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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor (LHR) in cultured hypothalamic cells and immortalized GnRH (gonadotropin-releasing hormone) neurons (GT1-7 cells) transiently stimulates and subsequently inhibits cAMP production and pulsatile GnRH release. The marked and delayed impairment of cAMP signaling and episodic GnRH release in GT1-7 cells is prevented by pertussis toxin (PTX). This, and the LH-induced release of membrane-bound Galpha(s) and Galpha(i3) subunits, are indicative of differential G protein coupling to the LHR. Action potential (AP) firing in identified GnRH neurons also initially increased and then progressively decreased during LH treatment. The inhibitory action of LH on AP firing was also prevented by PTX. Reverse transcriptase-PCR analysis of GT1-7 neurons revealed the expression of G protein-gated inwardly rectifying potassium (GIRK) channels in these cells. The LH-induced currents were inhibited by PTX and were identified as GIRK currents. These responses indicate that agonist stimulation of endogenous LHR expressed in GnRH neurons activates GIRK channels, leading to suppression of membrane excitability and inhibition of AP firing. These findings demonstrate that regulation of GIRK channel function is a dominant factor in gonadotropin-induced abolition of pulsatile GnRH release. Furthermore, this mechanism could contribute to the suppression of pituitary function during pregnancy.
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PMID:Essential role of G protein-gated inwardly rectifying potassium channels in gonadotropin-induced regulation of GnRH neuronal firing and pulsatile neurosecretion. 1682 87

The expression of the inner membrane protein NlpA is repressed by the enterotoxigenic Escherichia coli (ETEC) virulence regulator Rns, a member of the AraC/XylS family. The Rns homologs CfaD from ETEC and AggR from enteroaggregative E. coli also repress expression of nlpA. In vitro DNase I and potassium permanganate footprinting revealed that Rns binds to a site overlapping the start codon of nlpA, preventing RNA polymerase from forming an open complex at nlpAp. A second Rns binding site between positions -152 and -195 relative to the nlpA transcription start site is not required for repression. NlpA is not essential for growth of E. coli under laboratory conditions, but it does contribute to the biogenesis of outer membrane vesicles. As outer membrane vesicles have been shown to contain ETEC heat-labile toxin, the repression of nlpA may be an indirect mechanism through which the virulence regulators Rns and CfaD limit the release of toxin.
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PMID:Repression of the inner membrane lipoprotein NlpA by Rns in enterotoxigenic Escherichia coli. 1718 57

Potassium is an essential element for plant, and high-affinity K+ uptake system plays a crucial role in potassium absorption and transportation. Here we report the isolation and characterization of a HKT1 homolog from C3 halophyte Suaeda salsa (L.) (SsHKT1), particularly under low K+ treatment. The SsHKT1 cDNA was 2033 nucleotides long including 1650 bp ORF for a 550 amino acids peptide and a predicted molecular mass of 63.0 kDa. The deduced amino acid sequence of SsHKT1 was 39-64% identical to other plant HKT-like sequences. A SsHKT1-specific antibody was prepared and reacted with a 63.0 kDa protein from S. salsa plasma membrane. Reverse transcriptase-PCR analysis showed that SsHKT1 was mainly expressed in leaf tissues and to a lesser extent, in root tissues. Amounts of SsHKT1 transcript were developmentally controlled and significantly up-regulated by K+ deprivation and NaCl treatment. The results suggested that SsHKT1 might play an important role in ion homeostasis and salt tolerance of S. salsa.
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PMID:Cloning and expression pattern of SsHKT1 encoding a putative cation transporter from halophyte Suaeda salsa. 1785 52

Bacteria must adapt their transcription to overcome the osmotic stress associated with the gastrointestinal tract of their host. This requires the sigma 38 (rpoS) form of RNA polymerase. Here, chromatin immunoprecipitation experiments show that activation is associated with a poise-and-release mechanism in vivo. A C-terminal tail unique among sigma factors is shown to be required for in vivo recruitment of RNA polymerase to the promoter region prior to osmotic shock. C-terminal domain tail-dependent transcription in vivo can be mimicked by using the intracellular signaling molecule potassium glutamate in vitro. Following signaling, the barrier to elongation into the gene body is overcome and RNA polymerase is released to produce osmY mRNA.
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PMID:Poising of Escherichia coli RNA polymerase and its release from the sigma 38 C-terminal tail for osmY transcription. 1820 23

Hair disorders cause psychological distress but are generally poorly controlled; more effective treatments are required. Despite the long-standing use of minoxidil for balding, its mechanism is unclear; suggestions include action on vasculature or follicle cells. Similar drugs also stimulate hair, implicating ATP-sensitive potassium (K(ATP)) channels. To investigate whether K(ATP) channels are present in human follicles, we used organ culture, molecular biological, and immunohistological approaches. Minoxidil and tolbutamide, a K(ATP) channel blocker, opposed each other's effects on the growing phase (anagen) of scalp follicles cultured in media with and without insulin. Reverse transcriptase-polymerase chain reaction identified K(ATP) channel component gene expression including regulatory sulfonylurea receptors (SUR) SUR1 and SUR2B but not SUR2A and pore-forming subunits (Kir) Kir6.1 and Kir6.2. When hair bulb tissues were examined separately, epithelial matrix expressed SUR1 and Kir6.2, whereas both dermal papilla and sheath exhibited SUR2B and Kir6.1. Immunohistochemistry demonstrated similar protein distributions. Thus, human follicles respond biologically to K(ATP) channel regulators in culture and express genes and proteins for two K(ATP) channels, Kir6.2/SUR1 and Kir6.1/SUR2B; minoxidil only stimulates SUR2 channels. These findings indicate that human follicular dermal papillae contain K(ATP) channels that can respond to minoxidil and that tolbutamide may suppress hair growth clinically; novel drugs designed specifically for these channels could treat hair disorders.
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PMID:Human hair follicles contain two forms of ATP-sensitive potassium channels, only one of which is sensitive to minoxidil. 1825 87

Pressor effects of the vasoconstrictor hormone arginine vasopressin (AVP), observed when systemic AVP concentrations are less than 100 pM, are important for the physiological maintenance of blood pressure, and they are also the basis for therapeutic use of vasopressin to restore blood pressure in hypotensive patients. However, the mechanisms by which circulating AVP induces arterial constriction are unclear. We examined the novel hypothesis that KCNQ potassium channels mediate the physiological vasoconstrictor actions of AVP. Reverse transcriptase polymerase chain reaction revealed expression of KCNQ1, KCNQ4, and KCNQ5 in rat mesenteric artery smooth muscle cells (MASMCs). Whole-cell perforated patch recordings of voltage-sensitive K+ (Kv) currents in freshly isolated MASMCs revealed 1,3-dihydro-1-phenyl-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one (linopirdine)- and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991)-sensitive KCNQ currents that were electrophysiologically and pharmacologically distinct from other Kv currents. Suppression of KCNQ currents by AVP (100 pM) was associated with significant membrane depolarization, and it was abolished by the protein kinase C (PKC) inhibitor calphostin C (250 nM). The KCNQ channel blocker linopirdine (10 microM) inhibited KCNQ currents in MASMCs, and it induced constriction of isolated rat mesenteric arteries. The vasoconstrictor responses were not additive when combined with 30 pM AVP, and they were prevented by the L-type Ca2+ channel blocker verapamil. Ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl] carbamic acid (flupirtine) significantly enhanced KCNQ currents, and it reversed constrictor responses to 30 pM AVP. In vivo, i.v. administration of linopirdine induced a dose-dependent increase in mesenteric artery resistance and blood pressure, whereas flupirtine had the opposite effects. We conclude that physiological concentrations of AVP induce mesenteric artery constriction via PKC-dependent suppression of KCNQ currents and L-type Ca2+ channel activation in MASMCs.
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PMID:Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance. 1827 10

Calcium-dependent potassium channels are implicated in electrolyte transport, cell volume regulation and mechanical responses in epithelia, although the pathways for calcium entry and their coupling to the activation of potassium channels are not fully understood. We now show molecular evidence for the presence of TRPV4, a calcium permeable channel sensitive to osmotic and mechanical stress, and its functional coupling to the large conductance calcium-dependent potassium channel (BK(Ca)) in a human bronchial epithelial cell line (HBE). Reverse transcriptase polymerase chain reaction, intracellular calcium imaging and whole-cell patch-clamp experiments using HBE cells demonstrated the presence of TRPV4 messenger and Ca(2+) entry, and outwardly rectifying cationic currents elicited by the TRPV4 specific activator 4alpha-phorbol 12,13-didecanoate (4alphaPDD). Cell-attached and whole-cell patch-clamp of HBE cells exposed to 4alphaPDD, and hypotonic and high-viscosity solutions (related to mechanical stress) revealed the activation of BK(Ca) channels subsequent to extracellular Ca(2+) influx via TRPV4, an effect lost upon antisense-mediated knock-down of TRPV4. Further analysis of BK(Ca) modulation after TRPV4 activation showed that the Ca(2+) signal can be generated away from the BK(Ca) location at the plasma membrane, and it is not mediated by intracellular Ca(2+) release via ryanodine receptors. Finally, we have shown that, unlike the reported disengagement of TRPV4 and BK(Ca) in response to hypotonic solutions, cystic fibrosis bronchial epithelial cells (CFBE) preserve the functional coupling of TRPV4 and BK(Ca) in response to high-viscous solutions.
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PMID:Functional coupling of TRPV4 cationic channel and large conductance, calcium-dependent potassium channel in human bronchial epithelial cell lines. 1845 41

Transcription is often regulated at the level of initiation by the presence of transcription factors or nucleoid proteins or by changing concentrations of metabolites. These can influence the kinetic properties and/or structures of the intermediate RNA polymerase-DNA complexes in the pathway. Time-resolved footprinting techniques combine the high temporal resolution of a stopped-flow apparatus with the specific structural information obtained by the probing agent. Combined with a careful quantitative analysis of the evolution of the signals, this approach allows for the identification and kinetic and structural characterization of the intermediates in the pathway of DNA sequence recognition by a protein, such as a transcription factor or RNA polymerase. The combination of different probing agents is especially powerful in revealing different aspects of the conformational changes taking place at the protein-DNA interface. For example, hydroxyl radical footprinting, owing to their small size, provides a map of the solvent-accessible surface of the DNA backbone at a single nucleotide resolution; modification of the bases using potassium permanganate can reveal the accessibility of the bases when the double helix is distorted or melted; cross-linking experiments report on the formation of specific amino acid-DNA contacts, and DNase I footprinting results in a strong signal-to-noise ratio from DNA protection at the binding site and hypersensitivity at curved or kinked DNA sites. Recent developments in protein footprinting allow for the direct characterization of conformational changes of the proteins in the complex.
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PMID:Time-resolved footprinting for the study of the structural dynamics of DNA-protein interactions. 1863 Nov 51

Escherichia coli responds to stress by a combination of specific and general transcription signalling pathways. The general pathways typically require the master stress regulator sigma38 (rpoS). Here we show that the signalling from multiple stresses that relax DNA is processed by a non-conserved eight-amino-acid tail of the sigma 38 C-terminal domain. By contrast, responses to two stresses that accumulate potassium glutamate do not rely on this short tail, but still require the overall C-terminal domain. In vitro transcription and footprinting studies suggest that multiple stresses can target a poised RNA polymerase and activate it by unwrapping DNA from a nucleosome-like state, allowing the RNA polymerase to escape into productive mode. This transition can be accomplished by either the DNA relaxation or potassium glutamate accumulation that characterizes many stresses.
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PMID:General stress response signalling: unwrapping transcription complexes by DNA relaxation via the sigma38 C-terminal domain. 1876 24

The new non-reversed transcriptase inhibitor (NRTI) drugs for treatment of acquired immunodeficiency syndrome (AIDS) are reported. An improvement in the sensitivity and selectivity of high-performance liquid chromatography was obtained by diamond electrode-electrochemical detector and fluorescence detector owing to different structural information. The four anti-retroviral NRTI drugs (abacavir, didanosine, lamivudine and zidovudine) were separated on a CapcellPak C18 UG120 column (250 mm x 4.6 mm I.D., 5 microm) with an acetonitrile-25 mM potassium dihydrogenphosphate buffer (pH 8.0; 1:9, v/v) as the mobile phase. We applied dual detection (electrochemical detection and florescence detection) for improving the peak identification and also for improved selectivity, which assisted monitoring by trace-volume samples (e.g., plasma). The electrochemical detector, equipped with a diamond electrode, was set at 2000 mV (applied voltage) and the fluorescence detector was set at excitation wavelength 275 nm and emission wavelength 315 nm. The detection limits of the four NRTIs in spiked plasma were 1-100 ng/ml by electrochemical detection and 5-10 pg/ml by fluorescence detection. The calibration graphs were linear up to 20 microg/ml by electrochemical detection and 10 microg/ml by fluorescence detection. This is the first report of LC analysis of NRTIs by electrochemical detection, also combined with fluorescence detection. The detection limits of didanosine, lamivudine and zidovudine were improved 20-fold by electrochemical detection and 500-fold by fluorescence detection compared to previous reports on UV detection. The selectivity was also improved by dual detection. The proposed method was applied to the preliminary monitoring of NRTIs in plasma.
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PMID:Improvement of sensitivity and selectivity of high-performance liquid chromatography for anti-retroviral drugs (non-reverse transcriptase inhibitors) by diamond-electrode electrochemical and fluorescence detection. 1923 77


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