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

Cyclodiene resistance has accounted for over 60% of reported cases of insecticide resistance. Understanding of this resistance can therefore help us answer questions relating to the mechanism and origin of representative resistance-associated mutations, questions fundamental to the molecular and populations genetics of pesticide resistance. The cyclodiene resistance gene Rdl (resistance to dieldrin) was cloned from a mutant of the model insect Drosophila resistant to cyclodienes and picrotoxinin. Rdl codes for a subunit of a novel class of GABA gated chloride ion channels and resistance is correlated with replacement of the same amino acid residue in a wide range of species from different insect orders. This single amino acid replacement Ala302 > Ser, within the proposed lining of the chloride ion channel, also confers insensitivity to the blocking action of cyclodienes and picrotoxinin on GABA gated chloride ion channels expressed in Xenopus oocytes. The resistance mechanism involves both changes in cyclodiene binding site affinity and also a change in the rate of receptor desensitization which destabilizes the cyclodiene-favored conformation. Documentation of the resistance associated mutation has allowed for the design of a PCR based molecular monitoring technique. This technique gives more accurate estimates of resistance gene frequency from smaller sample sizes and has shown the frequency of resistance in apparently unselected populations of Drosophila to be as high as 1%. We are still uncertain as to why resistance persists in the apparent absence of selection pressure and any severe reduction in the fitness of resistant strains, besides a paralytic phenotype at high temperature, remains undocumented.
Insect Biochem Mol Biol 1994 Apr
PMID:The molecular and population genetics of cyclodiene insecticide resistance. 802 56

A polymerase chain reaction (PCR)-based homology probing strategy was employed to screen Drosophila melanogaster genomic DNA for sequences encoding a conserved amino acid 'signature motif' known to be present in vertebrate GABA receptor and glycine receptor subunit genes. This approach yielded three discrete amplified sequence elements (designated LCCH1, LCCH2, and LCCH3) that contained open reading frames and > 40% amino acid sequence identity to the corresponding regions of vertebrate ligand-gated chloride channel genes. Genomic DNA clones corresponding to each element were isolated and sequenced, and predicted amino acid sequences corresponding to the second (M2) and third (M3) transmembrane domains of vertebrate genes were analyzed for identity or similarity to known sequences. LCCH1 was identical to the Rdl gene, a known GABA receptor subunit gene from D. melanogaster, whereas LCCH2 and LCCH3 were novel D. melanogaster sequences that exhibited structural similarity to other members of the ligand-gated chloride channel gene family. LCCH2 was equally divergent in M2 and M3 (46-49% amino acid identity) from all other known members of this family and may therefore represent a new subunit or receptor class within this family. LCCH2 was localized by in situ hybridization to cytogenetic region 75A on the left arm of chromosome 3. LCCH3 was closely related to mammalian (79% amino acid identity) and snail (96% amino acid identity) GABA receptor beta subunits and may therefore be the homologue in D. melanogaster of this subunit class. LCCH3 was localized by in situ hybridization to cytogenetic region 13F on the X chromosome.(ABSTRACT TRUNCATED AT 250 WORDS)
Insect Biochem Mol Biol 1994 Apr
PMID:PCR-based homology probing reveals a family of GABA receptor-like genes in Drosophila melanogaster. 802 58

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


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