Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Glutamate is able to stimulate inositol phosphate (IP) formation in striatal neurons in primary culture, mainly via an excitatory amino acid receptor of the quisqualate subtype. In the present study we show that carbachol (Carb)-(a cholinergic agonist), but not neurotensin or norepinephrine-induced IP production could be reduced by 40% when measured in the presence of Glu. The inhibition of the Carb response by Glu was dose dependent and reproduced by N-methyl-D-aspartate (NMDA). Quisqualate elicited an additive response with Carb. 2-Amino-5-phosphonovalerate (APV) completely reversed the NMDA-induced inhibition. APV had no significant effect on Glu- or kainate-induced inhibition. Therefore, striatal neurons contain at least three different excitatory amino acid receptors: a quisqualate receptor triggering the stimulation of IP metabolism, and an NMDA and a kainate receptor, both able to decrease the Carb-induced IP formation.
Mol Pharmacol 1987 Sep
PMID:Dual action of excitatory amino acids on the metabolism of inositol phosphates in striatal neurons. 289 92

The substrate-promoted inactivation of glutamate decarboxylase from hog brain was studied. Inactivation was a slow process that was dependent on the concentration of glutamate. Glutamate-dependent inactivation was not first order but was best described as the sum of two exponential decay processes. At 10 mM glutamate, the half-lives at 30 degrees C were about 6 min for the fast component and 70 min for the slow component. Glutamate-dependent inactivation appeared to be due to the formation of apoenzyme since the rate and extent of inactivation were greatly reduced by the presence of pyridoxal 5'-phosphate (the cofactor, pyridoxal-P). Also, inactivated enzyme could be reactivated by adding pyridoxal-P (Meeley and Martin, 1983). Micromolar concentrations of ATP enhanced glutamate-promoted inactivation in the absence of pyridoxal-P. ATP also enhanced inactivation in the presence of 10 microM pyridoxal-P, but somewhat higher concentrations were required for an equal effect. ATP had little or no direct effect on the enzyme in the absence of glutamate. In the absence of pyridoxal-P, Pi reduced the enhancement of inactivation by 10 microM but not by 750 microM ATP. Glutamate-promoted inactivation, its enhancement by ATP, and the opposition to inactivation by pyridoxal-P and Pi appear to be important in the regulation of glutamate decarboxylase.
Cell Mol Neurobiol 1983 Mar
PMID:Inactivation of brain glutamate decarboxylase and the effects of adenosine 5'-triphosphate and inorganic phosphate. 613 27

Glutamate synthase catalyzes glutamate formation from 2-oxoglutarate plus glutamine and plays an essential role when glutamate biosynthesis by glutamate dehydrogenase is not possible. Glutamate synthase activity has been determined in a number of Neurospora crassa mutant strains with various defects in nitrogen metabolism. Of particular interest were two mutants phenotypically mute except in an am (biosynthetic nicotinamide adenine dinucleotide phosphate-glutamate dehydrogenase deficient, glutamate requiring) background. These mutants, i and en-am, are so-called enhancers of am; they have been redesignated herein as en(am)-1 and en(am)-2, respectively. Although glutamate synthase levels in en(am)-1 were essentially wild type, the en(am)-2 strain was devoid of glutamate synthase activity under all conditions examined, suggesting that en(am)-2 may be the structural locus for glutamate synthase. Regulation of glutamate synthase occurred to some extent, presumably in response to glutamate requirements. Glutamate starvation, as in am mutants, led to enhanced activity. In contrast, glutamine limitation, as in gln-1 mutants, depressed glutamate synthase levels.
Mol Cell Biol 1981 Feb
PMID:Glutamate synthase levels in Neurospora crassa mutants altered with respect to nitrogen metabolism. 615 51

Eleven soluble enzymes in the supernatant of bloodstream Trypanosoma brucei were compared for electrophoretic mobility and activity with those of T. brucei cultures grown in 3 different media. All bands of each enzyme found in the bloodstream form were also present in the cultured material, but extra bands of malate dehydrogenase (MDH) (EC 1.1.1.37), aspartate aminotransferase (ASAT) (EC 2.6.1.1), and in 2 to 6 cultures of isocitrate dehydrogenase (ICD) (EC 1.1.1.42) were present in culture forms but not in bloodstream forms. An interfering enzyme, peculiar to cultured T. brucei, which reacted with 2-oxoglutarate and possibly a trace amount of ammonium ions, ran with the fast-moving ASAT bands. Threonine dehydrogenase activity, high in cultured trypanosomes irrespective of the medium used but low in bloodstream trypanosomes, was markedly lower in Trypanosoma evansi and a much passaged T. brucei 8/18. Glucosephosphate isomerase activity on the other hand was high in bloodstream and low in cultured trypanosomes. Glutamate dehydrogenase activity was too low to record reliably in bloodstream trypanosomes, but could be clearly detected in cultured forms. As the differences point to some changes in gene expression between the two forms, culture material is likely to replace trypanosomes from living animals for electrophoretic characterization only when considerable comparative work has been done.
Mol Biochem Parasitol 1980 Oct
PMID:The electrophoretic mobilities and activities of eleven enzymes of bloodstream and culture forms of Trypanosoma brucei compared. 645 Aug 96

The pharmacological properties of two recombinant human N-methyl-D-aspartate (NMDA) receptor subtypes, comprising either NR1a/NR2A or NR1a/NR2B subunits permanently transfected into mouse L(tk-) cells, have been compared using whole-cell voltage-clamp electrophysiology. Glutamate was a full agonist at both receptors, having a modestly but statistically significant (p < 0.002) higher affinity for the NR2B- than the NR2A-containing receptor (microscopic Kd [mKd] = 0.76 and 0.43 microM, respectively). In comparison to glutamate, NMDA, quinolinic acid, and cis-2,3-piperidinedicarboxylic acid were partial agonists at both receptor subtypes. Maximal amplitude currents resulted when glutamate-site agonists were combined with either glycine or D-serine; both of these amino acids were, therefore, defined as full agonists at the glycine site. Glycine had an approximately 10-fold higher affinity (p < 0.0001) for NR2B- than for NR2A-containing receptors (mKd = 0.057 and 0.53 microM, respectively). D-Cycloserine, (+)-(3R)-3-amino-1-hydroxypyrrolidin-2-one, (+)-cis-(4R)-methyl-(3R)-amino-1-hydroxypyrrolidin-2-one, and 1-aminocyclobutanecarboxylic acid also had higher affinities for the NR2B-containing receptor but were partial agonists, at both receptor subtypes, unlike glycine. Agonist-evoked whole-cell currents were antagonized by D-(-)-2-amino-5-phosphonopentanoic acid, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid, and 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, all of which had slightly, but statistically significant, higher affinities (2.2-, 2.8-, and 5.5-fold, respectively) for the NR2A-containing receptor. Responses were also antagonized by the glycine-site antagonists 7-chlorokynurenic acid, 7-chloro-4-hydroxy-3-(3-phenoxy)phenylquinolin-2-(1H)-one, and (+/=)-4-(trans)-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino- 1,2,3,4- tetrahydroquinoline. The atypical NMDA antagonist ifenprodil showed the largest separation in functional affinity (IC50 values, 0.6 and 175 microM at NR2B- and NR2A-containing receptors, respectively). These experiments demonstrate the usefulness of permanently transfected L(tk-) cells for electrophysiological studies of recombinant NMDA receptor function and provide the first detailed functional pharmacological analysis of human NMDA receptor subtypes.
Mol Pharmacol 1995 Nov
PMID:Pharmacological properties of recombinant human N-methyl-D-aspartate receptors comprising NR1a/NR2A and NR1a/NR2B subunit assemblies expressed in permanently transfected mouse fibroblast cells. 747 14

The preovulatory gonadotropin surge is induced by progesterone in the cycling female rat or in the ovariectomized estrogen-treated female rat after adequate estrogen-priming activity is present. The source of progesterone under physiological conditions could be the ovary and/or the adrenal. Since the GnRH neuron does not possess estrogen and progesterone receptors, its function is modulated by other CNS neurotransmitters and neurosecretory products. Among these, excitatory amino acids (EAAs) have now been shown to play an important role in the regulation of pulsatile gonadotropin release, induction of puberty and preovulatory and steroid-induced gonadotropin surges. Glutamate, the major endogenous EAA exerts its action through ionotropic and metabotropic receptors. The ionotropic receptors consist of two major classes, the NMDA (N-methyl-D-aspartate) and non-NMDA: kainate and AMPA (DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. EAA receptors are found in hypothalamic areas involved with reproduction. While both NMDA and non-NMDA receptors are involved in the regulation of LH secretion, the NMDA receptors appear to be involved with the regulation of puberty and FSH secretion as well. Steroids increase the release rates of glutamate and aspartate in the preoptic area during the gonadotropin surge. Steroids may also regulate the hypothalamic AMPA receptors.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Glutamate: a major neuroendocrine excitatory signal mediating steroid effects on gonadotropin secretion. 762 74

The influence of glutamate and its analogues on the expression of BDNF mRNA was studied in cultured cerebellar granule cells. Four-hour exposure of the neurons to the glutamate receptor agonists, quisqualate, kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA), increased levels of BDNF mRNA. Glutamate in combination with antagonists of the ionotropic glutamate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), D-2-amino-5-phosphonovalerate (AP-5) and/or (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine hydrogen maleate (MK-801), also increased levels of BDNF mRNA. However, the addition of glutamate itself to the cultures produced severe neuronal death and failed to increase the mRNA level. The onset of the increase in BDNF mRNA by kainate and NMDA lagged behind that by quisqualate. These results indicate that the non-ionotropic glutamate receptor might be involved in the induction of BDNF mRNA. Quisqualate is known to be a potent agonist of both the AMPA/kainate receptor and the metabotropic glutamate receptor. The specific antagonists of the AMPA/kainate receptor, CNQX and 6,7-dinitroquinoxaline-2,3-dione (DNQX) failed to block the increase of BDNF mRNA by quisqualate. Moreover, the desensitization of the metabotropic glutamate receptor by phorbol ester abolished the increase of BDNF mRNA by quisqualate. These results suggest that stimulation of the metabotropic glutamate receptor may be the most predominant component to increase BDNF mRNA in cerebellar granule cell culture.
Brain Res Mol Brain Res 1993 May
PMID:Glutamate receptor agonists enhance the expression of BDNF mRNA in cultured cerebellar granule cells. 768 81

Glutamate-mediated neurotransmission occurs through the activation of multimeric postsynaptic receptors. One mechanism by which functional diversity of glutamate responsiveness may occur is by a single cell expressing multiple receptors containing different subunits. In a direct test of this hypothesis, we examined the glutamate receptor subunit mRNA composition of several individual CA1 neurons in hippocampal slices. Experiments used amplified antisense RNA coupled with expression profiling and polymerase chain reaction amplification to identify and determine the relative amounts of subunit mRNAs co-localized in single cells. The results demonstrate that each CA1 neuron contains varying amounts of most glutamate receptor mRNAs. In addition to relative mRNA levels, the single-cell approach also highlighted other possible sources of receptor diversity. This included the existence of novel, alternatively spliced forms of the N-methyl-D-aspartate receptor type 1 and glutamate-kainate receptor type 2 subunits. Surprisingly, levels of N-methyl-D-aspartate receptor type 1 mRNA were relatively low, compared with those of other glutamate receptor mRNAs. One postulated source of potential heterogeneity, RNA editing, was not a general cellular mechanism. There was no evidence that glutamate receptor type 5 mRNA was edited in any of the cells that were examined. These data show that individual CA1 neurons, in the intact synaptic network of hippocampal slices, generate glutamate receptor mRNA diversity in several ways, which together contribute to the diversity of functional receptors observed electrophysiologically.
Mol Pharmacol 1993 Aug
PMID:Diversity of glutamate receptor subunit mRNA expression within live hippocampal CA1 neurons. 768 43

The ets-1 protein has been primarily studied as a sequence-specific transcriptional regulator that is predominately expressed in lymphoid cells. In this report, we show that ets-1 is also expressed in astrocytes and astrocytoma cells and is regulated during both signal transduction and differentiation. Both isoforms of ets-1, p51 and p42, were found in astrocytes and astrocytoma cells, but whereas expression of p51 was strong, p42, the alternate splice product previously shown to lack the phosphorylation domain, was difficult to detect and was present at a level 10- to 40-fold lower than that of p51. This differed by roughly an order of magnitude from the ratio generally observable in T cells and thymocytes. In two astrocytoma lines of human origin, CCF and 1321N1, ets-1 phosphorylation was stimulated by bradykinin and carbachol, respectively. Glutamate, norepinephrine, and bradykinin elicited phosphorylation of p51 in cultures of primary rat type 1 astrocytes. ets-1 phosphorylation was dramatically blocked by KT5926, an inhibitor of myosin light-chain kinase, suggesting that this kinase may be involved in phosphorylation of ets-1 in vivo. Investigations of retinoic acid-induced differentiation in P19 cells provided further support for a strong correlation of ets-1 with the pathway for astrocyte differentiation.
Mol Cell Biol 1995 Feb
PMID:ets-1 in astrocytes: expression and transmitter-evoked phosphorylation. 782 57

We have investigated the role of serotonergic neurons on the astrocytes catabolism of glutamate by analyzing glutamine synthetase (GS) and glutamate dehydrogenase (GDH) expression in the hippocampus after the degeneration of serotonergic neurons by a specific neurotoxin (5,7-DHT). 5,7-DHT caused reactive gliosis with hypertrophy (increase in glial fibrillary acidic protein (GFAP) expression) but not proliferation of astrocytes. Glutamate metabolism appeared preferentially regulated by a control of GDH expression rather than GS since the expression of GDH was specifically and significantly induced in the hippocampus whereas the level of GS remained unchanged. The inhibition of serotonin synthesis (by para-chlorophenylalanine (p-CPA) administration) produced no significant increase of GDH level. This suggests that serotonin is not the principal factor involved in this control of GDH expression.
Brain Res Mol Brain Res 1994 Oct
PMID:Modifications of glial metabolism of glutamate after serotonergic neuron degeneration in the hippocampus of the rat. 785 35


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