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

---

Query: EC:4.1.1.15 (glutamate decarboxylase)
2,169 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The developmental profiles of gamma-aminobutyric acid (GABA), its biosynthesizing enzyme L-glutamic acid decarboxylase (GAD) and its degradating enzymes gamma-aminobutyric acid-alpha-ketoglutaric acid transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) in four different regions of human fetal brains have been evaluated. The GABA pathway was found to be maximally active in fetal brains during the third trimester of pregnancy. The relative activities of the enzymes as well as GABA content were least in pons compared to cerebrum, cerebellum and mid brain regions throughout the period of fetal development.
...
PMID:Ontogeny of GABA pathway in human fetal brains. 892 Sep 49

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is not solely located in the CNS, it and the enzymes responsible for its synthesis (glutamic acid decarboxylase, GAD, EC 4.1.1.15) and catabolism (GABA-transaminase, GABA-T, EC 2.6.1.19) are also present in non-neuronal organs. Following 2, 8 and 21 day oral administration of ethanolamine-O-sulphate (EOS) and gamma-vinyl GABA (GVG), two irreversible inhibitors of GABA-T, the GABA content and activities of GAD and GABA-T in rat brain, liver and kidney, and the GABA content of plasma were determined: GABA-T activity was significantly decreased (over 80%) in liver, brain and kidney, although there was 2-3 times the residual activity left in the brain compared with the peripheral organs. GABA content was subsequently significantly elevated in the liver (300-1500%), plasma (200-300%) and brain (200-300%), although, surprisingly, the kidney GABA content was reduced (by 60-70%) compared with control. GAD activity was decreased following 8 day treatment in liver and brain. Kidney GAD was reduced at all time points. These two compounds are anticonvulsant, GVG is used clinically for the treatment of epilepsy but it seems that these drugs have significant peripheral effects.
...
PMID:Effects of chronic oral treatment with GABA-transaminase inhibitors on the GABA system in brain, liver, kidney, and plasma of the rat. 893 45

The entopeduncular nucleus is one of the major output nuclei of the basal ganglia, with topographically organized projections to both motor and limbic structures. Neurons of the entopeduncular nucleus use GABA as the principal transmitter, and glutamic acid decarboxylase (the GABA synthetic enzyme) is widely distributed throughout the region. Previous studies have shown that glutamate decarboxylase exists in two forms (glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67), and that the messenger RNAs for these different enzymes are widely distributed in rat brain. The purpose of the present experiment was to describe the distribution of glutamic acid decarboxylase-65 and glutamic decarboxylase-67 messenger RNAs throughout the entopeduncular nucleus using recently developed oligodeoxynucleotide probes and in situ hybridization histochemical methods. In agreement with previous studies, northern analysis of rat brain poly(A)+ messenger RNA preparations showed that the glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 probes used in the present study hybridized to messenger RNAs of approximately 5.7 and 3.7 kb, respectively. Film autoradiographic analysis revealed large region-dependent, isoform-specific differences in the levels of expression of the two messenger RNAs, with glutamic acid decarboxylase-65 messenger RNA predominating in rostral and medial regions of the entopeduncular nucleus and glutamic acid decarboxylase-67 messenger RNA most abundant in the caudal region. Cellular analysis showed that these region-dependent differences in labelling were due to differences in the relative amounts of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 messenger RNAs expressed per cell rather than the number of cells expressing each form of glutamic acid decarboxylase messenger RNA. The differences in the distribution of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 messenger RNAs are closely related to the organization of limbic and motor circuits of the entopeduncular nucleus, suggesting that GABAergic transmission through the limbic pathway is regulated predominantly by glutamic acid decarboxylase-65, whereas glutamic acid decarboxylase-67 is of principal importance in the motor pathway. These data provide additional evidence that the neurons of the limbic and motor subregions of the entopeduncular nucleus are neurochemically distinct.
...
PMID:Differential distribution of glutamic acid decarboxylase-65 and glutamic acid decarboxylase-67 messenger RNAs in the entopeduncular nucleus of the rat. 913 91

The dose to the intracerebroventricularly administered (i.c.v.) tetanus toxin (Tetx) evoking the death of 50% of experimental mice (LD50) was estimated to be 18.0 (11.5-28.2) times the minimal lethal dose (MLD). MLD is defined as the lowest does of Tetx necessary to kill a 20-g albino mouse within 96 h after intraperitoneal treatment. Tetx (0.25 and 0.5 LD50) increased the convulsive threshold of electric current from 24 to 96 and 120 h, respectively, following i.c.v. administration. Both doses of Tetx diminished convulsant potencies of pentylenetetrazole, bicuculline, aminophylline and pilocarpine 24 h after application. At the same time Tetx (0.5 LD50) increased the protection afforded by carbamazepine, valproate, phenobarbital and diazepam in maximal electroshock (MES) by approximately 36, 11, 21 and 26%, respectively, without affecting total blood plasma levels of antiepileptic drugs. No marked changes in gamma-aminobutyric acid (GABA) concentration and total activity of L-glutamic acid decarboxylase (GAD) assessed in the whole-brain homogenates resulted from Tetx treatment. Our results seem to indicate that low doses (< LD50) of i.c.v. administered Tetx may lead to a relative prevalence of inhibitory over excitatory processes in the central nervous system suggesting a complex action of Tetx at the neuronal level.
...
PMID:Influence of intracerebroventricular administration of tetanus toxin on experimental seizures and protection afforded by some antiepileptic drugs in mice. 969 21

We have previously demonstrated that bilobalide, a constituent of the Ginkgo biloba extract, possesses anticonvulsant activity, and suggested that the mechanism of its anticonvulsant action involves modulation of y-aminobutyric acid (GABA)-related neuronal transmission. This study examined the effects of bilobalide on the level of GABA and glutamate, the activity and the amount of glutamic acid decarboxylase (EC 4.1.1.15), and the function of GABA(A) receptors in the hippocampus, cerebral cortex and striatum of the mouse. GABA levels, glutamic acid decarboxylase activity, and the protein amount of 67 kDa glutamic acid decarboxylase in the hippocampus of mice treated with bilobalide (30 mg/kg, p.o., once a day for 4 days) were significantly higher than those in controls. However, there were no significant differences in glutamate levels or, the number and the dissociation constants of GABA(A) receptors in the hippocampus between control and bilobalide-treated mice. These results suggest that the anticonvulsant effect of bilobalide is due to elevation of GABA levels, possibly through potentiation of glutamic acid decarboxylase activity and enhancement of the protein amount of 67 kDa glutamic acid decarboxylase by bilobalide.
...
PMID:Effects of bilobalide on gamma-aminobutyric acid levels and glutamic acid decarboxylase in mouse brain. 1007 89

The evolution of chordate glutamic acid decarboxylase (GAD; EC 4.1.1.15), a key enzyme in the central nervous system synthesizing the neurotransmitter gamma-amino-butyric acid (GABA) from glutamate, was studied. Prior to this study, molecular data of GAD had been restricted to mammals, which express two distinct forms, GAD65 and GAD67. These are the products of separate genes and probably are derived from a common ancestral GAD following gene duplication at some point during vertebrate evolution. To enable a comprehensive phylogenetic analysis, molecular information of GAD forms in other vertebrate classes was essential. By reverse transcriptase-polymerase chain reaction (RT-PCR), partial nucleotide sequences of GAD were cloned from brains of zebra finch (Taeniopygia guttata), turtle (Trachemys scripta), goldfish (Carassius auratus), zebrafish (Danio rerio), and armoured grenadier (Coryphaenoides (Nematonurus) armatus, a deep-sea fish), and from the cerebral ganglion plus neural gland of Ciona intestinalis, a protochordate. Whereas GAD65 and GAD67 homologs were expressed in birds, reptiles, and fish, only a single GAD cDNA with equal similarities to both vertebrate GAD forms was found in the protochordate. This indicates that the duplication of the vertebrate GAD gene occurred between 400 and 560 million years ago. For both GAD65 and GAD67, the generated phylogenetic tree followed the general tree topology for the major vertebrate classes. In turtle, an alternative spliced form of GAD65, putatively encoding a truncated, nonactive GAD, was found. Furthermore, a third GAD form, which is equally divergent from both GAD65 and GAD67, is expressed in C. (N.) armatus. This third form might have originated from an ancient genome duplication specific to modern ray-finned fishes.
...
PMID:Multiplicity of glutamic acid decarboxylases (GAD) in vertebrates: molecular phylogeny and evidence for a new GAD paralog. 1033 Dec 65

4-Aminobutyrate aminotransferase (GABA-transaminase, GABA-T, EC 2.6.1.19) deficiency (McKusick 137150), an inborn error of GABA degradation, has until now been documented in only a single Flemish child. Compared to the other defects of GABA degradation, succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24) deficiency with > 150 patients (McKusick 271980) and pyridoxine-dependent seizures with > 100 patients ('putative' glutamic acid decarboxylase (GAD, EC 4.1.1.15) deficiency; McKusick 266100), GABA-T deficiency is very rare. We present a summary of the clinical, biochemical, enzymatic and molecular findings on the index proband, and a recently identified second patient, with GABA-T deficiency. The phenotype in both included psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures and electroencephalographic abnormalities. In an effort to elucidate the molecular basis of GABA-T deficiency, we isolated and characterized a 1.5 kb cDNA encoding human GABA-T, in addition to a 41 kb genomic clone which encompassed the GABA-T coding region. Standard methods of cloning and sequencing revealed an A-to-G transition at nucleotide 754 of the coding region in lymphoblast cDNAs derived from the index proband. This mutation resulted in substitution of an invariant arginine at amino acid 220 by lysine. Expression of the mutant in E. coli, followed by isolation and enzymatic characterization of the recombinant protein, revealed an enzyme whose Vmax was reduced to 25% of wild-type activity. The patient and father were heterozygous for this allele; the second allele in the patient remains unidentified. Genomic Southern analysis revealed that the second proband most likely harbours a deletion in the 3' region of the GABA-T gene.
...
PMID:4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency. 1040 78

In the present work, we have characterized the maturation of the GABAergic system in mammalian retina. Immunoreactivity for GABA, GAD (glutamic acid decarboxylase, EC 4.1.1.15) -65 and -67 in the adult rat retina was localized in cells in the inner nuclear and ganglion cell layers. This pattern was established around postnatal day 8 and included transient GABA and GAD-67 expression in horizontal cells. GAD activity was very low at P1 and P4, increasing after P8, reaching maximal activity by P21 and decreasing to attain adult values by P30. GABA content was approximately constant from P1 to P13, increasing thereafter to reach adult levels. GAD protein content increased progressively with postnatal development and the two isoforms could be distinguished at P8. The disparity between retinal GABA content vs. presence and activity of the synthesizing enzyme, led us to investigate the alternative pathway for GABA synthesis that utilizes putrescine as a substrate. Highest levels of ornithine decarboxylase activity (the limiting step for putrescine synthesis) were found between P1 and P4, decreasing to very low levels after P13. The same pattern was observed for putrescine content in the retina. Highest amounts were found at P1, that decreased and remained constant after P13. Additionally, approximately 40% of tritiated putrescine incorporated by P1, P4 and adult retinas was converted into GABA. Our results suggest the existence of two different sources of GABA in mammalian retina, one that uses glutamate as a precursor and predominates in the mature nervous system and another that utilizes putrescine and is present transiently at early developmental stages.
...
PMID:GABAergic system in the developing mammalian retina: dual sources of GABA at early stages of postnatal development. 1045 64

GAD67, the larger isoform of the gamma-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase, is a hydrophilic soluble molecule, postulated to localize at nerve terminals and membrane compartments by heterodimerization with the smaller membrane-anchored isoform GAD65. We here show that the dimerization region in GAD65 is distinct from the NH(2)-terminal membrane-anchoring region and that a membrane anchoring GAD65 subunit can indeed target a soluble subunit to membrane compartments by dimerization. However, only a fraction of membrane-bound GAD67 is engaged in a heterodimer with GAD65 in rat brain. Furthermore, in GAD65-/- mouse brain, GAD67, which no longer partitions into the Triton X-114 detergent phase, still anchors to membranes at similar levels as in wild-type mice. Similarly, in primary cultures of neurons derived from GAD65-/- mice, GAD67 is targeted to nerve terminals, where it co-localizes with the synaptic vesicle marker SV2. Thus, axonal targeting and membrane anchoring is an intrinsic property of GAD67 and does not require GAD65. The results suggest that three distinct moieties of glutamate decarboxylase localize to membrane compartments, an amphiphilic GAD65 homodimer, an amphiphilic GAD65/67 heterodimer, tethered to membranes via the GAD65 subunit, and a hydrophilic GAD67 homodimer, which associates with membranes by a distinct mechanism.
...
PMID:The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65. 1060 Dec 83

The aim of this study was to investigate the amounts and epitope specificity of antibodies against heat shock protein 60 (hsp60) in the sera of type 1 diabetic and healthy children. Antibodies specific for peptide p277 of human hsp60 and of M. bovis as well as for human hsp60, M. bovis hsp65 proteins were measured by ELISA. Other autoantibodies (islet cell antibodies, glutamate decarboxylase antibodies and IA-2 antibodies) were also determined. A total number of 83 serum samples from children with type 1 diabetes mellitus and 81 samples of control children were investigated. Epitope scanning of the hsp60 for linear antibody epitopes was carried out using synthetic peptides attached to pins. The antibody levels specific for peptide p277 of human- and of M. bovis origin were significantly (human: P=0.0002, M. bovis: P=0.0044) higher in the diabetic children group than in the healthy children. We could not find significant difference in the antibody levels to whole, recombinant hsp proteins among the examined groups of children. Antibodies to two epitope regions on hsp60 (AA394-413 and AA435-454) were detected in high titres in sera of children with diabetes mellitus. The first region similar to the sequence found in glutamate decarboxylase, whereas the second one overlaps with p277 epitope to a large extent. Presence of antibodies to certain epitopes of hsp60 (AA394-413-glutamic acid decarboxylase-like epitope; AA435-454-p277-like epitope) in diabetic children may reflect their possible role in the autoimmune diabetogenic process of the early diabetes.
...
PMID:Antibodies against different epitopes of heat-shock protein 60 in children with type 1 diabetes mellitus. 1180 47


<< Previous 1 2 3 4 5 6 7 8 Next >>

---