose, oxygen or both glucose and oxygen, resulted in a decrease of the tissue ATP content and a reduction of (Na(+)+K+)-ATPase activity in membranes prepared from the slices. These treatments also inhibited partial reactions of (Na(+)+K+)-ATPase such as Na(+)-dependent phosphorylation and K(+)-stimulated phosphatase, as well as specific binding of [3H]ouabain in membranes prepared from the slices. Glucose deprivation and hypoxia decreased (Na(+)+K+)-ATPase activity in the absence of extracellular Ca2+, but the effects were blocked by 1,2-bis(2-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid tetra-acetomethyl ester (BAPTA-AM), a chelator of intracellular Ca2+. Metabolic inhibitors mimicked the effects of glucose deprivation and hypoxia. The effect of glucose-free hypoxia was dependent on extracellular Ca2+. It was blocked by Mg2+ at high concentration, bepridil or amiloride, but not by voltage-sensitive Ca2+ channel antagonists and glutamate receptor antagonists. None of the drugs tested here, except for dithiothreitol, affected the inhibitory effect of glucose-free hypoxia on the enzyme activity. In contrast to brain (Na(+)+K+)-ATPase, the kidney enzyme was insensitive to glucose and oxygen deprivation and metabolic inhibitors which depleted the tissue ATP.
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PMID:Glucose and oxygen deprivation induces a Ca(2+)-mediated decrease in (Na(+)+K+)-ATPase activity in rat brain slices. 138 78

1. Ca2+ signaling elicited by ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (iGluR) and metabotropic (mGluR) glutamate receptor agonists was studied in the somatic and dendritic regions of cultured cerebellar Purkinje neurons using microscopic video imaging and the Ca2+ sensitive dye fura-2. 2. iGluR and mGluR agonists and K+ depolarization applied by brief micropressure pulses evoked Ca2+ signals in both the somatic and dendritic regions of all Purkinje neurons studied. The Ca2+ signals were generated simultaneously in both cellular regions. The Ca+ signals to these stimulants were similar in general form, consisting of an initial peak and slow recovery phase, but differed in details of amplitude, time course, and complexity. 3. Removal of extracellular Ca2+ abolished the Ca2+ signal to the iGluR agonist AMPA, indicating that Ca2+ influx was essential to the generation of Ca2+ signals by iGluR agonists. The Ca2+ channel blocker lanthanum almost completely eliminated the Ca2+ signals to AMPA, indicating that Ca2+ influx through voltage-sensitive Ca2+ channels was the main pathway for Ca2+ influx. Omega-agatoxin IVA, a P-type Ca2+ channel blocker, significantly reduced the Ca2+ signals to AMPA suggesting that Ca2+ influx was predominately through P-type Ca2+ channels. 4. Pharmacological manipulation of intracellular Ca2+ stores significantly reduced the Ca2+ signals to AMPA, indicating that release of Ca2+ from intracellular Ca2+ stores also plays a prominent role in the generation of the Ca2+ signals to iGluR agonists. These manipulations included blocking Ca2+ release from intracellular stores with dantrolene, an antagonist at the ryanodine receptor that controls Ca2+ release from one pool of intracellular Ca2+ stores, and depletion of intracellular Ca2+ stores with caffeine or ryanodine. 5. Ca2+ influx through voltage-sensitive Ca2+ channels did not appear to be involved in the Ca2+ signals to mGluR activation, because neither lanthanum nor omega-agatoxin IVA altered Ca2+ signals to mGluR agonists. Manipulation of intracellular stores with Ca(2+)-ATPase inhibitors and dantrolene significantly reduced the Ca2+ signal to mGluR agonists, indicating that Ca2+ signals were derived from both the inositol trisphosphate (IP3) and the ryanodine receptor-controlled intracellular Ca2+ stores. 6. Ca2+ signals to the iGluR agonist AMPA correlated temporally with the prolonged, multiphasic membrane responses elicited by similar agonist application in parallel electrophysiological studies. Pharmacological manipulation of Ca2+ influx and release of Ca2+ from intracellular stores significantly influenced components of the membrane response to AMPA, indicating a potential modulator or mediator role for Ca2+ in the membrane response to iGluR activation.
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PMID:Ca2+ signaling pathways linked to glutamate receptor activation in the somatic and dendritic regions of cultured cerebellar purkinje neurons. 893 Feb 76

This mini-review describes our recent approach of mimicking transmembrane and intracellular signalings displayed by various receptors in biomembranes for the development of new sensing membranes. Several important modes of receptor signaling have been utilized exploiting bio and synthetic receptors; (i) Ca2+ signaling by calmodulin, (ii) active transport of target and relevant compounds displayed by Na+/D-glucose cotransporter and Na+,K(+)-ATPase, (iii) membrane permeability changes induced by glutamate receptor ion channel proteins and (iv) membrane potential changes induced by synthetic receptors. The newly designed sensing systems are demonstrated and discussed in terms of their novel mode of signal transduction, sensitivity and selectivity.
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PMID:Receptor based chemical sensing. 900 10

Kynurenic acid is an endogenous, competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor glycine site. Accordingly, increasing the brain extracellular concentration of this metabolite may be a suitable alternative to administration of exogenous NMDA antagonists for the treatment of neurological disorders involving excessive NMDA-receptor activation. As competitive inhibition of organic anion transport by probenecid increased brain extracellular levels of kynurenic acid, the purpose of this study was to examine whether intracerebral application of probenecid reduced depolarizations evoked at the same tissue site by NMDA. Microdialysis probes incorporating an electrode were implanted into the striatum of rats and perfused with artificial cerebrospinal fluid. Local depolarizations were produced by perfusing 200 microM NMDA for 2 min, either alone, or co-applied with 1, 5 or 20 mM probenecid. The lowest concentration of probenecid had no effect. At 5 mM, probenecid abolished the hyperpolarization which consistently followed NMDA-responses, but the slight decrease in depolarization amplitude did not reach significance. Inhibition of post-depolarization hyperpolarization suggests that sustained, high extracellular concentrations of probenecid reduce the capacity of the tissue to recover from a depolarizing stimulus, presumably because intensive transport of probenecid imposes a heavy load on Na+, K(+)-ATPase. At 20 mM, probenecid inhibited NMDA-evoked depolarization by approximately 60% (from 4.7 +/- 0.7 mV to 2.1 +/- 0.2 mV; n = 6, P < 0.005). This effect was more marked 30 min after returning to perfusion with normal artificial cerebrospinal fluid, suggesting that high concentrations of probenecid may be toxic to nerve cells, or initiate long-lasting effects linked to inhibition of the transport of important organic anions. These data suggest that inhibition of organic anion transport is not, by itself, sufficient to protect against neurological disorders involving excessive NMDA-receptor activation. However, results from other studies suggest that it may be a valid strategy for enhancing the neuroprotective actions of treatments which stimulate kynurenic acid synthesis, or those of exogenous glutamate receptor antagonists.
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PMID:Effect of probenecid on depolarizations evoked by N-methyl-D-aspartate (NMDA) in the rat striatum. 900 40

We have investigated the effects of glutamate and glutamate receptor ligands on the intracellular free Ca2+ concentration ([Ca2+]i) and the membrane potential (Em) of single, identified neuropile glial cells in the central nervous system of the leech Hirudo medicinalis. Exposed glial cells of isolated ganglia were filled iontophoretically with the Ca2+ indicator dye Fura-2. Application of glutamate (200-500 mumoll-1) caused biphasic membrane potential shifts and increases in [Ca2+]i, which were only partly reduced by either removing extracellular Ca2+ or blocking ionotropic glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50-100 mumol l-1. Metabotropic glutamate receptor (mGluR) ligands had the following rank of potency in inducing a rise in [Ca2+]i: quisqualate (QQ, 200 mumol l-1) > glutamate (200 mumol l-1) > L(+)2-amino-3-phosphonopropionic acid (L-AP3, 200 mumol l-1 > trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 400 mumol l-1). The mGluR-selective antagonist (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG, 1 mmol l-1] significantly reduced glutamate-evoked increases in [Ca2+]i by 20%. Incubation of the ganglia with the endoplasmic ATPase inhibitor cyclopiazonic acid (CPA, 10 mumol l-1) caused a significant (53%) reduction of glutamate-induced [Ca2+]i transients, while incubation with lithium ions (2 mmol l-1) resulted in a 46% reduction. The effects of depleting the Ca2+ stores with CPA and of CNQX were additive. We conclude that glutamate-induced [Ca2+]i transients were mediated by activation of both Ca(2+)-permeable ionotropic non-NMDA receptors and of metabotropic glutamate receptors leading to Ca2+ release from intracellular Ca2+ stores.
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PMID:Intracellular Ca2+ release mediated by metabotropic glutamate receptor activation in the leech giant glial cell. 936 87

Previously, we found that cytochrome oxidase-rich zones in the supragranular layers of the macaque striate cortex had more asymmetric, glutamate-immunoreactive synapses than the surrounding, cytochrome oxidase-poor regions. A major glutamate receptor family is N-methyl-D-aspartate, which is implicated in the stimulation of nitric oxide synthase and in the production of nitric oxide, a gaseous intra- and inter-cellular messenger. To determine if energy-generating and energy-utilizing enzymes bore any spatial relationship with neurochemicals associated with glutamatergic neurotransmission in the monkey visual cortex, serial cortical sections were processed histochemically for cytochrome oxidase and NADPH-diaphorase, and immunohistochemically for sodium/potassium-ATPase, nitric oxide synthase, and N-methyl-D-aspartate receptor subunit 1 protein, respectively. The general patterns were similar among the five neurochemicals, with layers 4C, 6 and supragranular puffs being labelled, although the intensity of labelling differed among them. Monocular impulse blockade with tetrodotoxin for two to four weeks induced a down-regulation of all five neurochemicals not only in deprived layer 4C ocular dominance columns, but also in deprived rows of puffs. Thus, the regulation of all five neurochemicals in the mature visual cortex is activity-dependent. Combined cytochrome oxidase histochemistry and nitric oxide synthase immunohistochemistry in the same sections revealed that double-labelled cells were primarily medium-sized non-pyramidals in various cortical layers. Likewise, those that were double-labelled by N-methyl-D-aspartate receptor subunit 1 immunohistochemistry and nitric oxide synthase immunogold silver staining in the same sections were of the medium-sized non-pyramidal neurons. At the ultrastructural level, combined cytochrome oxidase cytochemistry and postembedding immunogold labelling for nitric oxide synthase showed that immunogold particles for nitric oxide synthase were more heavily concentrated in cytochrome oxidase-rich type C cells. These medium-sized non-pyramidal cells were previously found to be gamma aminobutyric acid-immunoreactive and received both gamma aminobutyric acid- and glutamate-immunoreactive axosomatic synapses. Thus, our results are consistent with an enrichment of excitatory synaptic interactions in metabolically active regions of the primate visual cortex that involves glutamate-related neurochemicals, such as N-methyl-D-aspartate receptors and nitric oxide synthase. These interactions impose a higher energy demand under normal conditions and are down-regulated by retinal impulse blockade.
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PMID:Neurochemical organization of the macaque striate cortex: correlation of cytochrome oxidase with Na+K+ATPase, NADPH-diaphorase, nitric oxide synthase, and N-methyl-D-aspartate receptor subunit 1. 950 44

The role of cell type-specific Na+,K+-ATPase isozymes in function-related glucose metabolism was studied using differentiated rat brain cell aggregate cultures. In mixed neuron-glia cultures, glucose utilization, determined by measuring the rate of radiolabeled 2-deoxyglucose accumulation, was markedly stimulated by the voltage-dependent sodium channel agonist veratridine (0.75 micromol/L), as well as by glutamate (100 micromol/L) and the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) (10 micromol/L). Significant stimulation also was elicited by elevated extracellular potassium (12 mmol/L KCl), which was even more pronounced at 30 mmol/L KCl. In neuron-enriched cultures, a similar stimulation of glucose utilization was obtained with veratridine, specific ionotropic glutamate receptor agonists, and 30 mmol/L but not 12 mmol/L KCl. The effects of veratridine, glutamate, and NMDA were blocked by specific antagonists (tetrodotoxin, CNQX, or MK801, respectively). Low concentrations of ouabain (10(-6) mol/L) prevented stimulation by the depolarizing agents but reduced only partially the response to 12 mmol/L KCl. Together with previous data showing cell type-specific expression of Na+,K+-ATPase subunit isoforms in these cultures, the current results support the view that distinct isoforms of Na+,K+-ATPase regulate glucose utilization in neurons in response to membrane depolarization, and in glial cells in response to elevated extracellular potassium.
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PMID:Separate neuronal and glial Na+,K+-ATPase isoforms regulate glucose utilization in response to membrane depolarization and elevated extracellular potassium. 1047 57

We characterized swelling of rat cultured astrocytes induced by L-glutamate and its analogues. Among L-glutamate receptor agonists, L-glutamate, L-aspartate, L-cysteic acid, DL-homocysteic acid, quisqualate and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) increased astrocytic intracellular volume (3H-OMG space), while kainate, and N-methyl-D-aspartate did not. Threo-beta-hydroxyaspartate (TBHA), D-aspartate and L-trans-pyrrolidine-2,4-dicarboxylic acid, high-affinity substrates for Na+-dependent L-glutamate transporters, increased astrocytic 3H-OMG space. L-Glutamate (0.5 mM) increased astrocytic 3H-OMG space to 300% of control in 40-60 min. The increase in 3H-OMG space by 1 mM TBHA was comparable to the L-glutamate-induced one. After a 10 min-exposure to 0.5 mM L-glutamate, astrocytic 3H-OMG space was further increased to 200% even in the absence of L-glutamate. Astrocytes transiently exposed to L-glutamate did not increase their cell volume in K+-free medium and in the presence of 1 mM ouabain, a Na+-K+ ATPase inhibitor. The increase after a transient exposure was also observed by a treatment of 1 mM TBHA, but not by 0.5 mM quisqualate. These results suggest that the volume increases after a transient treatment are mediated by activation of Na+-dependent L-glutamate transporter.
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PMID:Transient treatments with L-glutamate and threo-beta-hydroxyaspartate induce swelling of rat cultured astrocytes. 1067 81


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