Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown that the enzyme glutamic acid decarboxylase (GAD; EC 4.1.1.15), which catalyzes the conversion of L-glutamate to gamma-aminobutyric acid in the central nervous system of vertebrates, can be first detected in rodents at late embryonic stages. In contrast, we have found that the gene coding for the 67-kDa form of GAD is already transcriptionally active at embryonic day E10.5 in the mouse. In addition to the 3.5-kb adult-type mRNA, we have detected two 2-kb embryonic messages that contain alternatively spliced exons of 80 (I-80) and 86 (I-86) bp, respectively. The overlapping stop-start codon TGATG, found in the embryonic exons, converts the monocistronic adult-type transcript into a bicistronic one, coding for a 25-kDa leader peptide and a 44-kDa enzymatically active truncated GAD. A second stop codon at the 3' end of the 86-bp exon abolishes the expression of truncated GAD. The products of the two embryonic mRNAs were identified in a rabbit reticulocyte in vitro translation system, COS cells, and mouse embryos. The two GAD embryonic forms represent distinct functional domains and display characteristic developmental patterns, consistent with a possible role in the formation of the gamma-aminobutyric acid-ergic inhibitory synapses.
Mol Cell Biol 1994 Nov
PMID:Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development. 793 69

The localization of the mRNAs encoding gamma-aminobutyric acidA receptor alpha 1 subunit (GABAA alpha 1) and L-glutamate decarboxylase (GAD) was elucidated in the rat retina by in situ hybridization. Soma diameter analysis of signal positive cells in the ganglion cell layer demonstrated that a subpopulation including alpha-cells of retinal ganglion cells expressed GABAA alpha 1 mRNA and a subpopulation of ganglion cells smaller than alpha-cells expressed GAD mRNA.
Brain Res Mol Brain Res 1994 Aug
PMID:Expression and localization of gamma-aminobutyric acid A (GABAA) receptor alpha 1 subunit and L-glutamate decarboxylase (GAD) mRNAs in rat retina: an analysis by in situ hybridization. 798 44

The effect of valproate and its more active metabolite E-delta 2-valproate on the rate of glucose oxidation through different metabolic pathways in neonatal rat brain slices was studied. The presence of valproate or E-delta 2-valproate did not change the rate of [3,4-14C]glucose or [6-14C]glucose incorporation into CO2, suggesting that glucose oxidation through the pyruvate dehydrogenase-catalyzed reaction and through the tricarboxylic acid cycle was not affected by these drugs. However, both drugs significantly enhanced the rate of [2-14C]glucose oxidation, supporting the notion that the activity of the gamma-aminobutyric acid (GABA) shunt is specifically stimulated by valproate and, to a greater extent, by E-delta 2-valproate. The presence of methionine sulfoximine or gamma-hydroxybutyrate did not change the GABA shunt activity. Brain glutamate decarboxylase activity was significantly increased after incubation of the brain slices in the presence of valproate. Consequently, our results suggest that the mechanism of action of valproate is related to the increase in the levels of the inhibitory neurotransmitter GABA caused by the enhancement of flux through the glutamate decarboxylase-catalyzed reaction.
Mol Pharmacol 1993 Mar
PMID:Evidence of stimulation of the gamma-aminobutyric acid shunt by valproate and E-delta 2-valproate in neonatal rat brain. 845 Aug 38

The effects of in vivo administration of dopamine receptor agonists or antagonists on the mRNA levels encoding for the two isoforms of glutamate decarboxylase, GAD65 and GAD67, and for preproenkephalin were studied in regions of the rat dorsal striatum by radioactive in situ hybridization histochemistry. Changes in striatal mRNA levels after drug treatment were quantified by computerized densitometry on X-ray films. Chronic administration of the dopamine receptor agonist apomorphine or the D1 dopamine receptor agonist SKF-38393 resulted in increased GAD65 mRNA levels in the dorsomedial, ventromedial, dorsolateral and ventrolateral sectors of the striatum. Apomorphine or SKF-38393 treatment did not induce significant effects on GAD67 and preproenkephalin mRNA levels in striatum. On the other hand, chronic administration of the D2 dopamine receptor agonist quinpirole significantly decreased GAD67 in the dorsolateral and ventrolateral and preproenkephalin in the ventrolateral sectors of the striatum. Quinpirole treatment did not induce significant changes in GAD65 mRNA levels. Chronic administration of the dopamine receptor antagonist haloperidol resulted in a significant increase in GAD67 and preproenkephalin mRNA levels in the dorsomedial, dorsolateral and ventrolateral striatal sectors. Chronic treatment with the D2/D3 dopamine receptor antagonist sulpiride resulted in a significant increase in GAD67 in the ventromedial and ventrolateral and PPE in the dorsomedial and ventrolateral striatal sectors. Haloperidol or sulpiride did not induce significant changes in striatal GAD65 mRNA levels. Chronic administration of the D1 dopamine receptor antagonist SCH-23390 had no significant effect on GAD67, GAD65 or preproenkephalin mRNA levels. In the present experimental conditions, stimulation of dopamine receptors with apomorphine or SKF-38393 resulted in increased GAD65 mRNA levels whereas blockade of dopamine receptors with haloperidol or sulpiride resulted in increased GAD67 mRNA levels. These results indicate that striatal GAD65 and GAD67 mRNA levels are differentially regulated by dopamine receptor subtypes.
Brain Res Mol Brain Res 1995 Dec 01
PMID:Differential regulation of mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) by dopamine receptors in the rat striatum. 875 Aug 62

The effect of dopaminergic denervation, alone or followed by chronic intermittent L-DOPA administration, on the levels of mRNAs encoding for the two isoforms of the GABA-synthesizing enzyme, glutamate decarboxylase (GAD65 and GAD67), were measured by in-situ hybridization in the caudate and putamen of macaque monkeys. When compared to control monkeys, the level of GAD67 mRNA was increased in the putamen and caudate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. On the other hand, GAD65 mRNA labeling in MPTP-treated monkeys was not significantly different from the controls. In MPTP-treated monkeys that received L-DOPA, a significant increase in both GAD67 and GAD65 mRNA levels was measured in the putamen when compared to control or MPTP-treated monkeys. The results suggest that the dyskinetic effect of L-DOPA is paralleled by an increased GABAergic activity in the striatum.
Brain Res Mol Brain Res 1996 Jul
PMID:L-DOPA regulates glutamate decarboxylases mRNA levels in MPTP-treated monkeys. 880 32

Calcium-binding proteins (CaBPs) are a family of proteins having a unique distribution in the brain and are thought to be important in buffering intracellular calcium. Glutamate neurotoxicity is a process by which the over-activation of glutamate receptors can cause the influx of excessive extracellular calcium and neuronal cell death. It has been proposed that neurons containing CaBP may be more resistant to glutamate neurotoxicity due to their increased ability to buffer calcium. Using a herpes simplex virus-1 (HSV-1) vector system we packaged the CaBP gene, parvalbumin, or the marker gene, beta-galactosidase (beta-gal), correctly in viron particles, which were found upon infection to express mRNA specific to these vectors. PC12 and neocortical cultures showed strong immunohistochemical staining for either beta-gal or parv. The cortical cultures stained positively for endogenous glutamate decarboxylase, a marker for GABAergic neurons, but not for endogenous parvalbumin, indicating that parvalbumin was being expressed ectopically from the HSV-1 vector. Interestingly, the expression of parvalbumin increased cortical culture's susceptibility to N-methyl-D-aspartate-induced neurotoxicity. This increase in neurotoxicity was not due to the wild-type virus or the helper virus which accompanies the packaging of these vectors. We speculate that the ectopic expression of parvalbumin in cortical cultures may be increasing glutamate release which in turn increases cell death.
Brain Res Mol Brain Res 1996 Sep 01
PMID:Expression of the calcium-binding protein, parvalbumin, in cultured cortical neurons using a HSV-1 vector system enhances NMDA neurotoxicity. 887 13

The present study examined the effects of glutamate transmission blockade through N-methyl-D-aspartate (NMDA) receptor subtype by repeated administration of dizocilpine maleate (0.2 mg/kg. i.p., twice a day for eight days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic pathway on GABAergic neurons in the adult rat striatum. For this purpose, the expression of the messenger RNA encoding for the 67 kDa isoform of the GABA synthesizing enzyme, glutamate decarboxylase (GAD67 mRNA), was studied in the various conditions by quantitative in situ hybridization. The dizocilpine maleate treatment alone did not induce significant change of GAD67 mRNA levels in the striatum, indicating that NMDA receptors may not have a major role in the transcriptional regulation of GAD67 in the adult rat striatum. As reported previously, the unilateral dopaminergic lesion resulted in marked increases in GAD67 mRNA levels in the ipsilateral striatum. This up-regulation was not significantly affected by the treatment with dizocilpine maleate started 12 days after the unilateral intranigral 6-hydroxydopamine injection. Therefore, NMDA receptors are unlikely to contribute to the dopamine lesion-induced GAD67 mRNA up-regulation in striatal projection neurons. This result is of major interest in comparison with our previous finding that NMDA receptor activation is necessary to maintain the up-regulation of enkephalin expression in the striatum after dopamine lesion.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Repeated injections of dizocilpine maleate (MK-801) do not suppress the effects of nigrostriatal dopamine deafferentation on glutamate decarboxylase (GAD67) mRNA expression in the adult rat striatum. 903 36

The mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) were measured in the adult rat striatum following systemic administration of dopamine receptor agonists. Double-labeling in situ hybridization histochemistry was used to measure GAD65 or GAD67 mRNA levels in neurons labeled or not with a preproenkephalin (PPE) cRNA probe. Chronic treatment with the D1/D2 dopamine receptor agonist apomorphine or with the D1 dopamine receptor agonist SKF-38393 induced an increase in GAD65 but not GAD67 mRNA levels in different sectors of the striatum. These effects were abolished by pre-administration of the D1 dopamine receptor antagonist SCH-23390. On double-labeled sections, GAD65 mRNA labeling was distributed in neurons labeled and unlabeled with the PPE cRNA probe. About half of all neuronal profiles labeled with the GAD65 cRNA probe were also labeled with the PPE cRNA probe. Quantification of labeling at cellular level demonstrated a significant increase of GAD65 mRNA levels in PPE-unlabeled neurons. On the other hand, no significant changes of GAD65 mRNA levels were detected in PPE-labeled neurons. Our results demonstrate a differential effect of dopamine receptor agonists on striatal GAD65 and GAD67 gene expression. In particular, we show that GAD65 mRNA levels are selectively increased in presumed striato-nigral neurons following treatments with dopamine receptor agonists. These data provide evidence that the GAD65 isoform is preferentially involved in the regulation of GABAergic neurotransmission in striato-nigral neurons.
Brain Res Mol Brain Res 1997 Sep
PMID:Glutamate decarboxylase (GAD65) gene expression is increased by dopamine receptor agonists in a subpopulation of rat striatal neurons. 933 31

This study examined the effects of chronic intrastriatal infusion of L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a selective competitive inhibitor of high affinity glutamate transport systems, via osmotic minipumps in rats. Injection of PDC at the rate of 25 nmol/h for 14 days caused striatal lesion. Histological evaluation on frontal striatal sections showed that the lesion was circumscribed to a circular area showing a dramatic neuronal loss accompanied by gliosis and representing 30% of the whole striatal surface at the level of the injection site. A total loss of neurons expressing glutamate decarboxylase (GAD67), enkephalin or substance P mRNA was observed on a similar circular area, suggesting degeneration of the two populations of striatal efferent neurons. In the whole striatum outside the region devoided of hybridization signal, a selective 27% decrease in enkephalin mRNA expression occurred, suggesting a higher sensitivity of enkephalin neurons versus substance P neurons to glutamate uptake-mediated alterations. Injection of PDC at the rate of 25 nmol/h for 3 days produced striatal lesion of similar extent. In contrast, PDC at the rate of 5 nmol/h did not produce neuronal damage when administered over 14 days. This study provides new in vivo evidence that defective glutamate transport is one of the critical conditions that may give rise to toxicity of an endogenous transmitter system in the striatum, and may underlie neuronal death in neurodegenerative diseases.
Brain Res Mol Brain Res 1997 Oct 15
PMID:Continuous administration of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate produces striatal lesion. 940 33

The effects of the dopamine D1 receptor agonist, SKF-38393, on the levels of mRNAs encoding for the proto-oncogene c-fos and the GABA-synthesizing enzyme glutamate decarboxylase (GAD65) were measured by in situ hybridization histochemistry in the striatum of adult rats depleted of dopamine as neonates. c-fos mRNA levels exhibited a prominent increase following the acute systemic administration of SKF-38393 in dopamine-depleted but not in normal rats. Double-labeling in situ hybridization histochemistry using a radioactive c-fos probe and a digoxigenin-labeled preproenkephalin (PPE) cRNA probe indicated that c-fos mRNA levels were increased by SKF-38393 exclusively in a subpopulation of PPE-unlabeled neurons. Dopamine-depleted rats exhibited an increase in GAD65 mRNA levels relative to control rats. Acute administration of SKF-38393 did not alter GAD65 mRNA levels in control or in dopamine-depleted rats. Our results demonstrate that an acute administration of a D1-receptor agonist induces c-fos but not GAD65 gene expression in a subpopulation of presumed striato-nigral/entopeduncular neurons. They also suggest that the D1-dependent behavioral plasticity exhibited by adult rats depleted of dopamine as neonates is not the result of an altered activation of the two subpopulations of striatal efferent neurons.
Brain Res Mol Brain Res 1998 Jun 01
PMID:c-fos gene expression is induced in a subpopulation of striatal neurons following a single administration of a dopamine D1-receptor agonist in adult rats lesioned with 6-OHDA as neonates. 963 May 93


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