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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In adrenal cortex and other steroidogenic tissues including glial cells, the conversion of cholesterol into pregnenolone is catalyzed by the cytochrome P450scc located in the inner mitochondrial membrane. A complex mechanism operative in regulating cholesterol access to P450scc limits the rate of pregnenolone biosynthesis. Participating in this mechanism are DBI (diazepam binding inhibitor), an endogenous peptide that is highly expressed in steroidogenic cells and some of the DBI processing products including DBI 17-50 (TTN). DBI and TTN activate steroidogenesis by binding to a specific receptor located in the outer mitochondrial membrane, termed mitochondrial DBI receptor complex (MDRC). MDRC is a hetero-oligomeric protein: only the subunit that includes the DBI and benzodiazepine (BZD) recognition sites has been cloned. Several 2-aryl-3-indoleacetamide derivatives (FGIN-1-X) with highly selective affinity (nM) for MDRC were synthesized which can stimulate steroidogenesis in mitochondrial preparations. These compounds stimulate adrenal cortex steroidogenesis in hypophysectomized rats but not in intact animals. Moreover, this steroidogenesis is inhibited by the isoquinoline carboxamide derivative PK 11195, a specific high affinity ligand for MDRC with a low intrinsic steroidogenic activity. Some of the FGIN-1-X derivatives stimulate brain pregnenolone accumulation in adrenalectomized-castrated rats. The FGIN-1-X derivatives that increase brain pregnenolone content, elicit antineophobic activity and antagonize punished behavior in the Vogel conflict test in rats. These actions of FGIN-1-X are resistant to inhibition by flumazenil, a specific inhibitor of BZD action in GABAA receptors but are antagonized by PK 11195, a specific blocker of the steroidogenesis activation via MDRC stimulation. It is postulated that the pharmacological action of FGIN-1-X depends on a positive modulation of the GABA action on GABAA receptors mediated by the stimulation of brain neurosteroid production.
J Steroid Biochem Mol Biol 1994 Jun
PMID:The pharmacology of neurosteroidogenesis. 804 4

Pathophysiological concentrations of ammonia, both in vivo and in vitro, suppressed the oxidation of glutamate by rat cerebellar mitochondria. The transport of glutamate into mitochondria was either unaltered or enhanced during hyperammonemic states. Activities of mitochondrial enzymes, aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase, glutaminase, and GABA-transaminase were suppressed during hyperammonemic states. Suppression of 14CO2 production with (aminooxy)acetic acid but not with glutamic acid diethyl ester indicated that transamination but not oxidative deamination of glutamate plays a major role in glutamate oxidation during normal and hyperammonemic states.
Mol Chem Neuropathol 1993 Aug
PMID:Transport and metabolism of glutamate by rat cerebellar mitochondria during ammonia toxicity. 810 3

1. Cl- ion outward permeation across microdissected Deiters' neuron plasma membranes is augmented by GABA on the membrane cytoplasmic side. When these neurons are preincubated with a PKC activator, phorbol-12,13-dibutyrate (PdBu), there is a complex pattern of effects on basal and GABA-activated 36Cl- in-->out permeation. A distinct fact is an increase in basal Cl- passage and a disappearance of the 10(-6) M GABA effect at [PdBu] = 0.1 microM. 2. Likewise, 0.1 microM oleylacetylglycerol (OAG) treatment erases the effect completely, further supporting a role for PKC in modulating GABA-stimulated Cl- in-->out permeation. 3. The inactive ester, phorbol-12,13-didecanoate (Pdd), at 0.1 microM, does not affect GABA stimulation of Cl- passage. 4. High concentration (15-20 microM) of OAG and PdBu block the "intracellular" GABA efefct. However, the 20 microM PdBu effect is reversed by 30 microM H7. 5. These results indicate a role of endogenous PKC in Cl- extrusion by GABAA receptors on the cytoplasmic side of the Deiters' neuron membrane.
Cell Mol Neurobiol 1993 Oct
PMID:The increase in Cl- permeation across the Deiters' neuron membrane by GABA on its cytoplasmic side is abolished by protein kinase C (PKC) activators. 811 26

The high-affinity GABA transporter in neurons and glial cells is the primary means of inactivating synaptic GABA. In the present study, a rat GABA transporter (GAT-1)-specific probe was used to quantitate GAT-1 mRNA in cultured neurons and glial cells from rat brain. GAT-1 mRNA is expressed in neurons but not in pure cultures of astrocytes. Incubation of neurons with forskolin led to concentration- and time-dependent decreases in GAT-1 mRNA. This effect could be also achieved by chronic exposure of neurons to 8-Br-cAMP and dib-cAMP but not with 1,9-dideoxyforskolin. This effect on the levels of GAT-1 mRNA correlates with a decrease in the Na(+)-dependent GABA transport activity in neurons. Treatment with agents that increase cellular levels of cAMP did not affect GABA transport or GAT-1 mRNA expression in glial cells.
Brain Res Mol Brain Res 1994 Jan
PMID:Cellular distribution and regulation by cAMP of the GABA transporter (GAT-1) mRNA. 816 15

The enzyme 4-aminobutyrate aminotransferase (EC 2.6.1.19) isolated from Pseudomonas fluorescens was inhibited by the nucleotide ATP in an apparent competitive manner (Ki = 10.4 mM). This reversible effect was antagonized by the substrate GABA, whose apparent Km was increased from 0.6 mM to 2 mM in the presence of 20 mM ATP, suggesting that ATP interferes with GABA binding to the active site of the enzyme. The apparent Km with respect to the second substrate alpha-ketoglutarate was also increased, although to a lesser extent, whereas the cofactor pyridoxal 5'-phosphate was unable to influence the inhibition by ATP. The ATP structural analogues ADP, CTP and XTP were also able to inhibit the enzyme to a similar extent. These data indicate that GABA concentrations within the bacterial cell can be regulated by the action of ATP on 4-aminobutyrate aminotransferase. In addition, because the inhibition by ATP is similar to the inhibition of the enzyme from mammalian brain, the bacterial enzyme could provide a convenient source of the enzyme for studies of drug effects on brain GABA metabolism in vitro.
Biochem Mol Biol Int 1993 Sep
PMID:Inhibition of 4-aminobutyrate aminotransferase from Pseudomonas fluorescens by ATP. 826 Sep 45

At present, it is known that a connection exists between neuronal activity and microvascular blood flow and permeability in the CNS. We have demonstrated the presence of immunoreactivities against both GABA and GAD as well in the endothelial capillary cells of rat cerebellar cortex, as in perivascular glia, neuronal bodies, dendrites and axon endings, in close association with the basal membrane of the pericyte or endothelial cells. These results support the suggestions from biochemical and pharmacological studies about the relationship between GABA and microvascular function in the CNS.
Cell Mol Biol (Noisy-le-grand) 1993 Dec
PMID:Electron microscopic immunolocalization of GABA and glutamic acid decarboxylase (GAD) in cerebellar capillaries and their microenvironment. 829 28

The goal of the present study was to determine whether alterations in neuronal morphology and connections in thalamic grafts were accompanied by changes in the expression of mRNA encoding glutamic acid decarboxylase (GAD), the key enzyme in the synthesis of GABA, the normal neurotransmitter of neurons of the thalamic reticular nucleus. Cell suspensions of rat fetal tissue containing both thalamic reticular nucleus and ventrobasal primordia were transplanted into the excitotoxically lesioned somatosensory thalamus of adult rats. Levels of messenger RNA (mRNA) encoding GAD (Mr 67,000; GAD67) were measured 7 days to 4 months following transplantation via quantitative in situ hybridization with 35S-radiolabeled antisense RNAs. Expression of GAD67 mRNA in the thalamic reticular nucleus was analyzed in parallel in rat pups between 0 and 30 days postnatally, and in adult animals. As already observed with immunohistochemistry, transplanted neurons of the thalamic reticular nucleus did not group in specific clusters but rather mingled with unlabeled (putatively ventrobasal) neurons. Levels of labelling for GAD67 mRNA per neuron increased over time and reached adult levels during the third week post-grafting, i.e. 2 weeks after the theoretical birthdate of the neurons (grafted at embryonic days 15-16). Similar values were observed and a plateau was reached at similar time points during normal ontogeny. The results suggest that, in contrast to morphology and size of the neuronal cell bodies, gene expression of GAD67 develops normally despite the ectopic location of neurons of the thalamic reticular nucleus in the somatosensory thalamus, the abnormal connectivity and the lack of segregation from non-GABAergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1993 Nov
PMID:Glutamic acid decarboxylase gene expression in thalamic reticular neurons transplanted as a cell suspension in the adult thalamus. 830 62

Homonuclear 1H 2D NMR spectroscopy (COSY experiments at 400 and 600 MHz) were used to study the rat brain in vivo and the rabbit spinal cord and sciatic nerve in vitro. The following metabolites were identified: lactate, alanine, threonine, GABA, glutamine/glutamate, N-acetyl aspartate, aspartate, taurine, inositol derivatives, choline derivatives, and glucose. The sciatic nerve spectra showed characteristic COSY graphs of saturated and unsaturated fatty acids, and linoleic and linolenic type structures were identified.
Mol Chem Neuropathol
PMID:Application of 2D 1H NMR spectroscopy to the study of the brain, spinal cord, and sciatic nerve. 836

gamma-Aminobutyric acid (GABA) modulates the convulsant binding site on GABAA receptors labeled by t-butylbicyclophosphoro[35S] thionate ([35S]TBPS). The modulation varies between different brain regions, reflecting the molecular heterogeneity of the GABAA receptors. In rat brain cryostat sections, the main sensitivity difference to GABA between brain regions was observed within the cerebellum. [35S]TBPS binding in the granule cell layer was more sensitive to GABA than was that in the molecular layer and was detected only after blockade of the GABA agonist sites by the specific GABAA antagonists SR 95531, RU 5135, and bicuculline. This indicates that the [35S]TBPS binding sites in cerebellar granule cells were blocked by endogenous GABA. In contrast, the internal rim of the granule cell layer had a small amount of binding that was largely insensitive to 50 microM GABA. The molecular basis for the sensitivity difference could be traced to the alpha subunits of the GABAA receptor. Expression in human embryonic kidney 293 cells of alpha 6 beta 2 gamma 2 receptors produced [35S] TBPS binding sites that were about 10-fold more sensitive to inhibition by GABA than were those inherent to alpha 1 beta 2 gamma 2 receptors. Coexpression of alpha 6 and beta 2 subunits produced [35S]TBPS binding sites that were largely insensitive to GABA inhibition, resembling in their pharmacological profile the sites in the internal granule cell layer. Furthermore, the differences between alpha 6 beta 2 and alpha 6 beta 2 gamma 2 receptors stress the importance of the gamma 2 subunit for the proper pharmacological fingerprint of the rest of the granule cell layer. The neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one affected the binding in both alpha 1 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 receptors, but inhibition was greater in alpha 6-containing than in alpha 1-containing receptors, suggesting differential coupling of both GABA and neurosteroid sites with the convulsant site. These data might serve as a platform for additional studies to assess the amino acid residues in the two alpha subunits that are critically involved in the allosteric interactions between the GABAA agonist/antagonist or neurosteroid domains and the convulsant site.
Mol Pharmacol 1993 Jul
PMID:Regional gamma-aminobutyric acid sensitivity of t-butylbicyclophosphoro[35S]thionate binding depends on gamma-aminobutyric acidA receptor alpha subunit. 839 26

1. The effects of external sodium on GABA-induced chloride currents were examined with whole-cell voltage-clamp recordings obtained from enzymatically dissociated solitary Muller cells in culture. Our goal was to determine whether a sodium-dependent GABA uptake mechanism influences the GABAa-mediated responses of skate Muller cells. 2. At low concentrations of GABA (0.01 to 0.5 microM), removal of sodium from the external solution resulted in a marked increase in the ligand-gated currents mediated by activation of GABAa receptors. The enhancement by lowered sodium was greatest at hyperpolarizing potentials and decreased progressively as the cell was depolarized. 3. The reversal potential for the GABA-induced response was not significantly altered by the removal of sodium, suggesting that sodium ions did not directly contribute to the GABAa-mediated current. 4. Lowering external sodium had no effect on the currents induced by the GABAa-agonist muscimol, consistent with its much lower affinity for the GABA transport carrier. 5. Application of the GABA uptake blocker nipecotic acid also abolished the effects of lowered sodium. 6. These findings suggest that the effects of lowered external sodium resulted from a decrease in the uptake of GABA into the Muller cells, thus raising the effective concentration of GABA acting upon the GABAa receptors.
Cell Mol Neurobiol 1993 Apr
PMID:The effects of lowered extracellular sodium on gamma-aminobutyric acid (GABA)-induced currents of Muller (glial) cells of the skate retina. 839 15


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