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

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurosteroids are steroids that are synthesized de novo in the brain and include some classical (adrenal and gonadal steroids) and some unique brain-specific steroids. Neurosteroids are thought to mediate their action through ion gated channel receptors such as gamma-aminobutyric acid(A) and N-methyl-D-aspartate rather than through classical nuclear steroid hormone receptors. Some enzymes involved in neurosteroidogenesis have been identified as those found in steroidogenic tissues, and some may be unique to the brain. We previously demonstrated that the messenger RNAs (mRNA) for the cholesterol side-chain cleavage enzyme, cytochrome P450scc, and one form of 11 beta-hydroxylase, cytochrome P450c11 beta, are regionally expressed in the adult rat brain. However, cytochrome P450c17, which has 17-hydroxylase and 17,20-lyase activity and is thought to be required for the synthesis of dehydroepiandrosterone, was not detected in any region of the rat brain, even though dehydroepiandrosterone is one of the most abundant neuroactive steroids. We now demonstrate that P450c17 is expressed in the nervous system of the developing rodent embryo. By ribonuclease protection assays, P450c17 mRNA was found in the trunk but not in the head of rat embryos but reverse transcriptase-polymerase chain reaction analysis showed expression of P450c17 mRNA in the head of E15.5 to E19.5 rat embryos. Immunocytochemically detectable P450c17 protein was expressed in the nervous system as early as embryonic day E10.5 in the mouse, mainly in tissue derived from the neural crest. Neuronal cell bodies as well as fibers staining for P450c17 were observed in the central and peripheral nervous systems. The sites of P450c17 expression in the peripheral nervous system suggest it may be involved in a wide variety of sensory-motor functions. In the central nervous system, cell bodies expressing P450c17 are found in the hind brain, in mesencephalic nuclei, and in a region in the location of the locus coeruleus, but in cells distinct from those expressing the dopamine-beta-hydroxylase. Furthermore, its particular location and temporal expression in axons reaching the cortical areas suggest it is a marker for the axonal growth in this region, and that its neurosteroid product may be a signal for targeting cortical axons during embryogenesis.
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PMID:Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system. 758 60

The reduced progesterone metabolite tetrahydroprogesterone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 3 alpha,5 alpha-THP) is a positive modulator of the gamma-aminobutyric acid type A (GABAA) receptor. Experiments performed in vitro with hypothalamic fragments have previously shown that GABA could modulate the release of gonadotropin-releasing hormone (GnRH). Using GT1-1 immortalized GnRH neurons, we investigated the role of GABAA receptor ligands, including 3 alpha,5 alpha-THP, on the release of GnRH. We first characterized the GABAA receptors expressed by these neurons. [3H]Muscimol, but not [3H]flunitrazepam, bound with high affinity to GT1-1 cell membranes (Kd = 10.9 +/- 0.3 nM; Bmax = 979 +/- 12 fmol/mg of protein), and [3H]muscimol binding was enhanced by 3 alpha,5 alpha-THP. mRNAs encoding the alpha 1 and beta 3 subunits of the GABAA receptor were detected by the reverse transcriptase polymerase chain reaction. In agreement with binding data, the benzodiazepine-binding gamma subunit mRNA was absent. GnRH release studies showed a dose-related stimulating action of muscimol. 3 alpha,5 alpha-THP not only modulated muscimol-induced secretion but also stimulated GnRH release when administered alone. Bicuculline and picrotoxin blocked the effects of 3 alpha,5 alpha-THP and muscimol. Finally, we observed that GT1-1 neurons convert progesterone to 3 alpha,5 alpha-THP. We propose that progesterone may increase the release of GnRH by a membrane mechanism, via its reduced metabolite 3 alpha,5 alpha-THP acting at the GABAA receptor.
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PMID:A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor. 773 81

The gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamate decarboxylase (GAD) was studied during development of the chick telencephalon. By means of reverse-phase HPLC analysis, we showed that GABA indeed accumulates during embryogenesis, whereas the levels of glutamate, the substrate for GAD, are more or less unchanged up to later developmental stages. The enzyme activity increased approximately 25-fold from embryonic day 3 to embryonic day 17. Immunoblotting data revealed that two GAD proteins, of approximately 65 and 67 kDa, were present during the period investigated. Furthermore, Northern blot analysis with probes obtained from rat cDNA sequences, as well as a chicken-specific probe for GAD65 generated by means of reverse transcriptase-polymerase chain reaction (RT-PCR), strengthened the interpretation that the chick embryo expresses genes corresponding to GAD65 and GAD67. The rat probes recognized transcript sizes of 3.9 kb (GAD65) and 5.6 kb (GAD67), sizes which are different from those of the rat brain (Erlander et al., Neuron, 7, 91-100, 1991). Sequencing of the RT-PCR products revealed a high level of homology (82% at the nucleotide level) between the mammalian and chick GAD65 genes. Taken together, these findings suggest that the chick embryo expresses two GAD genes during embryogenesis. The functional properties of each gene product remain to be investigated.
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PMID:Two glutamate decarboxylase forms corresponding to the mammalian GAD65 and GAD67 are expressed during development of the chick telencephalon. 892 2

The physiological actions of biogenic amine and amino-acid neurotransmitters are terminated by their removal from the synaptic cleft by specific high-affinity transport proteins. The members of the Na(+)- and Cl(-)-dependent neurotransmitter transporter family expressed in bovine retina and responsible for the uptake of biogenic amine and amino-acid neurotransmitters were identified using a reverse transcriptase-polymerase chain reaction-based approach. cDNA clones encoding bovine homologues of glycine (GLYT-1), gamma-aminobutyric acid (GAT-1), creatine (CreaT), and orphan (NTT4) transporters were identified using this strategy. The expression pattern of mRNAs encoding these proteins in the retina was determined by in situ hybridization histochemistry. GLYT-1, CreaT, NTT4, and GAT-1 mRNAs were expressed in the retina by cells in the inner nuclear, inner plexiform, and ganglion cell layers. They were not expressed at detectable levels in the photoreceptor cells whose cell bodies are in the outer nuclear layer and are the most abundant cell type in the retina. GLYT-1 mRNA was present exclusively in the proximal inner nuclear layer. GAT-1 mRNA was localized to both the inner nuclear and ganglion cell layers. CreaT mRNA was expressed in all cell types in the retina, except photoreceptors, and NTT4 mRNA was expressed by a subpopulation of cells in the ganglion cell layer. Elucidation of the expression pattern of these neurotransmitter transporter mRNAs in the retina provides a basis for studies of the role of glycine, gamma-aminobutyric acid, and creatine transporters in retinal function.
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PMID:Na(+)- and Cl(-)-dependent neurotransmitter transporters in bovine retina: identification and localization by in situ hybridization histochemistry. 896 32

1. After 8 days in vitro, rat cerebellar granule cells were exposed to 1 mM gamma-aminobutyric acid (GABA) for periods of 1, 2, 4, 6, 8 and 10 days. The effect of the GABA exposure on GABAA receptor alpha 1, alpha 6 and beta 2,3 subunit protein expression and alpha 1 and alpha 6 subunit steady-state mRNA levels, was examined using Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. 2. GABA exposure for 2 days decreased alpha 1 (35 +/- 10%, mean +/- s.e.mean), beta 2,3 (21 +/- 9%) and alpha 6 (28 +/- 10%) subunit protein expression compared to control levels. The GABA-mediated reduction in alpha 1 subunit expression after 2 days treatment was abolished in the presence of the GABAA receptor antagonist, Ru 5135 (10 microM). 3. GABA exposure for 8 days increased alpha 1 (26 +/- 10%, mean +/- s.e.mean) and beta 2,3 (56 +/- 23%) subunit protein expression over control levels, whereas alpha 6 subunit protein expression remained below control levels (by 38 +/- 10%). However, after 10 days GABA exposure, alpha 6 subunit protein expression was also increased over control levels by 65 +/- 29% (mean +/- s.e.mean). 4. GABA exposure did not change the alpha 1 or alpha 6 subunit steady-state mRNA levels over and 8 day period, nor did it alter the expression of cyclophilin mRNA over 1-8 days. 5. These results suggest that chronic GABA exposure of rat cerebellar granule cells has a bi-phasic effect on GABAA receptor subunit expression that is independent of changes to mRNA levels. Therefore, the regulation of the GABAA receptor expression by chronic agonist treatment appears to involve post-transcriptional and/or post-translational processes.
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PMID:The effect of GABA stimulation on GABAA receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells. 896 48

The alpha6 subunit of the gamma-aminobutyric acid type A receptor (GABA(A)-R) has been implicated in mediating the intoxicating effects of ethanol and the motor ataxic effects of general anesthetics. To test this hypothesis, we used gene targeting in embryonic stem cells to create mice lacking a functional alpha6 gene. Homozygous mice are viable and fertile and have grossly normal cerebellar cytoarchitecture. Northern blot and reverse transcriptase-polymerase chain reaction analyses demonstrated that the targeting event disrupted production of functional alpha6 mRNA. Autoradiography of histological sections of adult brains demonstrated that diazepam-insensitive binding of [3H]Ro15-4513 to the cerebellar granule cell layer of wild-type mice was completely absent in homozygous mice. Cerebellar GABA(A)-R density was unchanged in the mutant mice; however, the apparent affinity for muscimol was markedly reduced. Sleep time response to injection of ethanol after pretreatment with vehicle or Ro15-4513 did not differ between genotypes. Sleep time response to injection of pentobarbital and loss of righting reflex and response to tail clamp stimulus in mice anesthetized with volatile anesthetics also did not differ between genotypes. Thus, the alpha6 subunit of the GABA(A)-R is not required for normal development, viability, and fertility and does not seem to be a critical or unique component of the neuronal pathway mediating the hypnotic effect of ethanol and its antagonism by Ro15-4513 in mice. Similarly, the alpha6 subunit does not seem to be involved in the behavioral responses to general anesthetics or pentobarbital.
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PMID:Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. 910 23

Human alcoholics have reduced neuronal counts in certain brain regions, such as superior frontal cortex (SFC), where the form and quantity of synaptic gamma-aminobutyric acid type A (GABAA) receptor sites are atypical. We measured the expression of GABAA receptor isoform mRNA and protein, since GABAA receptor pharmacology is strongly influenced by its subunit composition. Cortex samples were obtained at autopsy; whole-tissue extracts were assayed for mRNA by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), while synaptic membranes were studied for both GABAA receptor pharmacology and subunit protein levels by Western blots with isoform-specific antibodies. Although alpha 1 and alpha 3 mRNA species were strongly expressed in alcoholics irrespective of cirrhosis than in controls, alpha 1 protein differed little between case groups, and alpha 3 protein showed some complex variations. Differences in GABAA pharmacology conformed more closely with differences in protein levels than with altered mRNA expression.
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PMID:Cell death mediated by amino acid transmitter receptors in human alcoholic brain damage: conflicts in the evidence. 966 64

The gamma-aminobutyric acid (GABA) receptor rho subunits recently cloned from rat and human retina are thought to form GABA receptor channels belonging to a pharmacologically distinct receptor class, termed GABA(C). In this work we have examined the distribution of rho1, rho2 and rho3 subunits, and found expression of all three transcripts in several regions of the rat nervous system. In situ hybridization revealed expression of rho2 in the adult rat retina and some other parts of the visual pathways. A high local rho2 expression was seen in the superficial grey layer of the superior colliculus, and in the dorsal lateral geniculate nucleus. Expression was also detected in the 6th layer of visual cortex and in the CA1 pyramidal cell layer of hippocampus. With reverse transcriptase-polymerase chain reaction, expression of rho1 was mainly seen in the adult rat retina and dorsal root ganglia, as well as, at a significantly lower level, in the superior colliculus, hippocampus, brain stem, thalamus, postnatal day 8 (P8) superior colliculus and P8 hippocampus. Expression pattern of rho3 mRNA was clearly different from that of rho1 and rho2, being strongest in the hippocampus, and significantly lower in the retina, dorsal root ganglia and cortex. No rho3 expression was observed in adult or P8 superior colliculus or in P8 hippocampus. The present results clearly demonstrate that expression of GABA receptor rho subunits is not restricted to the retina, but significant expression can also be detected in many other brain regions, especially in those belonging to the visual pathways. The expression pattern of the rho subunits may be helpful in solving the functional significance of the receptors formed from these subunits.
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PMID:Distribution of GABA receptor rho subunit transcripts in the rat brain. 975 43

The neurons responsible for the onset of sleep are thought to be located in the preoptic area and more specifically, in the ventrolateral preoptic nucleus (VLPO). Here we identify sleep-promoting neurons in vitro and show that they represent an homogeneous population of cells that must be inhibited by systems of arousal during the waking state. We find that two-thirds of the VLPO neurons are multipolar triangular cells that show a low-threshold spike. This proportion matches that of cells active during sleep in the same region. We then show, using single-cell reverse transcriptase followed by polymerase chain reaction, that these neurons probably contain gamma-aminobutyric acid (GABA). We also show that these neurons are inhibited by noradrenaline and acetylcholine, both of which are transmitters of wakefulness. As most of these cells are also inhibited by serotonin but unaffected by histamine, their overall inhibition by transmitters of wakefulness is in agreement with their relative inactivity during waking with respect to sleep. We propose that the reciprocal inhibitory interaction of such VLPO neurons with the noradrenergic, serotoninergic and cholinergic waking systems to which they project is a key factor for promoting sleep.
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PMID:Identification of sleep-promoting neurons in vitro. 1080 Nov 27

To examine the direct effects of neurosteroids on gamma-aminobutyric acid type A (GABA(A)) receptor expression, we exposed developing neuronal cells (P19) in vitro to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP, allopregnanolone). Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed a concentration-dependent decrease in GABA(A) receptor alpha4 subunit mRNA expression that reversed 24 h after steroid withdrawal. These data suggest that variations in neurosteroid levels regulate the pattern of GABA(A) receptor subunit expression and may alter the trophic effects of GABA.
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PMID:3alpha-hydroxy-5alpha-pregnan-20-one exposure reduces GABA(A) receptor alpha4 subunit mRNA levels. 1110 37


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