Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible involvement of quinolinic acid in the biochemical differentiation of cultured glutamatergic cerebellar granule neurons was studied in terms of the activity of phosphate-activated glutaminase (GLNase) and aspartate aminotransferase (ASP-AT). Treatment with quinolinate elevated the specific activity of GLNase and amount of protein per culture dish in a dose-dependent manner. The half maximal effect was obtained at about 0.5 mM quinolinate, whereas the maximum concentration, which produced about a 2.3-fold increase in GLNase activity, was about 2 mM. Quinolinate, like N-methyl-D-aspartate (NMDA), had no significant effects on the activities of ASP-AT and lactate dehydrogenase enzymes. The increases in the activity of GLNase and amount of protein were completely blocked by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid. The result would indicate that, (a) contrary to an earlier proposal, ASP-AT does not appear to be a good marker for studying dynamic responses of glutamatergic neurons, and (b) the trophic effect of quinolinic acid on the development of cerebellar granule neurons is mediated by selective activation of NMDA subtype excitatory amino acid receptors.
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PMID:Quinolinic acid promotes the biochemical differentiation of cerebellar granule neurons. 214 31

The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the biochemical differentiation of cultured neurons derived from the medial frontal part of the forebrain containing the septum-diagonal band region was studied in terms of the activities of enzymes important in the synthesis of neurotransmitter compounds. The activity of choline acetyltransferase (ChAT) was used as a marker for cholinergic neurons, glutamate decarboxylase (GAD) for GABAergic neurons and phosphate-activated glutaminase (GLNase) and aspartate aminotransferase (ASP-AT) for glutamatergic neurons, while lactate dehydrogenase (LDH) was included as an ubiquitous enzyme. The exposure of cultures to a depolarizing concentration of K+ (40 mM) for the last 3 days (i.e. between 2 and 5 days in vitro) significantly enhanced the expression of ChAT, GAD and GLNase activities, but high K+ caused little alteration in the activities of ASP-AT and LDH. On the other hand, treatment with NMDA markedly elevated the specific activities of GAD and GLNase only, and the compound had no significant effects on the activities of ChAT, ASP-AT and LDH enzymes. The enhancements of the specific activities of GAD and GLNase were completely blocked by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid, and by the NMDA receptor-linked Ca2+ ion channel blocker, MK-801. On the basis of the present findings it is concluded that, (a) contrary to an earlier proposal, ASP-AT does not appear to be a good marker for the glutamatergic neurons, (b) the failure of the subcortical cholinergic neurons to respond by an increase in ChAT activity to NMDA may indicate that these nerve cells lack NMDA subtype excitatory amino acid receptors, and (c) as the septal GABAergic input in the hippocampus is involved in the modulation of long-term potentiation, the presence of NMDA receptors on these neurons would now suggest that NMDA receptors are linked to both the initiation and the modulation of hippocampal plasticity in the mammalian brain.
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PMID:Cell-type specific effects of N-methyl-D-aspartate on biochemical differentiation of subcortical neurons in culture. 214 34

The role of protein kinase C (PKC) in N-methyl-D-aspartate (NMDA) receptor-mediated biochemical differentiation and c-fos protein expression was investigated in cultured cerebellar granule neurons. The biochemical differentiation of glutamatergic granule cells was studied in terms of the specific activity of phosphate-activated glutaminase, an enzyme treatment in the synthesis of the putative neurotransmitter pool of glutamate. When the partially depolarized cells were treated with NMDA for the last 1 to 3 days (between 2 and 5 days in vitro), it elevated the specific activity of glutaminase. In contrast, NMDA had little effect on the activity of aspartate aminotransferase or of lactate dehydrogenase. Treatment of 10-day old granule neurons with NMDA also resulted in a marked increase in the immunocytochemically measured expression of c-fos protein. The increases in both the activity of glutaminase and the steady state level of c-fos protein were specific to the activation of NMDA receptors, as they were completely blocked by D,L-2-amino-5-phosphonovaleric acid. The specific stimulation of NMDA receptors in PKC-depleted granule neurons or in the presence of reasonably specific PKC inhibitors also produced significant elevation in the activity of glutaminase and the expression of c-fos protein. These increases were similar in magnitude to those observed in the granule neurons of the respective control groups. Our findings demonstrate that PKC is not directly involved in the NMDA receptor-mediated signal transduction processes associated with biochemical differentiation and c-fos induction in cerebellar granule neurons.
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PMID:Effects of protein kinase C modulation on NMDA receptor mediated regulation of neurotransmitter enzyme and c-fos protein in cultured neurons. 764 61

The aim of this work was to assess whether perinatal hyperammonemia impairs the function of NMDA receptors and whether this impairment affords protection against acute ammonia toxicity and glutamate and NMDA neurotoxicity. Rats were exposed to ammonia during the prenatal and lactation periods by feeding the female rats an ammonium-containing diet since day 1 of pregnancy. After weaning (at postnatal day 21), the pups were fed a normal diet with no ammonia added. This treatment resulted in a marked decrease of the growth rate of the animals, which was maintained even 1 month after normalization of ammonia levels. Rats exposed to ammonia were more resistant than controls to acute ammonia toxicity 13 days after feeding a normal diet but not at 3 months. Primary cultures of cerebellar neurons from hyperammonemic rats showed decreased binding of [3H]MK-801 and were remarkably more resistant than controls to glutamate and NMDA toxicities. Also, the increase in aspartate aminotransferase activity induced by low concentrations of NMDA was not produced in such cultures. These results indicate that exposure to ammonia during the prenatal and lactation periods results in long-lasting impairment of NMDA receptor function. This would be the reason for the delayed protection afforded by exposure to low ammonia levels against acute ammonia toxicity in animals and against glutamate and NMDA toxicity in neuronal cultures.
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PMID:Prenatal exposure of rats to ammonia impairs NMDA receptor function and affords delayed protection against ammonia toxicity and glutamate neurotoxicity. 766 52

Acute ammonia toxicity is mediated by activation of NMDA receptors and is prevented by chronic moderate hyperammonaemia. The aim of this work was to assess whether the protective effect of chronic hyperammonaemia is due to impaired activation of the NMDA receptor. It is shown that chronic hyperammonaemia in rats decreases the binding of [3H]MK-801 to synaptosomal membranes from the hippocampus but not the amount of NMDAR1 receptor protein as determined by immunoblotting. In primary cultures of cerebellar neurons, long-term treatment with 1 mM ammonia also decreased significantly the binding of [3H]MK-801. These results suggest that ammonia impairs NMDA receptor activation. To confirm this possibility we tested the effect of long-term treatment of the cultured neurons with 1 mM ammonia on three well known events evoked by activation of the NMDA receptor: neuronal death induced by glutamate, increase in aspartate aminotransferase activity and increase in free intracellular [Ca2+]. Long-term treatment with ammonia prevented noticeably the effects of glutamate or NMDA on all these parameters. These results indicate that long-term treatment of neurons with 1 mM ammonia leads to impaired function of the NMDA receptor, which cannot be activated by glutamate or NMDA. Activation of protein kinase C by a phorbol ester restored the ability of the NMDA receptor to be activated in neurons treated with ammonia. This suggests that ammonia impairs NMDA receptor function by decreasing protein kinase C-dependent phosphorylation.
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PMID:Ammonia prevents activation of NMDA receptors by glutamate in rat cerebellar neuronal cultures. 884 43

The presence of 25 mm potassium (KCl) or N-methyl-d-aspartate (NMDA) in cultured cerebellar granule neurons (CGN) induces a trophic effect, including a specific regulation of the enzymes involved in the glutamate neurotransmitter synthesis. In this study we explored the effect of these conditions on the cytosolic and mitochondrial isoenzymes of aspartate aminotransferase (AAT), and phosphate-activated glutaminase (PAG) in CGN. We found that NMDA and KCl increased the AAT total activity by 40% and 70%, respectively. This effect was mediated by an augmentation in the protein levels (68% by NMDA, 58% by KCl). NMDA raised the Vmax and KCl raised both the maximol velocity (Vmax) and Michaelis constant (Km) of AAT. NMDA increased cytosolic AAT activity by 30% and mitochondrial activity by 70%; KCl increased cytosolic and mitochondrial AAT activity by 60% and 100%, respectively. This activation was also related to an increase in the protein levels. The effect of both conditions on the activity and protein levels were more pronounced in mitochondrial than cytosolic AAT and the increment elicited by KCl was higher in both isoforms than that produced by NMDA. The PAG and AAT mRNA levels were also regulated by incubation with NMDA and KCl similarly to the observed changes in the protein levels. These results suggest that NMDA receptor stimulation during CGN development differentially regulates the two AAT isoenzymes involved in the maturation of CGN and that the regulation of both AAT and PAG occurs also at the mRNA expression level, suggesting the involvement of a mechanism of gene expression regulation.
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PMID:Regulation of glutamate-synthesizing enzymes by NMDA and potassium in cerebellar granule cells. 1509 30

Intestinal ischemia/reperfusion causes severe injury and alters motility. N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to reduce ischemia/reperfusion injury in the nervous system, and in other organs. In this study, we set out to investigate the effects of NMDA receptor antagonists over intestinal ischemia/reperfusion injury. Male Wistar rats were randomly divided into four groups: (1) a control, sham-operated group; (2) an intestinal ischemia/reperfusion group subjected to 45 min ischemia and 1h reperfusion; (3) a group treated with 10 mg/kg ketamine before ischemia/reperfusion; and (4) a group treated with 10 mg/kg memantine before ischemia/reperfusion. Intestinal samples were taken for histological evaluation. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), malondialdehyde (MDA), total antioxidant capacity, tumor necrosis factor alpha (TNF-alpha), P-selectin and antithrombin III (ATIII) were measured. Intestinal transit time was determined to evaluate intestinal motility. Fecal pellet output and animal weight were also registered daily for 7 days post-ischemia. After reperfusion, AST, LDH, TNF-alpha and P-selectin levels were elevated, ATIII levels were depleted, and ALT levels were unchanged in serum. Additionally, levels of MDA were increased and total antioxidant capacity was reduced in serum, indicating oxidative stress. Intestinal mucosa showed severe injury. Ketamine, but not memantine, diminished these alterations. Intestinal motility and fecal pellet output were also altered after ischemia/reperfusion. Both drugs abolished the alterations in motility. In conclusion, ketamine's protective effects over ischemia/reperfusion do not appear to be NMDA mediated, but they could be playing a role in protecting the intestine against ischemia-induced functional changes.
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PMID:The effects of NMDA receptor antagonists over intestinal ischemia/reperfusion injury in rats. 1975 22